Multiple Myeloma Angela Dispenzieri

Martha Q. Lacy

Phi l ip R. Greipp

Mul t ip le myeloma is a neoplast ic p lasma cel l dyscras ia (PCD) character ized by a c l in ica l

pentad: (a) anemia, (b) a monoc lonal protein in the serum or ur ine or both, (c ) abnormal

bone rad iographs and bone pain, (d) hyperca lcemia, and (e) renal insuff ic iency or fai lure.

W ith the except ion of monoclonal gammopathy of undetermined signi f icance (MGUS), i t is

the most common PCD, wi th an inc idence of about 4 .5 per 100,000 per year in the Uni ted

States. Sol i tary p lasmacytoma and plasma ce l l leukemia (PCL) are recognized as separate

ent i t ies and are much less prevalent . The under ly ing pathogenes is of the p lasma cel l

mal ignanc ies is not wel l unders tood but is an area of act ive invest igat ion. At present ,

according to the W HO (World Heal th Organizat ion) and REAL (Revised European-Amer ican

Lymphoma) c lass i f icat ion systems, there is only one category for mul t ip le myeloma (1).

Resul ts o f c l in ica l t r ia ls are confounded by th is underc lass i f icat ion. Emerg ing in formation

about the genet ic underpinning of the d isease, however, wi l l l ike ly change th is def ic iency.

The in teract ions among the plasma ce l ls, the i r ant ibody product , the local bone and bone

marrow envi ronment , and other organs are complex. There is no cure for mult ip le myeloma,

but there are many ef fect ive t reatments that pro long and improve the qual i ty of l i fe o f

pat ients wi th the d isease.

History

Earliest Diagnoses and Diagnostic Methods Samuel Sol ley repor ted the f i rst wel l -documented case of myeloma in Sarah Newbury in

1844 (mol l i t ies ossium) (2 ,3) . Several years la ter , W i l l iam MacIntyre described and recorded

the proper t ies of the disease we now cal l mul t ip le myeloma in Thomas Alexander McBean

(4) . Both Drs . MacIntyre and Bence Jones noted and described some of the pecul iar ur ine

proper t ies of th is same pat ient . On heat ing, the ur ine was found to “abound in animal

mat ter , ” which d isso lved on the addi t ion of n i t r ic ac id but reappeared af ter cool ing. These

ur inary prote ins became known as Bence Jones proteins (5). MacIntyre and Dal rymple

descr ibed the postmortem examinat ion of Mr. McBean's bones (4) . The former described the

af fec ted bones as sof tened and f ragi le , wi th thei r in ter iors replaced wi th a soft “ge la t in form”

b lood-red substance. Dal rymple suggested that the disease began in the cancel lous bone

and extended through the perios teum. The nucleated ce l ls , which formed the bu lk o f the

ge la t inous mater ia l , were heterogeneous in s ize and shape, but the majori ty were round to

ova l . Many of the larger and more i r regular ce l ls f requent ly contained two or three nuc le i (3) .

The term “mult ip le myeloma” was coined in 1873 by von Rust izky (6) , who independently

descr ibed a s imi lar pat ient to emphasize the mul t ip le bone tumors that were present .

In 1889, Professor Ot to Kahler (7) descr ibed a case involv ing a 46-year-o ld physic ian wi th

mult ip le myeloma and publ ished a major review of the disease. He descr ibed the ske le tal

pa in , albuminuria , pal lor , anemia, a precip i table ur inary prote in, and the f ind ings on

necroscopy and l inked these f ind ings as par t o f a c l in ical syndrome, which bears h is name

(mult ip le myeloma is a lso known as Kahler d isease) .

In 1898, W eber pred ic ted the usefu lness of roentgen x-rays in es tab l ish ing the diagnos is

(3 ,8) and la ter postula ted that the Bence Jones protein was produced in the bone marrow

(9) . W right (10) emphas ized that mult ip le myeloma arose spec i f ica l ly from p lasma cel ls o f

the marrow; Jacobson (11) recognized Bence Jones prote ins in the b loodstream; and

Walters (12) conc luded that the Bence Jones prote in was probably der ived f rom b lood

proteins through the act ion of the abnormal cel ls in the bone marrow. The technique of bone

marrow aspira t ion (13) fac i l i ta ted the d iagnosis o f mul t ip le myeloma.

Bayne-Jones and W ilson (14) ident i f ied two s imi lar but dist inc t groups of Bence Jones

proteins by immunizing rabbi ts wi th Bence Jones proteins der ived f rom pat ients . Prec ip i t in

tes ts on these Bence Jones preparat ions revealed two d is t inct groups: I and I I . Using the

Ouchter lony tes t , Korngold and L ipar i showed that ant isera to Bence Jones protein a lso

reacted wi th myeloma prote ins. The two classes of Bence Jones prote ins have been

designated κand λas a t r ibute to these two men. In 1962, Edelman and Gal ly (15) showed

that the l ight chains prepared f rom an IgG monoc lonal protein and the Bence Jones protein

f rom the same pat ient 's ur ine were ident ica l .

Serum elect rophoresis, descr ibed by Tise l ius in 1937 (16) , made i t poss ib le to separate

serum prote ins . Longsworth et al . (17) appl ied e lect rophoresis to the study of mult ip le

myeloma and descr ibed the ta l l , narrow-based “church sp i re” peak. The use of f i l ter paper

as a support for prote in e lec t rophores is permi t ted the separat ion of protein in to d is t inc t

zones that could be s ta ined wi th var ious dyes (18) . Because th is technique was s imple and

inexpensive, th is test became universal ly avai lable in c l in ical laborator ies. Paper

e lec t rophores is was supplanted by f i l ter paper in 1957 and most recent ly by h igh-resolut ion

e lec t rophores is on agarose ge l . Immunoelect rophoresis (19) and immunofixat ion or d i rec t

immunoelect rophoresis (20) made i t poss ib le to detect smal l monoc lonal l ight chains not

recognizable by elec t rophores is . The immunoglobul in free l ight -chain assay has been added

to the diagnost ic armamentarium to detect c i rcula t ing f ree l ight chains in the majori ty o f

pat ients hencetofor th des ignated nonsecretory (21) .

Kunkel (22) hypothes ized that monoclonal prote ins were the product of mal ignant p lasma

ce l ls and were the equiva lent of normal ant ibodies produced by normal p lasma cel ls . Before

1960, the term “gamma g lobul in” was used for any prote in that migrated in the gamma

mobi l i ty reg ion of the elec t rophoret ic pattern; however, in 1959, Heremans (23) proposed

the concept o f a fami ly of prote ins wi th ant ibody act iv i ty. In 1961, in a Harvey Lecture (24),

Waldenström d is t inguished between monoc lonal and polyc lonal hypergammaglobul inemia.

In 1928, Geschick ter and Copeland (25) repor ted on the largest case series of mul t ip le

myeloma—13 cases—and reviewed the 412 cases repor ted in the l i terature s ince 1848.

They documented a h igher incidence in men than women and an overal l surviva l of about 2

years . They emphas ized s ix features: (a) invo lvement o f the skele ta l t runk, (b) patho log ic

r ib f ractures, (c ) Bence Jones proteinur ia in 65% of cases, (d) backache wi th early

parapleg ia , (e) anemia in 77% of cases, and (f ) chronic renal disease. They d id not note

abnormal i t ies o f blood prote in or an increased erythrocyte

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sedimentat ion ra te (3) . In 1931, Magnus-Levy (26) descr ibed amylo idos is as a compl icat ion

of mul t ip le myeloma. Salmon, Durie , and Smi th developed methods to quant i ta te the to tal

body burden of tumor ce l ls (27) and to s tage pat ients (28) in 1970 and 1975, respect ively.

Earliest Treatments for Multiple Myeloma

In 1947 Snapper (29) repor ted that s t i lbamidine a long wi th a low-animal -protein d ie t

re l ieved myeloma pain in 14 of 15 pat ients . Subsequent s tud ies d id not conf i rm th is benef i t .

Urethane was bel ieved to be ef fect ive unt i l 1966 (30) . I t was f i rs t used in the treatment o f

mult ip le myeloma by Alwal l in 1947 (31,32) and then by Loge and Rundles in 1949 (31,32) .

Thei r ear ly observat ions were encouraging, and the use of urethane became widespread.

Toxic e f fects inc luded severe anorexia , nausea, and vomi t ing. Leukopenia,

thrombocytopenia, and hepat ic damage a lso occurred (33) . In 1966, however, Hol land et al .

(30) publ ished the resu l ts o f a randomized control led t r ia l o f urethane versus placebo in 83

pat ients wi th symptomatic mul t ip le myeloma. They found that there was no d i f ference in any

ob ject ive measurement of improvement between the two groups and that the median overa l l

surviva l was higher in the p lacebo group. Previous ly unt reated pat ients had a median

surviva l o f 12 or 5 months, depending on whether they received p lacebo or urethane,

respect ive ly.

In 1950, Thorn et a l . (34) repor ted the f i rst observat ions on the salu tary ef fects o f

adrenocor t icot rop ic hormones on myeloma (F ig . 99.1) . Dur ing that decade, i t was

recognized that the adrenocor t icot ropic hormones cor t isone and prednisone were usefu l

agents in pat ients wi th mul t ip le myeloma. Cort icostero ids decreased bone pain, improved

hyperca lcemia, increased hemoglobin va lues, and decreased abnormal serum and ur ine

g lobul in concentrat ions (33) . However, i t was not unt i l 1967 that h igh-dose cort icostero ids

were recognized as ef fec t ive ant ineoplast ic agents against mult ip le myeloma (35) .

Blokh in et a l . (36) reported benef i ts in three of s ix pat ients wi th mul t ip le myeloma who were

t reated wi th sarcolys in (a racemic mixture of the d - and l - isomers of phenyla lan ine mustard).

Subsequently, the d - and l - i somers were tes ted separate ly, and the ant imyeloma act iv i ty

was found to res ide in the l - isomer, melphalan. Bergsagel e t al . (37) repor ted s ign i f icant

improvement in 14 of 24 pat ients wi th mul t ip le myeloma wi th the use of melphalan; this

ac t iv i ty was qu ickly substant ia ted by others (38) . Simi lar e f fect iveness was noted wi th

cyc lophosphamide (39). Subsequently, in terferon-α , doxorubic in , carmust ine, thal idomide,

bor tezomib, and lenal idomide (40,41,42,43,44,45) have each been repor ted to have act iv i ty

as a s ing le agent in myeloma (F ig . 99.1) .

Figure 99.1. Landmark therapeutic innovations (34,37,39,41,43,233,237,245,274,319,391,432,439,466,481,710,1002,1110). ASCT, autologous stem cell transplant; CCT, conventional chemotherapy; VAD, vincristine, doxorubicin, dexamethasone; VBMCP, vincristine, BCNU, melphalan, cyclophosphamide, and prednisone (M-2 regimen).

Incidence and Epidemiology

Epidemiology of Myeloma Approximate ly 16,570 new cases of mul t ip le myeloma are d iagnosed each year in the Uni ted

States, and 11,310 deaths are recorded (46) . SEER (Surve i l lance, Epidemiology and End

Resul ts) incidence data, age-adjusted ra tes f rom 1992 through 1998, show an overa l l

incidence of 4.5 per 100,000 per year , wi th the inc idence among whi tes be ing 4.2 per

100,000 per year and among b lacks, 9 .3 per 100,000 per year (47) . Male- to- female ra t io is

1 .3 to 1 (46) . The median age at diagnos is of myeloma is 71 years . Mortal i ty rates are

cons is tent ly h igher among men than women and among blacks than whi tes in each age

group (47) . Myeloma accounts for 1% of al l mal ignanc ies and 10% of al l hemato logic

mal ignanc ies in whi tes and 20% in Afr ican Amer icans (47) . In ternat ional morta l i ty data

reveal that the h ighest ra tes of myeloma occur in Northern Europe, North Amer ica, Austral ia ,

and New Zealand, and the lowest ra tes are in Japan, Yugos lavia , and Greece (48) .

Geographic c lus ters (49) and fami l ia l c lus ters (50,51,52,53,54,55) o f myeloma among f i rs t-

degree re lat ives have been documented. Modest increases in mult ip le myeloma rates were

observed when inc idence data from 1973 to 1992 were ca lcu la ted in nine populat ion-based

cancer regist r ies , wi th fur ther projec ted increases by 2007 (56) . Th is increase is l ike ly a

resul t o f he ightened awareness of the d isease.

Etiologic Factors

Radiation Exposures

Atomic Bomb Exposure

Reports o f increased myeloma inc idence and morta l i ty among Japanese atomic bomb

survivors have suggested an assoc ia t ion between ion iz ing rad ia t ion and mult ip le myeloma.

Evaluat ions of cancer inc idence (57) and morta l i ty (58) among Japanese atomic bomb

survivors have demonstrated an increased r isk o f mul t ip le myeloma wi th increasing

rad ia t ion dose. However, wi th an addi t ional 12 years of fo l low-up f rom previous repor ts , the

f indings of an increased myeloma r isk assoc ia ted wi th a tomic bomb i r rad ia t ion were not

maintained (59) .

Radiation-Related Occupation An excess of myeloma deaths among U.S. rad io log is ts was repor ted in the 1960s (60) .

Myeloma r isk was considered to be two t imes h igher among radio logis ts exposed to low

doses of radia t ion than among phys ic ians not exposed to rad iat ion (61) . However, among

27,000 Chinese diagnost ic radiography workers, no excess inc idence of myeloma was

observed in a 30-year per iod (62). An analysis o f 115,000 workers f rom the combined roster

o f four d i f ferent nuclear p lants showed a pos i t ive assoc ia t ion between mul t ip le myeloma

and radia t ion exposure in o lder age groups (63) . No increases in mul t ip le myeloma

incidence and mortal i ty have been observed among Bri t ish (64) or New Zealand (65) mi l i tary

men who part ic ipated in a tmospheric nuc lear weapons tes t ing.

Diagnostic and Therapeutic X-rays Diagnost ic x- ray exposure has not been l inked wi th the development o f mul t ip le myeloma in

most ep idemiologic studies (66,67,68,69,70,71) . A large mul t icenter, populat ion-based

case-contro l study showed no evidence of excess r isk o f myeloma among indiv iduals who

reported exposure of 10 or more d iagnost ic rad iographs (72). One s tudy repor ted that the

overa l l r isk for mul t ip le myeloma was not high (RR, 1 .14) , but that there was evidence of

increas ing r isk wi th exposure to increasing numbers of rad iographic procedures (73).

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Of h is tor ic interest is the f ind ing of an associa t ion between myeloma and the use of

Thorot ras t (67) . Stud ies of the ef fec ts of therapeut ic i r radia t ion on myeloma r isk have

shown conf l ic t ing resu l ts, but a s tudy of 180,000 women t reated for cervica l cancer

demonstrated no overal l excess r isk o f develop ing myeloma (74) . Simi lar ly, a study of

14,000 pat ients suf fer ing f rom ankylos ing spondyl i t is and t reated wi th rad ia t ion revealed no

s ign i f icant increase in the r isk o f developing myeloma (75) .

Workplace Exposures

Agricultural Occupations and Exposures Severa l epidemio log ic s tud ies have evaluated the r isk o f myeloma among agricul tura l

workers , wi th pos i t ive assoc iat ions repor ted by many (76,77,78,79,80,81) but not a l l of the

s tud ies (82,83,84) . Khuder and Mutg i (85) found a rela t ive r isk o f 1 .23 in a meta-analys is o f

several s tud ies .

Metal Industries Workers in var ious metal occupat ions and industr ies have been repor ted to have an

increased myeloma r isk (86,87,88) .

Benzene

Benzene has been suggested as a poss ib le e t io log ic agent for mult ip le myeloma (89,90,91) .

A comprehensive review of publ ished l i terature found no evidence of a l ink between

benzene exposure and myeloma (92) . Subsequently, Sonoda and co l leagues (93) conducted

a meta-analys is o f case-contro l studies and showed no excess r isk for the development of

mult ip le myeloma. A meta-analysis by W ong and Raabe (94) o f more than 350,000

petroleum workers s imi lar ly showed no increased r isk .

Lifestyle Factors

Cigarette Smoking and Alcohol Consumption Mul t ip le s tud ies to date have found no et io logic ro le for c igaret te smoking or alcohol

consumption in the development o f mul t ip le myeloma (95,96,97,98).

Dietary Links Tavani e t a l . (99) suggested a die tary l ink for mult ip le myeloma and found a higher r isk

among people consuming large quant i t ies o f l iver (odds ra t io [OR], 2 .0) and but ter (OR, 2 .8) ,

and a lower r isk among people consuming large amounts of vegetables (OR, 0.4) . Cof fee

and a lcohol had no assoc iat ion wi th mul t ip le myeloma. No associa t ion of mult ip le myeloma

and consumpt ion of red meat has been found (99) . Brown and co l leagues (100) looked at

d ie t and nutr i t ion as r isk factors for mult ip le myeloma among blacks and whi tes in the

Uni ted States. Elevated r isks were assoc ia ted wi th obes i ty in comparison to people of

normal weight . Obes i ty was more f requent in b lack than in whi te contro ls. Reduced r isks

were associated wi th the f requent in take of c ruc i ferous vegetables, f ish, and vi tamin C

supplements . The authors conc luded that the greater use of v i tamin C supplements by

whi tes and the higher f requency of obesi ty among b lacks may expla in par t o f the higher

incidence of mult ip le myeloma among b lacks compared wi th whi tes in the United States.

Socioeconomic Status Some invest igators have repor ted that there is an inverse re la t ionship between the r isk o f

mult ip le myeloma and soc ioeconomic s tatus (101) and that th is inverse corre lat ion may

account for a substant ia l amount o f the black and whi te di f ferent ial of mul t ip le myeloma

incidence (102). Earl ier s tud ies d id not show a l ink between soc ioeconomic s tatus and

myeloma (103) .

Hair Dyes Personal use of ha ir dyes was evaluated as a r isk fac tor for myeloma (104) , including two

prospect ive s tudies (105,106). Thun et a l . (105) found that women us ing permanent ha i r

dyes are not general ly at increased r isk of fata l cancer . W omen wi th pro longed use of dark ,

par t icular ly b lack, hai r dyes may have increased r isk of fata l non-Hodgkin lymphoma and

mult ip le myeloma, but these women are a smal l f rac t ion of hai r -dye users. A subsequent

meta-analysis by Correa et al . (107) showed no increased r isk .

Precursor Medical Conditions

Monoclonal Gammopathy of Undetermined Significance MGUS is cons idered a potent ial precursor condit ion for mult ip le myeloma. In a long-term

s tudy of prognos is in MGUS, Kyle and col leagues (108) ident i f ied 1,384 pat ients in

southeastern Minnesota in whom MGUS was d iagnosed. Dur ing 11,009 person-years of

fo l low-up, 115 of the 1,384 MGUS pat ients progressed to mul t ip le myeloma, IgM lymphoma,

pr imary amyloidos is , macroglobul inemia, chronic lymphocyt ic leukemia, or p lasmacytoma.

The r isk o f progress ion of MGUS to mult ip le myeloma-re la ted disorders is thus ~1% per

year (109) . Among a group of 1 ,231 pat ients in I ta ly wi th MGUS and smolder ing mul t ip le

myeloma, cumulat ive t ransformat ion probabi l i t ies a t 10 and 15 years were 14 and 30%,

respect ive ly (110) . A h igher ra te of MGUS in Afr ican Amer icans accounts for par t o f the

increased incidence of myeloma in th is populat ion (111) .

Chronic Antigenic Stimulation Repeated or chronic ant igenic s t imulat ion of the immune system may lead to myeloma.

Severa l case-contro l led s tud ies have suggested that myeloma r isk is assoc iated wi th a past

h istory of in fec t ions, in f lammatory condi t ions, connect ive t issue d isorders, auto immune

i l lnesses, and al lergy-rela ted d isorders (96,112,113) . Increased r isks of myeloma have been

observed in pat ients wi th rheumato id ar thr i t is (54,114,115) . Other s tud ies of ind iv iduals wi th

these condit ions have shown no increased r isk o f mul t ip le myeloma (116,117,118,119) .

Viral Infections Pat ients wi th the human immunodef ic iency v i rus may have an increased l ike l ihood of

develop ing myeloma (120,121) . In addi t ion, myeloma and hepat i t is C may be assoc iated

(122,123,124) . The f inding of human herpes vi rus 8 has been suggested as a poss ible

e t io log ic agent (125) , but this has not been conf i rmed (126,127,128,129) .

Clinical Manifestations The symptoms of mul t ip le myeloma may be nonspeci f ic and inc lude fat igue, bone pain, easy

bru isabi l i ty and b leeding, recurrent in fect ions, mani festat ions of anemia, hyperca lcemia,

ly t ic bone les ions, hyperviscosi ty, thrombocytopenia, and hypogammaglobul inemia (F ig .

99.2). W eakness, infec t ion, b leeding, and weight loss are repor ted in as many as 82, 13, 13,

and 24% of pat ients , respect ive ly (130,131,132,133). Hyperca lcemia is present in 18 to 30%

of pat ients (130,131,132) . One th i rd to two thi rds of pat ients present wi th spontaneous bone

pain (130,131,132) . “Tumor fever” is present in <1% of present ing pat ients .

Anemia The most common c l in ica l feature of mul t ip le myeloma is anemia. A hemoglob in

concentrat ion of <120 g/L occurs in 40 to 73% of pat ients a t presentat ion (130,131,132) and

contr ibutes to the weakness and fa t igue observed in as many as 82% of pat ients

(130,131,132) . The anemia is normochromic , normocyt ic in most pat ients, but macrocytosis

may be observed as wel l . W hen there are high concentrat ions of serum immunoglobul in ,

rou leau format ion may be observed (Fig . 99.3) . The combinat ion of anemia and

hyperproteinemia leads to a marked increase of the erythrocyte sedimentat ion rate in >90%

of cases (134) .

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Figure 99.2. Signs and symptoms of 1,027 newly diagnosed myeloma patients seen at the Mayo Clinic from 1985 trhrough 1998.

The anemia is re lated par t ia l ly to d irect in f i l t ra t ion and rep lacement o f the bone marrow.

Hemoglobin concentrat ion is also correla ted d i rect ly wi th the percentage of myeloma ce l ls in

S phase (135) , suggest ing that the bone marrow cytok ine mi l ieu, permissive for myeloma

ce l l pro l i ferat ion, is not conduc ive to ef f ic ient erythropoies is . Cytok ines, l ike tumor necrosis

fac tor-α (TNF-α ) and in ter leukin-1 ( IL-1) , may inh ibi t erythropoiesis (136) . Fas l igand-

mediated erythroid apoptos is is a lso increased in pat ients wi th myeloma (137) . F ina l ly,

re lat ive erythropoiet in def ic iency from myeloma-induced renal insuf f ic iency a lso contr ibutes

to the observed anemia.

Monoclonal Proteins The M prote in (M component, myeloma prote in , or M sp ike) is a hal lmark of the disease;

97% of myeloma pat ients have ei ther an in tac t immunoglobul in or a f ree l ight chain that can

be detected by prote in elec t rophores is (Fig . 99.4), immunoelect rophores is, or

immunof ixat ion s tud ies of the serum or ur ine (130,132). Those cases wi thout a detectab le

monoclonal prote in have been referred to as nonsecretory myeloma, which had accounted

for ~1 to 3% of myeloma cases. W ith the immunoglobul in f ree l ight-chain assay, smal l

quant i t ies of f ree l ight -chain monoc lonal prote ins , previously not seen by o lder methods, are

detected in approximately two th i rds of the cases we had referred to as nonsecretory(21) .

His tor ica l ly, monoclonal proteins have had a va luable role in the f ie lds of immunology and

molecular bio logy, for d is t inguish ing MGUS f rom myeloma and for ca lculat ing myeloma

tumor burden and k inet ics (27,108,138). Pract ica l ly, both serum and urine M-prote in

concentrat ions are used to stage myeloma pat ients and to document the i r response to

t reatment .

Figure 99.3. Rouleaux.

Figure 99.4. A: Serum protein electrophoresis. B: Immunofixation pattern.

An M prote in represents overproduct ion of a homogeneous immunoglobul in or

immunoglobul in f ragment . In a series of 1 ,027 newly d iagnosed cases of myeloma, the

immunoglobul in type was IgG, IgA, IgD, and free l ight chain only (Bence Jones myeloma) in

52, 20, 2 , and 16% of cases, respect ive ly (132) . Fewer than 1% of myelomas are IgM; most

IgM monoc lonal proteins are assoc ia ted wi th diagnoses of MGUS, lymphoma, W aldenström

macroglobul inemia, or pr imary systemic amylo idos is (139) . Ninety- three percent o f pat ients

have a monoc lonal protein detected in thei r serum. About 90% of myeloma pat ients have

reduct ions in at least one of thei r un invo lved immunoglobul ins (139) . About 70% have a

monoclonal prote in—or fragment thereof—detected in the ur ine.

Bone Disease Approximate ly one th ird to two thi rds of pat ients present wi th bone pain (130,131,132,133).

There is an uncoupl ing of the t ight ly regulated balance between osteoclast ic and

osteoblast ic ac t iv i ty seen under normal c i rcumstances. Even before the development o f

bone lesions, enhanced osteoblast ic recru i tment wi th an increased generat ion of new

osteoc lasts is observed in early mul t ip le myeloma (140) . Regard less of the in i t iat ing s ignal ,

whether IL-1β , IL-6, and s IL-6R, TNF-α , MIP-1α , receptor ac t ivator o f NF-κB (RANK) l igand,

or parathyro id hormone–re lated prote in (PTHrP) (141) , the eventual outcome is bone

destruc t ion (142) .

Myeloma bone d isease is a major source of morbid i ty and may present as an area of

persistent pa in or as a vague migratory bone pain, o f ten in the lower back and pelv is . The

type, locat ion, and durat ion of the pa in has no character is t ic features. At t imes, pain and

tenderness may be sudden in onset , espec ial ly when assoc ia ted wi th a patho logic f rac ture,

and is most commonly prec ip i ta ted by movement . Persistent loca l ized pa in a lso may be

associated wi th a patho log ic f racture.

A myelomatous les ion may extend through the cor tex of a ver tebra l body and cause ei ther

nerve root or sp inal cord compress ion in <2% of pat ients (131) . Al ternat ive ly, the myeloma

can d is turb the mechanica l integri ty of a vertebra l body, resu l t ing in

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compress ion f rac ture wi th re t ropuls ion of ei ther plasmacytoma or bony f ragments in to the

sp inal canal , again causing neuro log ic def ic i ts .

Figure 99.5. Myeloma bone disease. A: Skull. B: Compression fracture. C: Myelomatous marrow involvmement by MRI. D: FDG-PET/CT, spine and rib involvement.

Approximate ly 75% of pat ients have punched-out ly t ic les ions, os teoporos is , or f rac tures on

convent ional rad iography. The ver tebrae, skul l , r ibs, sternum, proximal humeri , and femora

are invo lved most f requent ly (130,132,133) (Fig. 99.5). A smal l subset o f pat ients have de

novo os teosc lerot ic lesions (143) , and osteoscleros is is seen in a few pat ients a fter therapy

and may serve as a marker o f heal ing.

Because myelomatous bone les ions are character is t ica l ly ly t ic , convent ional radiography is

super ior to technet ium-99m bone scanning (144,145) . About twice as many myelomatous

bone lesions are detected by rad iographs as by bone scans; an except ion to this genera l

f inding is at the lumbar sp ine and the r ib cage, where the two methods are equal ly rel iab le

(145). There have been repor ts support ing the use of technet ium-99m sestamib i scans.

These scans are almost as sensi t ive as p la in rad iographs for bone d isease in unt reated

pat ients wi th act ive d isease (146) . They may be ab le to d is t inguish act ive myelomatous

bone lesions f rom inact ive les ions (146) and are qui te sens i t ive for bone marrow

invo lvement (147,148,149) . There is a h igh concordance between sc in t igraphic f ind ings and

c l in ical sta tus in pat ients undergoing chemotherapy or autologous s tem cel l t ransplantat ion

(150,151) . Fluorodeoxyglucose posi t ron emiss ion tomography (FDG-PET) a lso shows

promise in the s tag ing of myeloma, wi th sensi t iv i ty and spec i f ic i ty ra tes of 84 to 92% and 83

to 100%, respect ive ly (152) .

Computed tomography (CT) and magnetic resonance imaging (MRI) are more sens i t ive than

convent ional rad iography. Both reveal spec i f ic les ions in 40% of stage I myeloma pat ients

(153). The presence of lacunae >5 mm wi th trabecular d is rupt ion on CT appears to be

sens i t ive and speci f ic for myeloma. This in format ion may be usefu l in d is t inguishing

between seni le and myelomatous osteoporos is and compression f rac tures (154). Among

asymptomatic mul t ip le myeloma pat ients wi th normal radiographs, 50% have tumor-rela ted

abnormal i t ies on MRI of the lower sp ine (155).

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In pat ients wi th Dur ie Salmon s tage I myeloma, MRI can dist inguish pat ients at higher and

lower r isks of progress ion (156) . One th i rd of pat ients wi th an apparent ly so l i tary

p lasmacytoma of bone have evidence of other plasma cel l tumors on MRI (157) .

MRI is super ior to rad iographs for the detect ion of les ions in the pe lv is and the sp ine, but

overa l l i t is in fer ior to rad iographs for detect ing bone invo lvement in mul t ip le myeloma (79

vs . 87%, respect ively) (158) . On MRI, ver tebral f rac tures due to sp inal in f i l t ra t ion or

os teoporos is are seen in 48% of pat ients wi th symptomat ic myeloma, and spinal canal

narrowing wi th impingement occurs in 20% (155) . Nanni et al . (159) compared MRI to FDG-

PET/CT in 28 newly d iagnosed myeloma pat ients . In 25% of the pat ients , FDG-PET/CT

detected more lyt ic bone les ions, al l o f which were out o f the f ie ld of v iew of MRI; and in

25% of the pat ients, MRI detected an in f i l t ra t ive pat tern in the sp ine that was not d iscerned

on FDG-PET/CT.

MRI has been said to have predict ive value in pat ients newly d iagnosed wi th myeloma and

in pat ients who have received chemotherapy (160,161) . Three pat terns are descr ibed: focal

lesions, d i f fuse involvement , and an inhomogeneous pat tern of t iny les ions against a

background of normal marrow (var iegated) (161,162) . Not surpr is ingly, there are

corre lat ions among MRI pat terns of marrow involvement , bone marrow p lasmacytosis

(161,163,164) , and the c l in ica l s tage (162,164) . Af ter t reatment , resolu t ion of marrow

abnormal i ty or pers is tent abnormal i ty wi thout enhancement corresponds to a complete

response (160) . In one analysis, the best independent prognost icators o f surviva l were the

MRI f ind ings and C-react ive prote in leve ls . Even though pat ients wi th the d i f fuse pat tern

had more bone marrow plasmacytos is , h igher serum calc ium va lues, higher β2 -microglobul in

(β2 -M) va lues, and lower hemoglobin concentrat ion, these fac tors were not s ign i f icant on

mult ivar ia te analysis (165) . However, given the expense of MRI, i t cannot be recommended

for rout ine c l in ica l use in a l l pat ients .

Hypercalcemia

Hypercalcemia occurs in 18 to 30% of pat ients. About 13% have concentrat ions >11 mg/dl .

Rates of hypercalcemia at presentat ion have been decreasing in the last few decades,

perhaps because of the ear l ier d iagnosis o f pat ients (130,131,132,133) . Hypercalcemic

pat ients may compla in o f fa t igue, const ipat ion, nausea, or confusion. Calc ium can

precipi ta te in the k idneys and aggravate renal insuf f ic iency. Inorganic phosphate is rarely

decreased, except in cases of acqui red Fanconi syndrome (166).

Renal Insufficiency Approximate ly 25% of myeloma pat ients have a serum creat inine va lue >2 mg/dL a t

d iagnos is . Another 25% have mi ld ly elevated creat inine va lues

(130,131,132,133,167,168,169,170) . Pat ients wi th Bence Jones or IgD myeloma have the

h ighest rates of renal insuf f ic iency (168,170) . Free l ight-chain proteinur ia is a r isk fac tor for

renal fa i lure (171) . Contr ibut ing fac tors to the renal insuf f ic iency associa ted wi th myeloma

k idneys inc lude hypercalcemia, dehydrat ion, hyperur icemia, and the use of nephrotoxic

drugs (172). I f the renal insuf f ic iency reverses wi th therapy, as i t does in more than ha l f of

cases (172,173), survival is four fo ld to sevenfold h igher than in those in whom i t does not

reverse (167,174). Factors predic t ing for renal funct ion recovery include a serum creat inine

of <4 mg/dl , serum calc ium value >11.5 mg/d l , prote inuria <1 g per 24 hours , and adequate

rehydrat ion (167) . For those pat ients wi th mult ip le myeloma and severe renal fai lure who

survive the f i rs t 2 months on dia lys is , 40% have an ob ject ive response to chemotherapy and

a median survival of almost 2 years (175) .

The patho logic les ion of myeloma kidney consists o f monoclonal l ight chains in the tubules

in the form of dense, o f ten laminated, tubular casts. These casts conta in a lbumin and

Tamm-Horsfa l l prote in . Light chains are normal ly f i l tered by the g lomeru l i and reabsorbed

and catabol ized in the nephron 's proximal tubules. I t is postu la ted that these systems

become overwhelmed, and casts resu l t . When other causes contr ibut ing to renal

insuf f ic iency are exc luded, there is a good corre lat ion between the extent o f myeloma cast

format ion and the sever i ty o f renal insuf f ic iency (176,177) . Tubular a t rophy and

degenerat ion corre la te wel l wi th renal dysfunct ion (178) . The most common f ind ings on

autopsy include tubular a t rophy and f ibrosis (77%), tubular hya l ine casts (62%), tubular

ep i thel ia l g iant ce l l react ion (48%), and nephrocalc inos is (42%). Evidence of acute and

chronic pyelonephr i t is were observed in 20 and 23% of cases, respect ive ly. Plasma ce l l

in f i l t ra tes and amylo id may be observed in 10 and 5% of cases, respect ive ly (133) . Rarely,

myeloma may be assoc iated wi th the acqui red Fanconi syndrome (166,179) .

An important feature of myeloma kidney is that i t is pr imari ly a tubular ra ther than a

g lomeru lar disease (178). Glomerular funct ion is preserved ini t ia l ly , and there is a

predominance of immunoglobul in l ight -chain protein in the ur ine ins tead of the nonspeci f ic

protein loss observed in g lomeru lar disease. Th is feature helps predic t the renal les ion:

nonspec i f ic protein loss ( i .e . , most ly albumin) is more compatib le wi th pr imary systemic

amyloidos is , l ight -chain depos i t ion disease of the k idney, or prote inuria unrela ted to the

p lasma ce l l dyscrasia (176) ; a f ree l ight -chain predominance is cons is tent wi th myeloma

k idney.

Infection Pat ients wi th mult ip le myeloma are at h igh r isk for bacter ial in fec t ions and for dying of

overwhelming bacteremia. Overa l l , the inc idence of bacter ia l sepsis var ies between 0.8 and

1.4 in fec t ions per pat ient-year (180,181,182) . During the f i rs t 2 months after in i t ia t ing

chemotherapy the in fec t ion incidence is as h igh as 4.68 in fect ions per pat ient -year (182)

but decreases to 0.44 to 0 .49 per pat ient -year in those reaching a pla teau phase (181,182) .

Risk fac tors for in fect ion are serum creat in ine values ≥2 mg/d l (180,182) and decreased

leve ls of po lyclonal serum immunoglobul ins (181,182) .

Since the 1960s, Gram-negative baci l l i have become more common pathogens than

Streptococcus pneumoniae in pat ients wi th myeloma (183) . At d isease onset , infec t ions wi th

encapsulated organisms such as Streptococcus pneumoniae and Haemophi lus in f luenzae

are most common (183) . Af ter d iagnosis , the propor t ion of in fec t ions due to Gram-negative

baci l l i and Staphy lococcus aureus increases markedly, and are respons ible for >90% of

deaths f rom in fec t ion (183) . The mechanism of the immunodefic iency observed in these

pat ients is not unders tood complete ly.

Hemostasis in Myeloma Mul t ip le myeloma can be assoc ia ted wi th hemostat ic abnormal i t ies , more of ten bleeding

than thrombosis . Bleeding as a compl icat ion of myeloma may be present in as many as one

th i rd o f pat ients (184) and is rela ted to thrombocytopenia, uremia, hyperviscosi ty, and

in ter ference wi th the funct ion of coagulat ion fac tors .

Rare ly, myeloma proteins may a lso interact wi th coagulat ion prote ins. The immunoglobul in

may in terfere wi th f ibr in monomer aggregat ion (184,185) or serve as a spec i f ic inh ib i tor o f

thrombin (186), von W il lebrand factor , and fac tor VI I I (184) . Heparin l ike ant icoagulants have

been observed (187). Nonspeci f ic inhibi tors may a lso be present, but un l ike the speci f ic

inhib i tors , they do not corre late wi th c l in ica l ly observed bleeding tendenc ies (184) .

Depression of c lo t t ing fac tors I I , V, VI I , VI I I , X, and f ibr inogen has been descr ibed (184) .

The assoc ia t ion wi th thrombosis is less c lear because of coexis t ing fac tors such as o ld age

and immobi l i ty , which confound the interpretat ion of avai lab le data; however, the r isk o f

thrombosis may be increased in myeloma pat ients (184,188). Ind iv idual cases of aberrance

have been repor ted. Monoc lonal prote ins have been shown to be responsib le for the

development o f lupus ant icoagulants

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(189,190) , acqui red prote in S def ic iency (191,192) , acqui red act ivated prote in C resis tance

(193), and inhibi t ion of t issue p lasminogen act ivator (194).

Fewer than 7% of myeloma pat ients have a v iscos i ty >4 (130,132) . Symptoms of

hyperviscos i ty inc lude b leeding, par t icular ly f rom the oronasal areas, purpura, decrease in

v isual acui ty, re t inopathy, neuro log ic symptoms, dyspnea, expanded plasma volume, and

congest ive hear t fa i lure. Most pat ients become symptomat ic when the serum viscos i ty is 6

or 7 cent ipo ise (normal is ≤1.8 cent ipo ise) .

“Acute Terminal Phase of Plasma Cell Myeloma” and C ause

of Death Bergsagel and Pruzansk i (195) descr ibed the “acute terminal phase” o f pat ients wi th

myeloma, which they observed in about one th i rd o f thei r preterminal pat ients . They def ined

the syndrome as rap id ly progress ive d isease wi th an unexpla ined fever and pancytopenia

and a hyperce l lu lar marrow. Ext ramedul lary plasmacytomas are a lso not uncommon

preterminal ly (196). As the disease progresses, and at autopsy, cutaneous, v isceral , and

even meningeal invo lvement is poss ib le (196) . Bes ides “progress ive d isease,” the most

f requent causes of death are in fect ion in 24 to 52% and renal fai lure in ~20%

(133,172,195,196). Acute leukemia, myelodysplast ic syndromes, and hemorrhage are the

causes of death in a minor i ty of pat ients (133,195,196) . In one autopsy ser ies , 85% of

pat ients had evidence of e i ther bacter ial or fungal infec t ion, and myelomatous invo lvement

was found in the spleen, l iver , lymph nodes, and k idneys in 45, 28, 27, and 10% of pat ients ,

respect ive ly. Other, less f requent areas of myelomatous invo lvement were the lung, pleura,

adrenal g lands, pancreas, and tes t is (133).

Histopathology The bone marrow microenvi ronment is hospi table to mal ignant plasma ce l ls that c i rcula te

through the b lood. There is a complex in teract ion among the mal ignant c lone, i ts

surrounding s t romal ce l ls , and the remain ing immune ce l ls. The morpholog ic and

immunolog ic phenotypes of myeloma ce l ls can vary, and they of ten resemble normal plasma

ce l ls. P lasma cel ls are at least two to three t imes the s ize of peripheral lymphocytes and

are round to oval , wi th one or more eccentr ical ly p laced nuc le i (F ig . 99.6). The nuc leus,

which conta ins e i ther d i f fuse or c lumped chromatin , is d isplaced f rom the center by an

abundance of rough-surfaced endoplasmic ret icu lum—the s i te of spec ia l ized

immunoglobul in synthesis . In t ranuc lear and cytoplasmic inc lus ions are not uncommon (197).

There is a perinuclear c lear zone that is the s i te o f the Golg i apparatus, the machinery used

for immunoglobul in packaging and g lycosyla t ion for secret ion. Derangements of

immunoglobul in secret ion are responsible for an assor tment of cyto log ic aberrat ions,

includ ing f laming ce l ls, Mot t ce l ls , Russel l bodies, and Gaucher- l ike cel ls. F laming cel ls are

p lasma ce l ls that have intensely eosinophi l ic cytoplasm wi th a magenta or carmine color ing

of the i r marg ins, which is due to plugging of per iphera l secretory channels by precipi tated

immunoglobul in or immunoglobul in f ragments. These ce l ls are most commonly seen in IgA

myeloma. Thesaurocytes are large f laming cel ls wi th a pyknot ic nuc leus that is pushed to

the s ide. Mot t cel ls (grape ce l ls or morula forms) are plasma ce l ls f i l led wi th dense

spher ical immunoglobul in inc lusions; these inclus ions are co lor less, pink, or b lue. Other

inclus ions are Russel l bodies and the i r in tranuclear counterparts ( int ranuc lear dense

bodies) ; these appear cherry red and can be as large as severa l micrometers in d iameter.

Gaucher- l ike ce l ls are not uncommon in myeloma inf i l t ra tes; these ce l ls are macrophages

laden wi th sphingol ip ids re leased by the dying plasma cel ls (198) . None of these in terest ing

inclus ions are spec i f ic for mal ignancy, nor do they have prognost ic va lue.

Figure 99.6. Bone marrow. Myeloma cells on aspirate specimen.

In myeloma, there is o f ten d iscordance between the nucleus and cytop lasm, the former

appear ing immature and the la t ter h igh ly di f ferent ia ted. About 20% of myeloma cases have

p lasmablast ic morphology: a d i f fuse chromatin pat tern, nucleus >10 µm or nuc leo lus greater

than 2 µm, re lat ive ly less abundant cytop lasm, and a concentr ica l ly p laced nuc leus wi th

l i t t le or no hof (199,200). Both di f fuse and nodular in f i l t rat ion pat terns can be observed,

a l though the former is more common. A minor i ty o f pat ients have plasma ce l ls that have a

lymphoplasmacyt ic appearance. Myeloma cel ls are commonly present in cords around bone

marrow microvessels. There is a high correla t ion between the extent of bone marrow

angiogenes is , eva luated as microvessel area, and the pro l i ferat ing frac t ion of marrow

p lasma ce l ls in pat ients wi th mul t ip le myeloma (201,202) . Mi ld marrow f ibros is may be

observed in as many as 27% of cases; extens ive f ibrosis is rare (203,204). Less than 1% of

cases have an extensive id iopathic granulomatous react ion (197) . Growth pat terns may be

nodular, in f i l t rat ive, or both. In cases in which the marrow invo lvement is foca l ra ther than

d i f fuse, bone marrow spec imens f rom al ternate s i tes may vary.

The immunophenotype of myeloma ce l ls is complex. In general , myeloma ce l ls are CD45 - ,

CD38+ and CD138+ (205,206) . However, there is increasing evidence that a subset o f

myeloma ce l ls is CD45+ (206,207) , wi th an increas ing propor t ion of CD45+ myeloma ce l ls in

less advanced disease (208,209) . CD19 and CD20 are ear l ier B-cel l ant igens that are

var iably expressed on myeloma ce l ls; sur face immunoglobul in is seen in up to one th i rd of

pat ients . CD56 is s t rongly posi t ive in about 55 to 78% of myeloma cases (206,210,211) .

CD56-negat ive myeloma ce l ls tend to be present in more aggress ive d isease, such as end-

s tage myeloma or PCL (211,212) . Other sur face ant igens such as CD10 (CALLA), CD28,

CD117 (c-k i t ) , CD13, CD33, and CD20 are present on a minori ty o f pat ients ' myeloma ce l ls

(205,206,207,213,214) . Cost imulatory molecules involved in the act ivat ion of B and T

lymphocytes (CD28 and CD40) are seen in 40 and 70% of pat ients , respect ively (215,216) .

The label ing index of bone marrow p lasma ce l ls can be used to ident i fy plasma ce l l c lonal i ty

and ra te of d iv is ion. Th is assay has some va lue in d i f ferent ia t ing MGUS f rom myeloma and

indolent myeloma f rom act ive myeloma (217,218). Th is determinat ion can be done by 5-

bromo-2-deoxyur id ine immunof luorescence s ta in ing,

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thymid ine label ing, or f low cytometry. In general , myeloma is a low-growth- f ract ion tumor

wi th on ly a smal l percentage of cel ls in the S phase of the cel l cyc le at any g iven t ime.

No ind iv idual bone marrow f ind ing, however, is pathognomonic for a mal ignant plasma ce l l

process; the bone marrow d iagnos is o f myeloma re l ies on percentage of c lonal bone marrow

p lasma ce l ls, wi th 10% accepted as a cutof f . The c l in ical diagnos is , o f course, is made f rom

a synthes is of bone marrow f ind ings and other c l in ica l features.

Diagnosis The d iagnosis o f mul t ip le myeloma has not been subject to s tat ic norms. In 1973, the

Chronic Leukemia-Myeloma Task Force (219) set for th gu ide l ines for the d iagnos is of

myeloma (Table 99.1) . These cr i ter ia , which by today's s tandards are not s t r ingent enough,

have been replaced by a more modern def ini t ion (Table 99.2) (220) . In the las t 3 decades,

the terms and def ini t ions of MGUS, smolder ing myeloma, indolent myeloma, and

symptomat ic mul t ip le myeloma (130,221,222,223) have evolved and are now to be replaced

by the fo l lowing des ignat ions: MGUS, inact ive (smoldering) myeloma, and act ive (or

symptomat ic ) mul t ip le myeloma (220).

Th is in ternat ional ly accepted classi f icat ion schema is derived f rom more than 3 decades of

exper ience of t reat ing and s tudying mul t ip le myeloma pat ients . Because mult ip le myeloma

includes a spectrum of bio log ic features, physic ians should not feel compel led to s tart

t reatment as a resul t o f a s ingle threshold va lue. The d iagnosis o f act ive myeloma is not a

s t raight forward pathologic one; ra ther , i t is a c l in ica l d iagnosis that requi res thought ful

synthesis o f mul t ip le var iab les . Pat ients wi th Dur ie-Salmon stage I d isease, who also meet

the cr i ter ia for smolder ing or asymptomat ic myeloma, should be managed expectant ly.

Median progress ion- f ree survival in asymptomatic stage I pat ients, observed wi thout any

therapy, is 12 to >48 months (224,225,226,227) ; for s imi lar s tage I I pat ients , progress ion-

f ree survival is 12 months (224) . No survival advantage has been demonstrated by t reat ing

asymptomatic myeloma pat ients (223,225,226,228) .

Treatment for Multiple Myeloma Before star t ing therapy for mul t ip le myeloma, a dis t inc t ion must be made between

smolder ing (asymptomat ic ) myeloma and act ive myeloma (Table 99.2) . Approximately 20%

of pat ients wi th mul t ip le myeloma are recognized by chance wi thout s igni f icant symptoms;

such pat ients can be carefu l ly monitored wi thout inst i tu t ing therapy. Weber e t a l . ident i f ied

three r isk fac tors for progress ion: serum M protein >3 g/dl (30 g/L), IgA isotype, and Bence

Jones prote in excret ion >50 mg per day. Pat ients wi th two or more of these features

requi red t reatment a t a median of 17 months, whereas the absence of any adverse var iab les

was assoc iated wi th pro longed s tab i l i ty (median, 95 months) (p < .01) (229) . Cesana et al .

ident i f ied >10% bone marrow p lasmacytos is , Bence Jones proteinuria , and IgA isotype as

r isk fac tors for evo lu t ion. Other r isk fac tors for progression include ci rcu lat ing p lasma ce l ls

(230) and myeloma cel ls that produce h igh leve ls o f in ter leukin-1β (231) .

Table 99.1 Chronic Leukemia-Myeloma Task Force Definition of Multiple Myeloma (1973)

If M protein present in serum or urine, one or more of the following must be present: Marrow plasmacytosis >5% in absence of underlying reactive process Tissue biopsy demonstrating replacement and distortion of normal tissue by plasma cells More than 500 plasma cells/mm3 in peripheral blood Osteolytic lesion unexplained by other causes If M protein absent in serum and urine, there must be radiologic evidence of osteolytic lesions or palpable tumors and one or more of the following must be present: Marrow plasmacytosis of >20% from 2 sites in absence of a reactive process Tissue biopsy demonstrating replacement and distortion of normal tissue by plasma cells

Data from Proposed guidelines for protocol studies. I. Introduction. II. Plasma cell myeloma. 3. Chronic lymphocytic leukemia. IV. Chronic granulocytic leukemia. Cancer Chemother Rep 1973;4:141–173.

Table 99.2 Criteria for Diagnosis of MGUS, SMM, and MM, International Working Group

Monoclonal Gammopathy of Undetermined Significance Serum monoclonal protein (<30 g/L) Bone marrow <10% plasma cells No evidence of other B-cell proliferative disorders No related organ or tissue impairmenta,b Smoldering Myeloma (asymptomatic) Serum monoclonal protein (≥30 g/L) and/or Bone marrow clonal plasma cells ≥10% No related organ or tissue impairmenta Multiple Myeloma (active or symptomatic) Monoclonal protein present in serum and/or urine Clonal bone marrow plasma cells or plasmacytoma Related organ or tissue impairmenta

MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; SMM, smoldering multiple myeloma. aThe absence of CRAB (calcium elevation [>1 mg/dl above upper limit of normal], renal dysfunction [creatinine >2 g/dl], anemia [hemoglobin 2 g/dl below lower limit

of normal], bone lesions [lytic lesions or osteoporosis with compression fracture] attributable to the plasma cell disorder). bThe existence of immunoglobulin light-chain amyloidosis or another paraneoplastic disorder attributable to the monoclonal gammopathy, such as a peripheral neuropathy, would be termed “monoclonal gammopathy associated with—.” Source:Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003; 121:749–757

Once the dec is ion has been made to treat for symptomat ic disease, a long- term plan for

managing the d isease should be formulated before ins t i tut ing therapy. F igure 99.7A,B

out l ines a poss ib le t reatment algori thm. Because h igh-dose therapy wi th hematopoiet ic s tem

ce l l support has been accepted as an important treatment modal i ty for pat ients younger

than age 65, cumulat ive doses of a lkyla tor-based therapy should be avoided prior to the

co l lec t ion of hematopoiet ic s tem cel ls in pat ients considered candidates for high-dose

therapy.

Systemic Therapy

General Comments

Histor ica l ly, bi funct ional a lkyla t ing agents , such as melphalan and cyc lophosphamide, have

been the foundat ion of therapy for mul t ip le myeloma. Myeloma cel ls tend to pro l i ferate

s lowly, and alkyla tors , whose ef fec t iveness does not re ly heavi ly on cel l d iv is ion and DNA

rep l icat ion, are usefu l therapeut ic agents . Prior to 1999, the bi funct ional a lkyla tors ,

n i t rosoureas, doxorubic in , and g lucocort ico ids were the pr imary agents shown to have

s ing le-agent ac t iv i ty against mul t ip le myeloma in vivo (232) . These drugs, a long wi th

v incr is t ine, ei ther s ing ly or in combinat ion, had been the mainstay of chemotherapy for

myeloma f rom the early 1960s to the present (Fig . 99.1). Unt i l recent ly, the higher response

rates seen wi th reg imens that combine mul t ip le ac t ive agents as part o f in i t ia l therapy had

not resu l ted in improved overa l l surviva l ra tes (233) .

In terferon-α has been incorporated into induct ion and maintenance protocols wi th minimal

benef i t (40,234,235,236). Both autologous and a l logeneic s tem cel l t ransplantat ion have

become important therapeut ic opt ions s ince McElwain and Powles ' descrip t ion in 1983 (237)

o f the benef i t o f dose intensi f icat ion of melphalan

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in pat ients wi th mul t ip le myeloma. W ith the recogni t ion of thal idomide 's ac t iv i ty against

myeloma in 1999 (43) and the subsequent development o f bor tezomib (44) and lenal idomide

(45) , there is hope that the next 4 decades of myeloma t reatment wi l l be even more

promising than the las t.

Figure 99.7. Mayo stratification for myeloma and risk-adapted therapy. A: Risk stratification. B: Possible treatment algorithm for patients with newly diagnosed myeloma for patients not being treated on a clinical trial. Dex, dexamethasone; HR, high risk (see text);

lenalid, lenalidomide; MP, melphalan, prednisone; PR, partial response.

Before discussing induct ion, t ransplantat ion, maintenance, and sa lvage therapies, two

genera l concepts wi l l be reviewed: in terpretat ion of study response data, and the ef f icacy of

s ing le chemotherapeut ic agents commonly used to t reat myeloma. Figure 99.7 is an

a lgor i thm for t reat ing pat ients wi th newly d iagnosed myeloma. Table 99.3 serves as a

re ference for commonly c i ted reg imens.

Interpreting Study Response and Survival Data Four poin ts are emphas ized regarding the in terpretat ion and comparisons of the myeloma

t reatment l i terature. F i rst , def in i t ions of response vary (Table 99.4) . Second, def in i t ions of

eva luable pat ients may be d i f ferent. Th i rd, concurrent cort icostero id therapy, e i ther as par t

o f the reg imen or for o ther ind icat ions, may confound in terpretat ion of e f f icacy. Final ly,

pat ient populat ion r isk and prognos is may d i f fer substant ia l ly . Lead-t ime b ias and t reatment

o f MGUS or smolder ing myeloma can s ign i f icant ly d is tor t survival f igures, as can ef fec t ive

sa lvage regimens.

The measurement o f myeloma d isease burden, and therefore i ts response to therapy, is

complex, and invest igators have used di f ferent methods to def ine response (Table 99.4) .

The four most common response cr i ter ia are those of the Chronic Leukemia-Myeloma Task

Force (CLMTF) (219) , the Southwest Oncology Group (SW OG) (238,239), the Eastern

Cooperat ive Oncology Group (ECOG) (240) , and the Autologous Blood and Marrow

Transplant Regist ry and In ternat ional Bone Marrow Transplant Regis t ry ( IBMTR/ABMTR)

(241). These response cr i ter ia are re levant f rom a h is tor ica l prospect ive because they

should al l be supplanted by the new In ternat ional Response Consensus Cr i ter ia (242) .

Al though al l par t ia l ly take into account hemoglobin

P.2381

ca lc ium, bone changes, and bone marrow p lasmacytosis, the main dist inc t ion among them is

the ir cons iderat ion of the serum and ur ine M components. W ith the except ion of the old

SW OG cr i ter ia (238,239), a par t ia l response (PR) has been considered to be a 50%

reduct ion in serum M component and a >50 to 90% reduct ion in ur ine M component . In the

ear l ies t l i terature, response inc luded such factors as increas ing hemoglob in concentrat ion

or per formance sta tus, or decreasing b lood urea n i t rogen leve ls . Nei ther the CLMTF nor the

SW OG cr i ter ia or iginal ly had a complete response category, because i t was unusual for the

M prote in to d isappear complete ly. I t was not unt i l the advent o f h igh-dose melphalan that

invest igators such as Selby et a l . (243) and Gore et al . began (244) to def ine a complete

remiss ion category. Their def ini t ion, unl ike more modern def ini t ions, on ly included

d isappearance of M prote in as determined by e lec t rophoresis, which is less sensi t ive than

immunoelect rophoresis or immunofixat ion. Subsequent def in i t ions have requi red

immunof ixat ion negat iv i ty to qual i fy as complete remiss ion (241). Unt i l about 1990, a SW OG

object ive response was def ined as a 75% reduct ion in the tumor mass index (not serum M

protein), and improvement was def ined as a 50 to 74% reduct ion in the tumor mass index

(239). A new i terat ion of the SW OG response cr i ter ia uses the M component ( ra ther than

the tumor mass index) as the pr imary measurement o f the p lasma cel l burden. The f i rst

i terat ion of an in ternat ional consensus def in i t ion of myeloma response were the

IBMTR/ABMTR response cr i ter ia (241). Af ter near ly 8 years of use, severa l def ic ienc ies

were noted, and the Internat ional Myeloma W orking Group has recent ly issued a new

consensus def ini t ion cal led the In ternat ional Response Cri ter ia ( IRC), which inc ludes the

In tergroupe Français du Myélome ( IFM) very good part ia l response category (245) , the

ab i l i ty to measure response us ing the serum immunoglobul in f ree l ight chain, and a new

category of “s t r ingent

P.2382

complete response” that requi res documentat ion of the absence of c lonal i ty (242).

Table 99.3 Commonly Cited Regimens and Their Dosage Schedules

Regimen VCR Mel CTX BCNU ADR Gluco IMiD Bortez

MP — 9 mg/m2/d, d 1–4 q 4 wk or 0.15 mg/kg/d, d 1–7b

— — — P 100 mg/d, d 1–4 q 4 wk or P 60 mg/d, d 1–7b

— —

CPa — — 0.25 g/m2 per d, d 1–4 or 1 g/m2 IV

— — P 100 mg/d, d 1–4 or P 50 mg, qod

— —

ABCMc (251)

— 6 mg/m2/d, d 1–4

100 mg/m2/d, d 1–4

30 mg/m2 IV, d 1

30 mg/m2 IV, d 1

— — —

VBMCPd

0.03 mg/

0.25 mg/

10 mg/

0.5 mg/k

— P 1 mg/k

— —

(274) kg IV, d 1

kg, d 1–7

kg IV, d 1

g IV, d 1

g, d 1–7

VADd (391)

0.2 mg/m2/d CI, d 1–4

— — — 9 mg/m2/d CI, d1–4

D 40 mg/d, d 1–4, 9–12, 17–20

— —

C-VAMPa (395)

0.4 mg/d CI, d 1–4

— 500 mg IV, d 1, 8, 15

— 9 mg/m2/d CI, d 1–4

Methylpred 1 g/m2/d, d 1— 4

— —

Regimen

VCR

Mel CTX

Cisplatin (CDDP)

ADR

Gluco

IMiD

Bortez

DT-PACEd (672)

— — 400 mg/m2/ d× 4 d, CI

CI: CDDP 10 mg/m2/d × 4 d & Etop40 m/m2/d × 4 d both by CI

10 mg/m2/d× 4 d, CI

40 mg/d × 4 d

— —

Thal-dex

— — — — — 40 mg, d

Thal

—

(441) 1–4, 9–12, 17–20 or d 1, 8, 15, 22

50–100 mg/d

Len-dex (439)

— — — — — As above (441)

Len 25 mg/d, d 1–21, q 28 d

—

MPT (263,451)

— 0.25 mg/kg, d 1–4 q 6 wk

— — — P 2 mg/kg, d 1–4, q 6 wk

Thal 200 mg/d

—

Doxil/Borteza (677)

— — — — Pegylated dox 30 mg/m2, d 4

— — 1.3 mg/m2

, d 1, 4, 8, 11

VMPe (459)

— 9 mg/m2, d 1–4 q

— — — P 60 mg/m2, d 1–4 q 6 wk

— 1.3 mg/m2

, d 1,

6 wk

4, 8, 11, 22, 25, 29, & 32

IMiD, immune modulatory drug; ABCM, VBAP/VMCP without vincristine or prednisone; ADR, doxorubicin (Adriamycin); BCNU, carmustine; CDDP, cisplatin; CI, continuous infusion; CP, cyclophosphamide and prednisone; CTX, cyclophosphamide; C-VAMP, cyclophosphamide, vincristine, doxorubicin, and methylprednisolone; d, day; DT-PACE, dex, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide; gluco, corticosteroid; IV, intravenous; Mel, melphalan; MP, melphalan and prednisone; po, by mouth; MPT, MP and thalidomide; P, prednisone; q, every; qod, every other day; VAD, vincristine, doxorubicin, and dexamethasone; VAMP, vincristine, doxorubicin, and methylprednisolone; VBAP, vincristine, BCNU, doxorubicin, and prednisone; M-2, VBMCP; VCR, vincristine; VMCP, vincristine, melphalan, cyclophosphamide, and prednisone; Thal, thalidomide; Rev, lenalidomide; VMP, MP and bortezomib; wk, week. aRepeated at 3-wk intervals. bRepeated at 6-wk intervals. cAB and CM portions of regimen are given alternately every 3 wk. dRepeated every 5 wk. eRepeated every 6 wk for 4 cycles, and then repeated every 5 wk, with bortezomib schedule changing to weekly administration for 4 wk followed by 1 wk rest.

Table 99.4 Response Criteria

M protein Response Study % BMPC Serum Urine

Duration (wk)

Stringent CR (sCR)

IRC (242) <5a IF-b IF- 0

IRCc ≤5 IF- IF- 6

IBMTRc (241) <5 IF- IF- 6

Complete response

SWOG (239) <1a IF- IF- 8

ECOG (240) ≤3 IF- IF- 6

CLMTF (219) Not defined

—

Very good partial response

IRC — ≥90% reduction

<100 mg/24 h

—

Objective response

SWOG — ↓≥75%c ↓≥ 0% 8

IRCd — ↓≥50% ↓≥90% 6

ECOG/IBMTR — ↓≥50% ↓≥90%e

6

SWOG (“Improvement”)

— ↓≥50%c ↓≥75% 8

Partial Response

CLMTFf — ↓≥50% ↓≥50% —

Minimal response

IBMTR — ↓≥25% ↓≥50% —

IRC/IBMTR/SWOG

— >25%g >25%h — Progression

ECOG — ≥50%i ≥50%h —

BMPC, bone marrow plasma cells; IRC, International Response Consensus; IF, immunofixation; CLMTF, Chronic Leukemia-Myeloma Task Force; CR, complete response; ECOG, Eastern Cooperative Oncology Group; IBMTR, International Blood and Bone Marrow Transplant Registry; IF, immunofixation; MR, minimum response; PR, partial response; SWOG, Southwest Oncology Group. aClonal plasma cells as measured by flow cytometry, immunohistochemistry, or immunofluorescence.

bAlso requires normalization of serum immunoglobulin free light chain ratio. cChange in synthetic index and not monoclonal protein concentration. dAllows for immunoglobulin free light-chain responses in patients whose serum and urine are not measurable. eOr <200 mg/24 hours. fResponse also takes into account reduction in size of plasmacytomas, >2 g/dl Hb rise, weight gain, correction of calcium, renal function, albumin. gAbsolute increase must be at least 5 g/L. hAbsolute increase must be >200 mg/24 hours. iFor ECOG, absolute increase must be at least 20 g/L.

The roving denominator a lso creates chal lenges in interpret ing therapeut ic studies . Of ten,

an in tent - to- t reat analys is is not used to describe response rates or surviva l , which

ar t i f ic ia l ly in f la tes these endpoints. Def ini t ions of eva luable pat ients may of ten include on ly

those pat ients who received an “adequate” t r ia l (3 or 6 months) o f therapy, thereby

exc lud ing pat ients wi th ear ly deaths or progress ion. In addi t ion, in a steroid-responsive

tumor such as myeloma, co incident use of prednisone or dexamethasone (246,247) as an

ant iemet ic or as therapy for hyperca lcemia may ser iously confound the resu l ts . F inal ly, the

s t r ik ing heterogenei ty of prognoses in myeloma pat ients cannot be exc luded as a major

confounding fac tor in interpret ing both Phase I I and Phase I I I t r ia ls . Severa l prognost ic

indicators have been ident i f ied, including stage, β2-M, label ing index, renal funct ion, serum

a lbumin, and chromosomal abnormal i t ies . Unfor tunately, the i r pred ic t ive va lue is l imi ted and

only skims the surface of myeloma bio logy and prognos is .

Efficacy of Single Chemotherapeutic Agents

Melphalan Bergsagel e t al . (37) demonstrated the benef i t of melphalan in 14 of 24 pat ients wi th

mult ip le myeloma. Others (Table 99.5) have substant ia ted that melphalan as a s ing le agent

resul ts in response rates of 20 to 34% and median overal l surviva l o f 15 to 27 months

(38,248,249,250,251).

Cyclophosphamide Korst e t a l . were the f i rst to report on the act iv i ty o f ora l cyclophosphamide. Twenty- four

percent o f mul t ip le myeloma pat ients achieved a part ia l response (50% M-prote in reduct ion),

and 48% had object ive improvement , that is , an improvement in the peripheral blood va lues,

bone marrow f ind ings, or serum b lood urea ni t rogen. Median surviva l was 24.5 months in a l l

207 pat ients and 32 months in the group that rece ived at least 2 months of

cyc lophosphamide therapy. The single-agent ac t iv i ty o f cyc lophosphamide (Table 99.5) has

been demonstrated in a p lacebo-contro l led t r ia l (249) , in mul t ip le s tud ies of previous ly

unt reated pat ients (252,253) , and in those who re lapsed or had re f rac tory d isease (254).

Glucocorticoids

In 1950, Thorn et a l . (34) repor ted the f i rst observat ions on the benef ic ia l e f fec ts of

adrenocor t icot rop ic hormones in myeloma. Adams and Skoog (33) observed a marked

decrease in the myeloma serum prote in in 18 of 26 pat ients t reated wi th cor t icostero ids .

Surpr is ingly, Mass (255) fa i led to show a d i f ference between the surviva l o f 55 pat ients

randomly ass igned to prednisone therapy or placebo despite c l in ical improvement in the

former group. Subsequent ly, high-dose cor t icostero ids have been shown to produce

response rates of 40 to 50%, in previous ly unt reated pat ients , and 25% in re f ractory or

re lapsed pat ients (35,247,256,257,258,259,260,261) ; median surviva l o f responding

pat ients is 16 to 22 months (247,258,259) . In reviewing the i r exper ience wi th s ing le-agent

dexamethasone and vincr is t ine, adr iamycin, dexamethasone (VAD), Alexanian et a l . (258)

noted that in pat ients wi th re f ractory disease, response rates wi th s ingle-agent

dexamethasone are comparable to those wi th VAD (27 vs. 32%). In contrast , in relapsed

d isease, response rates achieved wi th s ing le-agent dexamethasone are infer ior to those

wi th VAD. These data are not randomized but ra ther seria l observat ions. On occas ion,

pat ients who do not respond to h igh-dose dexamethasone can be sa lvaged wi th in termit tent

h igh-dose methylpredniso lone (259).

Despi te thei r contr ibut ion to quicker and more abundant responses, there are conf l ic t ing

data as to whether cor t icostero ids prolong surviva l (248,250,262) . As ini t ia l therapy for

e lder ly pat ients , s ing le-agent dexamethasone is respons ible for both higher t reatment-

re lated morb id i ty and morta l i ty compared to melphalan-conta in ing reg imens (263) .

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Table 99.5 Early (1969 to 1982) Randomized Trials—Untreated Myeloma

Study Agent Schedule N RR (%) OS (mo)

CTX 2–4 mg/kg/d 54 21 11.5a Rivers and Patno, 1969 (249)

Placebo 3.5

CTX 4 mg/kg/d 49 28 13 Rivers and Patno, 1969 (249)

M 0.1 mg/kg/d 54 34 15.5

M qd 0.025 mg/kg/d 35 17 18

M intermittent

0.25 mg/kg d 1–4 69 32 18

Alexanian et al., 1972 (250)

M alt. P 0.25 mg/kg d 1–4 28 61 24

& 1 mg/kg MWF

M concurr P 0.25 mg/kg d 1–4 & 2 mg/kg d 1–4

51 65 17

CTX 150 mg/d 114 NG 28b MRC, 1971 (252)

M 4 mg/d 105 NG 24b

MP M: 0.25 mg/kg & P: 2 mg/kg d 1–4

83 52a 21 Alexanian et al., 1972 (238)

MP & procarbazine

M: 0.2 mg/kg & P: 2 mg/kg d 1–4 & Pro: 3 mg/kg d 2–10

79 41 23

M qd 0.15 mg/kg ×7, maintenance 0.05 kg/d

53 20 27 (30,21)c

M qd & P M: as above & P: 1.25 mg/kg/d with taper 8 wk

70 39 NG (53,9)

Costa et al., 1973 (248)

M qd, P, & testosterone

M & P as above & testosterone: 10 g/kg/wk

56 43 NG (36,4)

MP M: 10 mg /d d 1–7; P: 40 mg/d d 1–7 q 3 wk

174 NG 32d,e

CTX IV 600 mg/m2 q 3 wk

179 24

MRC, 1980 (253)

MP See above 71 NG 6b,e

CMLP C: 250 mg/m2 po d 1–3; M: 5 mg/m2 d 1–3; L: 50 mg/m2 d 4; & P: 40 mg/m2 d 1–3 q 4 wk

61 NG 6

MP M: 0.15 mg/kg d 1–7; P: 0.8 mg/kg with taper

100 44f 27

Carmustine-P Carmustine: 150 mg/m2 IV; P: 0.8 mg/kg with taper

124 34 21

Cornwell et al., 1982 (276)

Lomustine-P Lomustine: 100 mg/m2 qd; P: 0.8 mg/kg with taper

137 30 21

Alt, alternating; C, cyclophosphamide; concurr., concurrently; CTX, cyclophosphamide; IV, intravenous; L, lomustine; M, melphalan; MRC, Medical Research Council Working Party on Leukaemia in Adults; NG, not given; OS, overall survival; P, prednisone; po, by mouth; qd, daily. aOverall survival is significant at p=.03. No corticosteroids allowed in trial. bSurvival estimated from survival curves. cPatients stratified for good and poor risk; median survival given as all patients (good risk, poor risk). Authors note that much quicker response observed with prednisone but worse survival with prednisone in poor-risk patients. dPatients were required to have BUN≤10 mM. Difference not significant (p=.16). eAll patients had BUN >10 mM. fResponse rate between melphalan and lomustine arms significant. Median survival is not different.

The mechanism of ac t ion of th is drug c lass is complex. Cort icosteroids suppress the

product ion of cytok ines that are important in myeloma growth, such as IL-6 and IL-1β , and

reduce nuc lear factor κB act iv i ty, resu l t ing in enhanced apoptos is (264,265,266,267) .

Vincristine Al though vincr is t ine has never been evaluated as a s ing le agent in newly d iagnosed

myeloma, i t has l i t t le ac t iv i ty as a s ing le agent in re f rac tory d isease. Twenty-one pat ients

were t reated wi th a 0.5-mg bolus of v incr ist ine fo l lowed by 0.25 to 0.5 mg/m 2 per day as a

cont inuous in fusion over 5 days on a 3-week schedule. Two pat ients had t rans ient

responses (1.2 and 2.2 months) (268) . F inal ly, the act iv i ty c redi ted to v incr is t ine as a

maintenance therapy is a lso ambiguous. Al though superior surviva l (35 vs . 27 months, p

= .003) was repor ted in pat ients treated wi th s ing le-agent melphalan and mainta ined on

b imonth ly v incr is t ine (1 mg/m2) and prednisone (0.6 mg/kg for 7 days) , the benef i t cou ld

easi ly be at t r ibuted to prednisone a lone (269) .

Alexanian et a l . (270,271) suggested that reg imens that inc luded vincr is t ine resul ted in

bet ter pat ient outcome than protocols that d id not inc lude this agent . The theory behind i ts

posi ted ut i l i ty was that af ter an in i t ia l k i l l o f myeloma ce l ls by a lkyla t ing agents , the

subsequent increase in the mi to t ic index made myeloma ce l ls more sensi t ive to v incr is t ine

(272). Reports by Lee et a l . , Salmon, and Case have been c i ted as conf i rmatory evidence

for ac t iv i ty o f v incr is t ine in myeloma (273,274,275) . However, several randomized control led

t r ia ls have not supported th is premise (276,277,278,279) (Table 99.6) . The most compel l ing

of these is the MRC IV Tr ia l in Myelomatosis , which randomized 530 newly d iagnosed

myeloma pat ients to month ly melphalan and prednisone, wi th or wi thout monthly v incr is t ine.

Median surviva l in both arms was 26 months (278) . Even though vincr is t ine has not been

shown to have signi f icant s ingle-agent in v ivo act iv i ty or to improve overa l l surviva l

(268,278,279,280), i t is inc luded in mul t ip le therapeut ic regimens.

Anthracyclines Doxorubic in is the most commonly used anthracyc l ine in the t reatment o f myeloma, but i t

has not been s tud ied as a s ingle agent in newly diagnosed myeloma pat ients . I ts ac t iv i ty as

a s ingle agent in re lapsed or re f rac tory d isease is modest, wi th response rates of about

10% (41,281) .

A Phase I I t r ia l o f mi toxantrone as a s ing le agent (12 mg/m 2 every 3 weeks) y ielded a

par t ia l response rate of 3% (1 of 35). An addi t ional four pat ients showed c l in ical

improvement las t ing 4 to 7 months (282) . Idarubic in is another anthracyc l ine that has been

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s tud ied in mult ip le myeloma. Response rates of 0 to 27% have been observed in re lapsed

and ref rac tory pat ients wi th s ing le-agent ora l regimens (30 mg/week in three div ided doses

g iven 3 of 5 weeks or 40 mg/m 2 every 3 weeks) (283,284) .

Etoposide In relapsed and ref rac tory d isease, s ingle-agent e toposide (200 to 250 mg/m 2 over 5 days)

has min imal ac t iv i ty; in 85 pat ients the response rate was <5% (285) . Bar log ie e t a l . (286)

t reated 14 pat ients wi th 200 mg/m 2 by cont inuous in fus ion, and 2 responded. In addi t ion,

there are 2 anecdotal repor ts of ac t iv i ty o f low-dose (25 to 50 mg/day) ora l etoposide

(287,288) .

Nitrosoureas The n i t rosoureas have sing le-agent ac t iv i ty in myeloma. In a randomized tr ia l o f 361

previously unt reated pat ients (Table 99.5), ob jec t ive response f requenc ies wi th carmust ine

(BCNU) (40%) and lomust ine (CCNU) (42%) were lower than that of melphalan (59%),

a l though the survival for a l l groups was not s ign i f icant ly di f ferent (276) .

Table 99.6 MP versus Combination Chemotherapy as Induction: Selected Randomized Trials

Study Regimen N RR (%)a

Overall Survival (mo)

P (RR) P (OS)

MP 125 40† 28 NS NS SWOG 727/1972 (238)

MP-Pcb 116 47 31

MP 187 29 36 NS NS SECSG 343/1984 (359)

BCP 186 37 36

MP 126 56 NG 0.047 NS CALGB 7161/1979 (353)

MCBP 124 68

MP 125 40b

28 NS NS NCI-C-MY1/1979 (583)

MCBP 239 39 31

MP 92 40 19 NS NS ECOG 4472/1982 (360)

BCP 96 50 25

MP 67 40 38 NS NS GATLA3-M-73/1980 & 198 (361,1087) CP-

MeCCNU 83 40 30

MP 145 33 42 NS NS GATLA3-M-77/1984 & 1988 (361,937) MPCV-

MeCCNU 115 44 44

Pavia MM-75/ MP 39 41 54 NS 0.039

(1088) Pept-VP 36 58 26

MP 77 32b

23

VMCP/VCAP

80 58 43 0.001 0.004c

SWOG 7704/1983 & 1986 (368,369)

VMCP/VBAP

80 49 43 0.028

MP 30 53b

38 NS NS

VMCP/VCAP

42 55 27

MDA7704/1984 (271)

VMCP/VBAP

34 60 28

MP (IV) 146 47 34 NS d

MCBP 140 56 29

Seq-MCBP 148 47 22

CALGB 7761/1986 (354)

MCBPA 157 44 26

MP 47 19†

30 NS NS

VMCP 53 19 45

IMMSG M-77/1985 (279)

BC-Pept 33 3 58

Gentofte, MP 31 45 21 NS NS

VMP 32 73 30 Denmark/1985 (277)

VBMCP 33 58 21

MP 230 51 27 <0.0001 NS ECOG 2479/1997 (373)

VBMCP 235 72 29

MP 261 NG

26 NS NS MRC MYEL-4/1985 (278)

VMP 269 26

MP 66 54 41 < 0.02 NS Finnish MM80/1987 (363)

MOCCA 64 75 45

MP 48 48 29 NS NS Norwegian Trial 1986 & 1988 (364,385) VBMCP 44 54 33

MP 44 61 28 NS NS MGCS stage III/1989 (365)

VMCP/VBAP

42 52 24

MP 170 33b

60% 4 y OS

NS <0.02 MP

GMTG MM01/1988 & 1991 (371,384)

VMCP 150 33

MGCS stage MP 29 69 46 NS NS

II/1990 (370) VMCP 25 56 33

MP 55 58 26 NS NS MGCS stage III/1990 (370)

VMCP/VBAP

53 57 24

MP 146 64 37 0.02 NS IMMSG M-83/1991 (366)

VMCP/VBAP

158 77 32

MP 247 32 27 0.004 NS PEETHEMA 85/1993 (372)

VMCP/VBAP

241 45 32

MP 87 24 All 24

NS NS Pavia 1986/1994 (225)

Pept-VP 83 24

MP 74 64 31 NS 0.02 NMSG/1993 (367)

NOP 77 60 14

MP (IV)e 99 43 ~37 0.01 NS GMTG MM02/1995 (374)

VBAMDe 105 64

Meta-analysis Group (233)

MP vs. CCT 6,633

53 29 <0.00001

NS

A, doxorubicin; B, BCNU or carmustine; C, cyclophosphamide; CCT, combination chemotherapy; D, dexamethasone; IV, intravenous; M, melphalan; MeCCNU, methyl-CCNU; MOCCA, the additional C is for CCNU (lomustine); NG, not given;

NOP, mitoxantrone, vincristine, and prednisone; NS, not significant; P, prednisone; Pcb, procarbazine; Pept, peptichemo; V, vincristine. aExcept where stated, response is according to Myeloma Task Force criteria or modification. bSWOG response criteria. cSignificantly superior survival in combination chemotherapy arms compared to MP in the 174 stage III patients but not in the 74 stage I or II patients. dThe sequential arm was significantly worse than either the MP (p=.01) or the MCBP (p=.02) and marginally worse than MCBPA (p=.09). ePart of an interferon trial; stage III patients only. Data from Anonymous. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' Collaborative Group. J Clin Oncol 1998;16:3832–3842.

Interferon Despi te the encouraging repor ts that da i ly human leukocyte in ter feron (3 to 9 MU/day) could

induce responses in as many of 60% of myeloma pat ients (40,234) subsequent s tud ies wi th

recombinant in ter feron-α y ie lded ra tes of 10 to 20% (236,289,290,291,292) . Toxic i ty was

not inconsequent ia l (292) . In v i t ro act iv i ty had good predic t ive va lue for in v ivo c l in ica l

response in 26 pat ients s tud ied (290). However, in ter feron has a s t imulatory e f fec t in about

one th i rd of myeloma samples tes ted in v i t ro (290) .

Thalidomide Thal idomide is the f i rst in the c lass of drugs cal led immune modulatory drugs ( IMiDs) .

Recognit ion of the ro le of increased

P.2385

angiogenes is in the pathogenesis and progress ion of myeloma (201), and evidence of

tha l idomide 's ant iangiogenic proper t ies (293,294) , led to c l in ica l t r ia ls in mult ip le myeloma

(43,295). The observed responses in pat ients wi thout h igh-grade angiogenesis suggest that

tha l idomide may act v ia o ther mechanisms as wel l (296). In v i t ro data suggest that the drug

and i ts metabol i tes may inh ib i t angiogenesis, but in addi t ion may modulate adhes ion

molecules of myeloma ce l ls and thei r surrounding s troma, modulate cytok ines, and af fec t

natura l k i l le r ce l ls. There is evidence that tha l idomide and i ts analogs induce apoptos is and

G1 growth arrest in myeloma ce l ls (296) .

The f i rs t publ ished report o f the ut i l i ty o f thal idomide in pat ients wi th re lapsed myeloma was

by Singhal e t a l . (43) . Eighty- four pat ients wi th re lapsed myeloma, 76 of whom had relapsed

af ter h igh-dose chemotherapy wi th s tem cel l support , were t reated wi th escalat ing doses of

tha l idomide. Pat ients were star ted on 200 mg each evening; the dose was escalated every 2

weeks i f to lerated to a f ina l maximal dose of 800 mg dai ly. Twenty- f ive percent o f pat ients

had at least a 50% reduct ion in the i r serum paraprotein . Pre l iminary evidence of response

was apparent wi th in 2 months in more than three quarters of the pat ients who d id respond.

Other invest igators have conf i rmed par t ia l response rates of 25 to 58%, with an addit ional 6

to 26% achieving a minimal response, median response durat ion of 9 to 12 months, 2-year

progress ion- f ree survival o f 10 to 20%, and 2-year overal l survival of 48%

(295,297,298,299,300,301,302,303,304,305) .

When tha l idomide is used as a s ingle agent in previous ly unt reated pat ients , response rates

of 25% may be achieved (306,307,308).

The ro le o f dose intens i ty in tha l idomide ef fec t iveness is unc lear (302,309) . In the or iginal

reports , the highest dose to lerated was admin is tered (43) . In h igh-r isk pat ients there was a

suggest ion that response rates were h igher and surviva l longer in pat ients receiv ing h igh

doses of thal idomide (≥600 mg/day) (310) . However, in some pat ients , responses may be

seen wi th doses as low as 50 to 100 mg/day (309) .

Toxic i t ies assoc ia ted wi th tha l idomide inc lude fe ta l malformations, const ipat ion, weakness

or fat igue, somnolence, skin problems, and sensory neuropathy in more than one thi rd o f

pat ients . There is a lso an increased r isk o f thrombosis in pat ients t reated wi th thal idomide,

which appears to be exacerbated by the use of concurrent combinat ion chemotherapy, wi th

ra tes as high as 28% (311,312,313) . Other l i fe-threaten ing compl icat ions have inc luded

Stevens-Johnson syndrome and hepat i t is (314,315) .

Thal idomide is now considered a standard therapy for mul t ip le myeloma, a l though U.S.

Food and Drug Admin is t ra t ion approval for th is ind icat ion is pending.

Lenalidomide (CC-5013; Revlimid) Lenal idomide is a smal l -molecule der ivat ive of tha l idomide and a member of the IMiD c lass.

Lenal idomide is more potent than tha l idomide in mediat ing di rec t cytokine-re lated and

immunomodulatory e ffects against human mul t ip le myeloma cel l l ines and pat ient -der ived

ce l ls in v i t ro. I t induces apoptos is of myeloma cel ls; overcomes cytokine and bone marrow

s t romal ce l l -mediated drug res is tance; has ant iangiogenic e ffec ts ; and s t imulates host

ant imyeloma T- and natura l k i l le r ce l l immuni ty (45,316) . In the or ig ina l Phase I s tudy, 30%

of pat ients responded to s ing le-agent therapy, wi th a 6-month median durat ion of response

(45) . At 50 mg/day the dose-l imit ing toxic i ty was myelosuppress ion. In the randomized

Phase I I t r ia l , two schedules were evaluated: 25 mg dai ly and 15 mg twice dai ly. In both

arms, drug was g iven only 21 out o f 28 days. Overa l l , ~17% of relapsed or re fractory

pat ients ach ieved a part ia l response, inc luding a 4% complete response rate, wi th a median

progress ion- f ree surviva l o f 4 .6 months for the pat ients receiv ing once-dai ly dosing (45,316).

An addi t ional 9% of pat ients achieved a minimal response. Aside f rom myelosuppression,

o ther grade 3–4 toxic i t ies included neuropathy and fa t igue in 3 and 7% of pat ients,

respect ive ly. In the open- label Phase I I t r ia l o f 222 pat ients , there was a 25% par t ia l

response rate, wi th a

P.2386

t ime to progress ion of 5 .1 months (317) . Lenal idomide has never been s tud ied as a s ingle

agent in newly d iagnosed myeloma.

CC-4047 (Actimid) CC-4047 is another IMiD wi th act iv i ty in MM (318) ; 54% of previous ly treated pat ients

respond to s ingle-agent therapy. Median progress ion- f ree survival was 9 months.

Bortezomib (Velcade)

Bortezomib is the f i rs t drug in i ts c lass of proteasome inh ib i tors . I t is a boronic ac id

d ipept ide that reversib ly and selec t ively inh ibi ts the proteasome, an in t race l lu lar complex

that degrades primar i ly ub iqu i t inated prote ins. The proteasome has a key ro le in prote in

degradat ion, cel l -cyc le regulat ion, and gene express ion. Tumor ce l ls, includ ing mul t ip le

myeloma ce l ls , are heavi ly dependent on proteasome-regulated proteins for the i r growth

and in teract ion wi th s tromal ce l ls . Inhibi t ion of the proteasome has emerged as an important

ant i tumor target, and bor tezomib has been shown in v i t ro and in v ivo to cause growth arrest ,

to induce apoptosis , and to inhib i t angiogenes is .

In myeloma pat ients, the same schedule (days 1, 4 , 8, and 11, every 21 days) o f two dose

leve ls , 1 .0 and 1.3 mg/m2 , has been s tud ied as second-l ine therapy as par t o f a randomized

Phase I I study. Pat ients had dexamethasone added to the bor tezomib ei ther because they

had progressed af ter two cyc les or they had not achieved a par t ia l response or bet ter a fter

four cyc les. Though no di rect comparisons were made, in the 1.3-mg/m2 arm there was a

t rend toward h igher s ingle-agent response rates (38 vs . 30%), less f requent dexamethasone

usage (46 vs . 57%), longer durat ion of response (417 days vs . 288 days), and longer t ime

to progress ion (333 vs . 212 days) , but h igher ser ious adverse events . Dose reduct ion was

necessary in a higher propor t ion of pat ients in the 1.3-mg/m 2 arm (35 vs . 11%).

Single-agent response rates in relapsed/ref rac tory myeloma range f rom 28 to 38%, wi th a

median durat ion of response of 8 months (319,320,321,322) . In the APEX t r ia l—the

randomized tr ia l comparing bor tezomib to dexamethasone—the response rates, progress ion-

f ree survival , and overal l survival at 1 year were s ign i f icant ly superior in the bor tezomib-

t reated pat ients compared to the dexamethasone-t reated pat ients (320) . Al though the

or iginal s tud ies using this drug inc luded only eight cyc les of therapy, 63 pat ients were

t reated on an extens ion s tudy wi thout s igni f icant ly more ser ious adverse events than were

seen in the parent s tud ies of e ight cycles alone (323) . In previous ly unt reated myeloma,

response rates were 40% (324) .

The most common adverse events associa ted wi th bortezomib are gast ro in tes t ina l

d isturbances, fa t igue, per ipheral neuropathy, and myelosuppress ion. Seventy- f ive percent

o f pat ients had serious (grade 3–4) adverse events , the most common of which were

thrombocytopenia, neutropenia, anemia, gast ro intes t ina l d is turbances, fa t igue, and

neuropathy (320) .

Arsenic Trioxide In v i t ro , arsenic t r ioxide (ATO) induces growth inh ibi t ion and apoptosis (325) . Generat ion of

react ive oxygen spec ies wi th subsequent accumulat ion of hydrogen peroxide enhances

ATO-induced apoptos is . Because glu ta thione is be l ieved to sa lvage f ree rad icals , methods

to reduce g luta th ione have been explored, the most popular of which is coadminist ra t ion of

ascorbic ac id. In v i t ro, th is approach has appeared to be more ef fec t ive against myeloma

ce l ls o f pat ients wi th ref rac tory d isease than those wi th newly d iagnosed d isease (326) .

As a s ingle agent in re f rac tory d isease, the overa l l part ia l response rate is 7 .1% (327) , wi th

a to ta l o f one thi rd ach ieving a 25% reduct ion in M prot in in one s tudy (328) .

Other Agents Bar log ie e t a l . (286) exp lored the ut i l i ty o f c ispla t in therapy for pat ients wi th myeloma.

Four teen pat ients were treated wi th 10 mg/m 2 for 7 days by cont inuous infus ion, and two

responded. The drug has been incorporated in to o ther reg imens for re lapsed d isease

(286,329,330) and induct ion therapy (331) .

Cytos ine arabinos ide (332) , ten ipos ide (333), topotecan (334) , deoxycoformyc in (335,336),

and pac l i taxe l (337,338) have been repor ted to produce response rates of 7 , 28, 16, 0 to 15,

and 15 to 29%, respect ive ly. Topotecan induces signi f icant toxic i ty, including ≥grade 3

granulocytopenia and thrombocytopenia in 93 and 53% of pat ients, respect ive ly (334) .

Pat ients t reated wi th pacl i taxe l were premedicated wi th 40 mg of dexamethasone every 21

days (337,338) , br ing ing in to quest ion whether the observed responses were at t r ibutable to

dexamethasone or pac l i taxe l .

Agents that do not appear to have any act iv i ty in myeloma include drugs that are interest ing

f rom a h is tor ica l perspect ive and drugs that have known act iv i ty in o ther d iseases. Agents

in the former category inc lude d iamid ines, such as st i lbamid ine; 1-

aminocyc lopentanecarboxyl ic ac id ; amsacr ine (339,340) , aclarub in (341) , ch lorozotocin

(342), hexamethylmelamine (343) , and azaser ine (38). Other agents wi thout ac t iv i ty against

myeloma inc lude methotrexate, 6-mercaptopur ine, 6- th ioguanine, 5- f luorouraci l ,

f luorodeoxyur id ine, hydroxyurea, mi tomyc in C (38) , v inb las t ine, v indes ine (247) , carboplat in

(344), bleomycin (281), ATRA (a l l - t rans - re t ino ic ac id) , f ludarabine (345) , 2-

ch lorodeoxyadenos ine (346) , f lavopi r idol (347), and imat inib (348) . Al though Durie e t a l .

(349) repor ted a 57% response rate wi th c lar i thromycin, subsequent repor ts d id not

corroborate this response rate, and the act iv i ty observed in the or ig ina l repor t was

at t r ibuted to concurrent cor t icosteroid therapy (350,351,352) .

Combination Chemotherapy for Induction

A combinat ion of mult ip le ac t ive agents in an ef for t to achieve synergy is a log ical corol lary.

The las t three decades of the 20th century were spent combining a lkylators , anthracyc l ines,

cor t icosteroids , and interferon. Th i r ty years of s tudy indicate that though these

combinat ions as in i t ia l therapy resul ted in h igher response rates, this d id not trans la te into

longer overa l l survival rates than s tandard melphalan and prednisone therapy (233) (Table

99.6) (F ig . 99.8) . Al though i t has been suggested that pat ients wi th more advanced disease

benef i t f rom combinat ion chemotherapy compared to melphalan (251,272,353,354,355) , that

hypothesis has not been proven (225,233). Now that IMiDs and proteasome inh ib i tors have

been shown to have act iv i ty, c l in ical invest igators have begun us ing these drugs in

combinat ion. For expediency, these regimens wi l l be separated in to f ive categor ies for

d iscussion: Alkyla tor-based wi thout anthracyc l ines, anthracyc l ine-contain ing reg imens,

anthracyc l ine-contain ing regimens wi th in tensi f ied doses of cor t icosteroids , reg imens

incorporat ing inter feron, and novel therapies (Tables 99.6,99.7,99.8) . As a general rule ,

pat ients who are be ing considered for s tem ce l l co l lec t ion and t ransplantat ion rece ive non–

a lkyla tor-containing induct ion reg imens, or i f a lkyla tor-conta ining reg imens are used, the

number o f cyc les is res t r ic ted to four pr ior to stem cel l mobi l izat ion. Cl in ica l research in

myeloma is moving at breakneck speed, and the current preferred induct ion therapies are

a l l in the “novel ” category (Tables 99.7 and 99.8). Descr ip t ions of older reg imens are

provided for two reasons: to g ive a histor ical backdrop; and to fami l iar ize the reader wi th

these reg imens. As “novel ” therapies move to f ront - l ine, these older “ induct ion” regimens

wi l l be important as sa lvage regimens. In t ime, we may be able to bet ter ascer ta in b io log ic

d i f ferences (356) between myeloma pat ients and d i rec t speci f ic types of therapy to thei r

b iology.

In the sett ing of induct ion pr ior to s tem cel l col lec t ion and t ransplantat ion, major quest ions

revo lve around “does i t mat ter” and is “best response” necessary before proceeding to stem

cel l co l lec t ion and t ransplantat ion. Unfor tunate ly, no completed prospect ive randomized t r ia l

has yet addressed this quest ion. Retrospect ive analyses have shown that pat ients

proceeding to stem cel l t ransplantat ion wi th deeper responses do bet ter (357) ; however,

does the bet ter outcome ref lec t on the therapies that brought the pat ient to the bet ter

response? Or does i t just re f lec t the fact that pat ients who

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have chemotherapy-sensi t ive d isease do bet ter? Is bio logy or therapy provid ing the better

outcomes in these ret rospect ive analyses?

Figure 99.8. Melphalan and prednisone (MP) versus combined chemotherapy (CCT) as induction. Results from 6,633 patients from 27 randomized trials. A: Overall survival. B: Response duration. (From Anonymous. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' Collaborative Group. J Clin Oncol 1998;16:3832–3842. By permission of the American Society of Clinical Oncology.)

Melphalan ± Corticosteroids as Induction Therapy Since ear ly reports by Blokhin et a l . (36) and Bergsagel e t a l . (37) , various schedules of

melphalan have been t r ied, including cont inuous da i ly dose, 6 to 10 mg/day for 2 to 3 weeks,

fo l lowed by maintenance therapy of 0 .01 to 0 .03 mg/kg per day; in termi t tent total doses of

0 .25 mg/day g iven for 4 days every 4 to 8 weeks; or 0.15 mg/kg per day for 7 days every 6

weeks (250,358) . Several s tudies suggest that the intermi t tent schedule is super ior to

cont inuous da i ly dos ing (250,358)

Table 99.7 Induction for Patients Who Are Not Candidates for Hematopoietic Stem Cell Transplantation, Recent Publications

Author Regimen Phase N CR (%)

VGPR (%)

PR (%)

OR (%)

PFS (mo)

OS (mo)

Dex 3 127 1 0 41

42

12.2

33

Dex-IFN

3 121 1 0 42

43

15.2

32

MP 3 122 1 0 40

41

21.1

34

Facon (IFM 95-01) (263)

MD 3 118 3 0 67

70

22.9

40

Dex 3 235 — — — — — 25 Rajkumar, 2006 (446)

Thal-dex

3 235 — — — — — 25

Klueppenlberg, 2005 (1089)

LD-Thal-Dex-Z

2 45 0 30

68

98

2 y, 68%

Thal-dex

3 125/2

10

27

15

52

— — Ludwig, 2005 (450)

MP 3 125/2

3 12

20

35

— —

MP 3 3 5 26

34

17.5

30.3

Facon (IFM 99-06) (476)

MPT 3 0 14

37

33

84

29.5

NR

Palumbo, 2006 (436)

MP 3 126 2 10

36

48

~14

NR

MPT 3 129 16

21

40

76

~25

NR

Dimopoulos, 2006 (1090)

MDT 2 50 10

0 62

72

TTP 21.2 mo

28.2

Palumbo, 2006 (443)

MPR 1/2

50 10

60

70

— —

Offidani, 2006 (453)

ThaDD

2 50 34

24

30

88

3-y EFS 57% 16 mo

3 y, 74% 16 mo

Mateos, 2006 (459)

V-MP

2 60 32

11

45

88

EFS 83%

EFS 90%

Hussein, 2006 (454)

T-DVd

2 53 36

13

34

83

28- NR at 50 mo

CR, complete response; Dex, dexamethasone; EFS, event-free survival; IFN, interferon; LD-Thal-Dex-Z, low-dose thalidomide, dexamethasone, and zolendronic acid; MD, melphalan, dexamethasone; MDT, MD and thalidomide; mo, months; MP, melphalan, prednisone; MPR, MP and lenalidomide; N, number of patients; NR, not reached; OR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; T-DVd, thalidomide, pegylated doxorubicin, vincristine, and dexamethasone; thal, thalidomide; ThaDD, thalidomide, pegylated doxorubicin, and dexamethasone; TTP, time to progression; VGPR, very good partial response; VMP, MP and bortezomib; y, year.

The combinat ion of melphalan and prednisone (Tables 99.5,99.6,99.7) has been s tudied

extens ive ly (238,248) . Response rates are 40 to 60%, and ant ic ipated median surviva ls are

18 to 42 months

(225,233,238,248,250,253,271,277,278,354,359,360,361,362,363,364,365,366,367,368,369,

370,371,372,373,374) . Because of the var iable gast ro intes t ina l t rac t absorpt ion of

melphalan, in t ravenous reg imens of 15 to 25 mg/m 2 every 4 weeks along wi th ora l

prednisone or dexamethasone have been t r ied and resul ted in response rates of 50 to 82%

(374,375) .

Table 99.8 Induction Regimens for Hematopoietic Stem Cell Transplantation– Eligible Patients

Reference Regimen Phase N CR (%)

VGPR (%)

PR (%)

OR (%)

Rajkumar, 2003 (307)

Thal 2 29 0 0 34 34

Rajkumar, 2001 (306)

Thal 2 16 0 0 37 37

Weber, 2003 (308)

Thal 2 28 0 0 36 36

Dex 3 104 0 0 41 41 Rajkumar, 2006 (441)

Thal-Dex 3 99 4 0 59 63

Rajkumar, 2002 (445)

Thal-Dex 2 50 0 0 64 64

Weber 2003 (308) Thal-Dex 2 40 16 0 56 72

Sidra, 2006 (668) CDT 2 15 0 27 60 87

Rajkumar 2005 (439)

Rev-Dex 2 34 6 32 53 91

Niesvizky, 2006 (465)

BiRD 2 40 25 18 53 95

Jagannath, 2005 Bortez 2 32 3 9 28 40

(324,1091) Bortez +/- dex

2 32 6 19 63 88

Anderson, 2006 (457)

Bortez 2 60 10 0 28 38

Harousseau, 2005 (458)

Bortez-Dex

2 20 0 47 67

Wang, 2005 (462) VTD 2 36 19 0 73 92

Hussain, 2002 (405)

DVD 2 33 12 0 55 67

VAd 3 95 0 0 41 41 Rifkin, 2006 (407)

DVd 3 97 3 0 41 44

VAD 3 127 13 0 49 62 Dimopoulos, 2003 (406)

DVD 3 132 13 0 48 61

VAD 3 406/3 3 0 60 63 Goldschmidt, 2005 (448)

TAD 3 406/2 7 0 73 80

Hassoun, 2006 (455)

AD + TD 2 45 16 20 49 85

Zervas, 2004 (452)

T-DVD 2 39 10 0 64 74

Oakavee, 2005 (460)

PAD 2 21 24 0 71 95

Popat, 2005 (461) LD-PAD 2 19 11 28 50 89

Badros, 2005 (463)

VDT-PACE

1/2 11 9 9 92 100

TT1 2 231 12 0 51 63 Barlogie, 2006 (1092)

TT2 no thal

3 323 10 0 30 40

Barlogie, 2006 (594)

TT2 +thal

3 345 19 0 41 60

See Table 99.7 for abbreviations.

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Not unt i l the report by McElwain and Powles (237) on the successfu l use of high-dose

melphalan (140 mg/m 2 int ravenously) had dose intens i ty been studied in myeloma. In

previously unt reated pat ients , Selby et al . (243) conf i rmed a 78% response rate, inc lud ing

27% of pat ients whose M component was no longer v is ible by prote in elect rophores is . Th is

dose in tensi ty wi thout s tem cel l salvage was assoc ia ted wi th pro longed, severe

thrombocytopenia and leukopenia ( las t ing a median of 24 and 28 days, respect ive ly) .

Treatment- re lated mortal i ty was 19%. The benef i t o f melphalan dose in tens i f icat ion was

conf i rmed by others who used at tenuated doses (50 to 70 mg/m 2 ) and repor ted response

rates of 50 to 85% (376,377,378) . These dose schedules are assoc iated wi th 8 and 6 days

of severe neutropenia and thrombocytopenia, respect ive ly (377). Doses of 25 to 30 mg/m 2

wi l l e f fec t responses in ~35 to 40% of re lapsed, re f rac tory pat ients (379,380) .

Cyclophosphamide ± Corticosteroids as Induction The rapy Since the or ig ina l repor t by Korst e t a l . (39) of the ut i l i ty o f cyclophosphamide in myeloma

pat ients , severa l s ingle-agent induct ion reg imens have been s tud ied. Despite documented

equiva lency for low-dose oral reg imens of cyc lophosphamide and melphalan (252),

induct ion therapies of melphalan and prednisone tend to be preferred over those of

cyc lophosphamide and prednisone. Most commonly, cyclophosphamide has been used in

mult idrug combinat ions for induct ion, for therapy in re lapse, and for s tem ce l l mobi l izat ion

ra ther than as a s ing le agent for induct ion, as has melphalan. For newly d iagnosed

myeloma, ora l da i ly dos ing of cyc lophosphamide (150 mg/day) (252,381,382) or in t ravenous

doses of 600 mg/m 2 every 3 weeks (253) , wi th or wi thout prednisone, has resul ted in a

response rate of ~25% and median surviva l o f 24 months.

Multidrug Combination Chemotherapy without Anthracy cline for

Induction

The 1970s and 1980s were a tes t ing ground for var ious combinat ions of alkylators ,

cor t icosteroids , and doxorubic in . Melphalan/cyclophosphamide/prednisone (270) ,

carmust ine/ cyclophosphamide/prednisone (359,60) ,

melphalan/cyc lophosphamide/armust ine/prednisone (MCBP) (270,353) , and

vincr is t ine/melphalan/cyc lophosphamide/prednisone (VMCP) (270) resul ted in response

rates of 47, 37 to 50, 49 to 68, and 62%, respect ive ly. Median survivals with these reg imens

were 25 to 36 months (270,353,359,360) . Lee and Case (274) int roduced the f ive-drug

reg imen of v incr is t ine/carmust ine/melphalan/cyc lophosphamide/prednisone (VBMCP or the

M-2 reg imen), which inc luded the same four drugs as MCBP p lus v incr is t ine; dose

in tensi t ies, however, were d i f ferent in these two reg imens. Response rate for VBMCP was

~85% in previous ly unt reated pat ients , wi th a median surviva l o f 38 months (274,383) . The

success of the VBMCP regimen supported the value of v incr ist ine. However, the MRC IV

t r ia l , which randomized 530 previous ly unt reated pat ients wi th myeloma to melphalan and

prednisone versus melphalan/vincr is t ine/prednisone, revealed no d i f ference in e i ther

response rate or overal l surviva l between the two arms (278). VMCP has not produced any

response or surviva l advantage over melphalan and prednisone (371,384). F ina l ly, the

MOCCA regimen, which is essent ial ly VBMCP wi th CCNU replac ing BCNU, resu l ts in

response rates s imi lar to those for VBMCP (75%), but again no surviva l benef i t in

comparison to melphalan and prednisone (363)

Al though subsequent randomized t r ia ls have substantia ted the superior response rates of

VBMCP over s tandard melphalan and prednisone (Table 99.6) , they have not demonstrated

super ior

P.2389

surviva l (277,364,373,385) . In fac t , the meta-analys is per formed by the Myeloma Tr ial is ts '

Col laborat ive Group (233) , invo lv ing 6,633 pat ients in 27 randomized t r ia ls , revealed a

super ior response rate (60.2 vs . 53.2%, p < .000001, two- ta i led) but no surviva l benef i t for

combinat ion chemotherapy over standard melphalan and prednisone (F ig . 99.8) . A pr ior

meta-analysis o f 18 publ ished t r ia ls (3 ,814 pat ients) a lso demonstrated no benef i t for

combinat ion chemotherapy in terms of survival . There might be a survival advantage in the

subgroup of pat ients wi th more aggress ive d isease (355) , but th is was not substant iated in

the larger meta-analys is (233).

Combination Chemotherapy with Anthracycline for Ind uction The use of a lkylator /doxorubic in-based combinat ion chemotherapy was s t imulated by a

report on the benef i ts o f a combinat ion of doxorubic in and BCNU in pat ients who had

become res is tant to melphalan (386) . Regimens such as MAP

(melphalan/doxorubic in/prednisone), CAP (cyclophosphamide/doxorubic in /prednisone),

VCAP (vincr ist ine and CAP), and VBAP (vincr is t ine/BCNU/ doxorubic in /prednisone) were

t r ied; by SW OG response cr i ter ia , objec t ive response rates were 41, 46, 64, and 61%,

respect ive ly (270,387) . Median surviva l ranged from 30 to 32 months; subsequent analys is

demonstrated a super ior median surviva l for the VBAP arm of 37 months (388).

Enthus iasm for a l ternat ing VMCP and VBAP (or VCAP) was generated by the SW OG study

of 237 pat ients randomized to melphalan and prednisone or the above regimens (Table

99.9) (368,369). Response rates were super ior in the a l ternat ing combinat ion chemotherapy

arms compared to the melphalan arm. Survival was a lso super ior in the combinat ion

chemotherapy arms (43 vs . 23 months for melphalan and prednisone, p = .004) (387).

However, a subsequent analys is wi th longer fo l low-up showed less separat ion of the

surviva l curves (median surviva l , 25 vs . 36 months) (388) . The survival benef i ts o f th is

in i t ia l study were not reproduc ib le by others (271,365,366,370,372,389,390) .

The Vth MRC myelomatos is t r ia l randomized pat ients to ABCM (VBAP/VMCP wi thout the

v incr is t ine or prednisone) or melphalan as a s ing le agent on the basis o f f ind ings emanat ing

f rom the IV MRC t r ia l , which demonstrated a lack of benef i t a t t r ibutable to the addit ion of

v incr is t ine. Median surviva l in the ABCM group was super ior to that o f the melphalan-only

arm (32 vs . 24 months, p = .0003) (251) . W hen corrected for adverse prognost ic fac tors

such as e levated β2 -M va lues, low hemoglobin va lues, renal insuff ic iency, performance

s ta tus, and s tage, the s ign i f icance of the survival d i f ference was p = .003 (280) .

Table 99.9 Risk of IMiD-Associated Thromboembolism

Reference N Regimen Prophylaxis TE (%)

134 TT2 No 14

87 TT2 + Thal No 34

35 TT2 + Thal LD coumadin 31

62 TT2 Enox 15

68 TT2 + Thal Enox 15

Zangari 2004 (437)

19 DVd-T No 58

26 DVd-T Late ASA 15 Baz, 2005 (438)

58 DVd-T ASA 19

Rajkumar 2005 (439)

34 Len-Dex ASA 0

65 MPT No 17 Palumbo, 2006 (436)

64 MPT Enox 3.1

Palumbo 2006 (443) 50 MPR ASA 2

102 Thal-Dex No 17 Rajkumar 2006 (441)

102 Dex No 3

132 Len-Dex No 18 Rajkumar 2006 (440)

134 Len-LD-Dex No 4

87 Len-Dex +Epo

No 23

83 Len-Dex No 5

67 Dex +Epo No 7

Knight 2006 (442)

103 Dex No 1

Dex, dexamethasone; Enox, enoxoparin 40 mg/d; Epo, erythropoietin; LD, low dose, TE, thromboembolism; Thal, thalidomide; TT2, total therapy 2, a complex anthracylcine containing multiagent chemotherapy regimen.

Combination Chemotherapy with Doxorubicin and Dose- Intensive

Corticosteroids for Induction The next leve l o f combinat ion chemotherapy includes programs that conta in anthracyc l ines

and h igh-dose cor t icostero ids . VAD-l ike regimens are commonly used as induct ion therapy

before s tem cel l col lec t ion and t ransplantat ion. These reg imens inc lude VAP (247) , VAD

(391), VAMP (vincr is t ine/doxorubic in /methylpredniso lone) (260) , and C-VAMP

(cyc lophosphamide/vincr is t ine/doxorubic in /methylprednisolone) (260) , al l o f which had

been t r ied wi th sa lutary e f fec t in re lapsed d isease. Subsequently, several o f these regimens

were appl ied in previously unt reated pat ients , and response rates were 50 to 84%

(392,393,394,395,396,397,398,399,400,401) . The complete response rate of C-VAMP was

h igher than that o f VAMP alone, but surviva l was not di f ferent (395). Severa l other

var ia t ions have been repor ted in which a l ternat ive anthracycl ines or cort icostero ids were

used (367) . Median surviva l for pat ients t reated in i t ia l ly wi th VAD is about 36 months (402) .

The response rate of s ing le-agent h igh-dose dexamethasone is about 43% (257) , which is

on ly 15% lower than for VAD. This has prompted myeloma experts to use s ing le-agent

dexamethasone in l ieu of VAD for induct ion in those pat ients dest ined for s tem cel l

co l lec t ion. Ora l , noncont inuous in fus ional therapy has the advantage of avo idance of

immediate placement of a long- term centra l venous catheter (257). Th is st ra tegy has been

used successful ly, resu l t ing in adequate col lec t ions of per iphera l b lood stem cel ls wi thout

any apparent adverse ef fec ts on complete remission rates or progression- free survival in

several s ing le-arm s tud ies (403,404) . W ith the advent o f other ora l therapies, s ing le-agent

dexamethasone has been los ing favor as induct ion.

In another a t tempt to avo id the cont inuous in fus ion requi red to admin is ter VAD, several

invest igators have explored the use of the pegylated l iposomal doxorubic in . The

combinat ion of v incr is t ine, pegylated l iposomal doxorubic in , and dexamethasone (DVD) has

been studied. Response rates f rom s ingle ins t i tu t ions suggested that DVD was more

convenient and less toxic than VAD (405) . Two randomized t r ia ls comparing DVD to VAD—

using e i ther s tandard h igh-dose dexamethasone (406) or a t tenuated doses of

dexamethasone (407)—have been completed. Results were comparable between arms wi th

regard to response rates, 42% in the at tenuated-dexamethasone t r ia l (407) and 61% in the

s tandard-dose dexamethasone t r ia l (406). There was more alopecia in the non–l iposomal

doxorubic in arms and more pa lmar-p lantar erythrodysesthesia in the l iposomal doxorubic in

arms.

In a randomized t r ia l o f 151 pat ients compar ing the NOP reg imen (mi toxantrone, v incr ist ine,

and h igh-dose prednisone) to melphalan and prednisone, response rates were equiva lent

(~60%), but overal l surviva l was in fer ior in the NOP arm (14 vs . 31 months, p = .02) (367) .

Response rates of 80% have also been achieved using the CAD

(cyc lophosphamide/doxorubic in /dexamethasone) reg imen (408) . The addit ion of e topos ide

to C-VAD appears to contr ibute only toxic i ty (409) .

Combination Chemotherapy with Interferon for Induct ion In terferon-α ( INF) and dexamethasone have been combined as an induct ion reg imen in

pat ients wi th newly d iagnosed myeloma and a low tumor mass. A ret rospect ive comparison

showed that the response rate of th is regimen (57%) was s imi lar to the response rate (48%)

previously observed wi th dexamethasone alone (410) . A recent randomized t r ia l comparing

MP, melphalan/dexamethasone, dexamethasone, and dexamethasone/ IFN d id not

demonstrate any added benef i t by incorporat ing IFN into the t reatment reg imen (263) . Ahre

et al . (411) randomized 55 pat ients to melphalan and prednisone

P.2390

or in ter feron (3 to 6 MU dai ly) ; response rates in the melphalan and prednisone arm were

s ign i f icant ly h igher than in the in ter feron arm (44 vs . 14%, p < .001) .

In terferon has been combined wi th melphalan and prednisone

(412,413,414,415,416,417,418,419,420) ; VMCP (414,421,422,423); VMCP/VBAP (424) ,

prednisone, cyc lophosphamide, doxorubic in (Adr iamycin) , and carmust ine (BCNU) (PCAB)

(425,426) ; VAD (427) ; VBMCP (428) ; VBAP (429) ; and cyc lophosphamide (430) as par t o f

an induct ion reg imen. Resul ts have been mixed. Two meta-analyses have been per formed in

an at tempt to reconc i le these conf l ic t ing resu l ts (431,432) . The f i rs t , repor ted in 2000 by

Ludwig and Fr i tz (431) , used publ ished data and inc luded 17 induct ion t r ia ls

(412,413,414,415,416,417,418,419,420,422,423,424,425,426,427,429,430) wi th 2 ,333

evaluable pat ients ; the second, repor ted by The Myeloma Tr ia l is ts ' Col laborat ive Group in

2001 (432) , used pr imary data f rom 12 induct ion t r ia ls

(412,413,414,415,416,417,418,419,420,422,424,425,426,428,429,430,433) invo lv ing 2,469

pat ients . Overa l l , the resu l ts were s imi lar . In the f i rs t meta-analys is , the benef i ts

at t r ibutable to the addi t ion of in terferon to the induct ion reg imen included a 6.6% higher

response rate (p < .002) and a 4.8- and 3.1-month prolongat ion of relapse- f ree (p < .01)

and overal l survival (p < .01) , respect ive ly (431) . In the second meta-analys is , pat ients

receiv ing in terferon had a s l ight ly bet ter response rate (57.5 vs . 53.1%, p = .01) and

progress ion- f ree survival (30 vs. 25% at 3 years , p < .0003) , wi th a super ior median t ime to

progress ion of about 6 months. The surviva l advantage of 2 months, however, was not

s ign i f icant (p = .1) (432). F igure 99.9 demonstrates progress ion-f ree surviva l and overa l l

surviva l in pat ients receiv ing IFN as ei ther induct ion or maintenance versus those who

received none (432).

These meta-analyses suggest that incorporat ion of in terferon in to induct ion provides a

modest pro longat ion of response and possibly o f surviva l . The quest ion is whether these

s ign i f icant d i f ferences are c l in ica l ly re levant . W islo f f e t a l . (434) eva luated the qual i ty o f l i fe

o f 583 pat ients randomized to ei ther melphalan and prednisone or melphalan, prednisone,

and in ter feron as induct ion. Dur ing the f i rs t year o f t reatment wi th in ter feron, the pat ients

reported s igni f icant ly more fever, ch i l ls , dry sk in, fa t igue, pa in , nausea/vomi t ing, and

appet i te loss than the control pat ients . After the f i rs t year , however, the on ly symptom

reported more of ten was d izziness. Al though pat ients receiv ing inter feron had a 5- to 6-

month pro longat ion of the response and p lateau phase, there was no la te qual i ty-of - l i fe

benef i t observed to compensate for the ear ly impai rment. The authors quest ioned the

c l in ical va lue of the p lateau-phase prolongat ion and repor ted that only 60% of pat ients

cont inued to rece ive inter feron after 24 months, suggest ing that thei r data might

underest imate the potent ia l toxic i ty of the drug. A cost -ef fec t iveness est imat ion for

induct ion was also per formed. The authors conc luded that in ter feron admin is t ra t ion and

moni tor ing expenses amounted to $US 41,319.28 to save a year o f l i fe of myeloma pat ients ,

assuming a dosage of 12.1 MU/week (431).

A s tudy on pat ient preference also deserves mention. Ludwig et a l . (435) surveyed cancer

pat ients about “acceptable” toxic i ty o f an unident i f ied drug, which had the toxic i ty prof i le o f

in ter feron, re la t ive to i ts hypothet ical benef i t . About 50% of surveyed pat ients accepted the

toxic i ty o f an unident i f ied drug i f remiss ion or surviva l or both would be improved by at least

6 months. Of those pat ients who re jec ted the 6-month hypothet ica l benef i t , 25 to 50% were

wi l l ing to accept the toxic i t ies i f the benef i ts were ≥12 months.

Novel Therapies for Induction (Tables 99.7 and 99.8)

Complications Specific to Novel Therapies These new drugs can cause the compl icat ions seen wi th o ther agents , such as fa t igue,

myelosuppress ion, fevers , in fec t ions, and gastro in tes t ina l symptoms; however, there are

several s ide ef fec ts par t icu lar to these new agents—the most important o f which are

thrombosis and periphera l neuropathy.

Figure 99.9. Interferon (IFN) chemotherapy as induction or maintenance therapy influences progression-free and overall survival curves from the meta-analysis by the Myeloma Trialists' Collaborative Group. Results from 24 randomized trials and 4,012 patients. Interferon curves include patients who received interferon as part of induction or of maintenance program. A: Progression-free survival after 23 months with interferon and after 17 months without. B: Overall median survival after 40 months with interferon and after 36 months without. (From Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 2001;113:1020–1034. By permission of Blackwell Science.)

Thrombosis

Thrombosis is an important compl icat ion in pat ients undergoing treatment wi th IMiDs. As

s ing le agents , there does not appear to be any he ightened r isk ; however, concomi tant

chemotherapy (436)—especial ly anthracycl ines (437,438)—high-dose cort icosteroids

(439,440,441) , and erythropoiet in (442) appear to increase the r isk o f thrombosis to as h igh

as 58% (Table 99.9) . Prophylact ic low-molecular-weight hepar in (e .g . , enoxapar in 40 mg

dai ly) (436,437)or fu l l ant icoagulat ion wi th Coumadin abrogates that r isk. Low-dose

Coumadin is not protect ive. Dai ly asp i r in a lso appears to be protect ive (441,442,443) .

Peripheral Neuropathy

Thal idomide and bor tezomib are known to cause per iphera l neuropathy in more than a th i rd

o f pat ients . Pat ients treated wi th lenal idomide are a lso at r isk for neuropathy, but because

most s tudy pat ients receiv ing lenal idomide have been previous ly t reated, the raw rates are

unknown. The neuropathy associa ted wi th thal idomide is an i r revers ib le smal l - f iber

per iphera l neuropathy that appears to be both t ime- and dose-dependent.

The peripheral neuropathy assoc iated wi th bor tezomib has been bet ter character ized (444) .

I t comes in a l l forms: sensory, motor , and pa inful . In a recent review of 256 pat ients treated

in

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two Phase I I s tud ies, >80% of pat ients had basel ine peripheral neuropathy. Treatment-

emergent neuropathy was repor ted in 35% of pat ients . Grade 1 or 2 , 3 , and 4 neuropathy

occurred in 22, 13, and 0.4% of pat ients, respect ive ly. Grade 3 neuropathy was more l ikely

to occur in pat ients wi th a basel ine neuropathy. Seventy-one percent o f pat ients wi th

neuropathy ≥grade 3 and/or requi r ing discont inuat ion exper ienced resolut ion to basel ine or

improvement.

Thalidomide Combinations for Induction Therapy As a s ingle agent , response rates occur in about one th i rd of pat ients (306,307,308) . The

combinat ion of tha l idomide and dexamethasone resul ts in response rates of 63 to 72%

(308,445,446) . The tha l idomide/dexamethasone combinat ion has been compared to

dexamethasone a lone in two separate randomized t r ia ls (446). In the smal ler o f the two

t r ia ls (n = 207) , the overa l l response rate of tha l idomide/dexamethasone was s ign i f icant ly

h igher than that o f dexamethasone alone (63 vs. 41%); however, toxic i ty was greater using

the combinat ion, wi th grade 4–5 toxic i ty being 45 vs . 21%, p < .001 (441) . In the second,

larger t r ia l (n = 470 pat ients) , t ime to progress ion was signi f icant ly better in the

combinat ion arm (17.4 months, 95% CI : 8 .1 months—not reached vs . 6 .4 months, 95% CI :

5 .6 to 7.4 months) . Grade 3–4 adverse events were higher us ing the combinat ion therapy:

deep ve in thrombosis (DVT)/pu lmonary embol ism (PE) 15.4 versus 4.3%; cerebral ischemia

3.4 versus 1.3%; myocard ial in farc t ion 4.7 versus 1.3%, per iphera l neuropathy 3.8 versus

0.4% (446) . Th is combinat ion is commonly used as induct ion in the months before s tem cel l

co l lec t ion because of i ts h igh response rate and ease of admin is t rat ion, using only oral

medicat ions. The r isk o f thrombosis and other s ide ef fects make the combinat ion less

convenient than original ly thought . L imited use of thal idomide pre–stem cel l mobi l izat ion

does not impai r stem ce l l co l lect ion or engraf tment , al though pre l iminary data suggest that

there may be a de lay in p la te le t engraf tment wi th longer cont inuous use (447) .

Goldschmidt e t a l . (448) have repor ted prel iminary resul ts f rom the induct ion por t ion of the

HOVON 50/GMMG-HD3-Tr ia l , which is a Phase I I I s tudy of the ef fec t o f tha l idomide fo l lowed

by t ransplant in myeloma pat ients up to 65 years of age. Pat ients were randomized to e i ther

3 cycles of TAD ( thal idomide, 200 mg for HOVON/400 mg for GMMG; Adr iamyc in 9 mg/m 2 ,

days 1 to 4 ; dexamethasone 40 mg, days 1 to 4 , 9 to 12, 17 to 21) or VAD. The f i rs t group

of 406 pat ients (o f 1 ,050 inc luded) are evaluable for the compar ison of VAD versus TAD. A

t rend for a h igher toxic i ty was observed in the TAD arm compared wi th the VAD arm

(dropouts : 15 vs . 8%, p = .10) , though the overal l (80 vs . 63%, p < .001) and complete

response (7 vs . 3%, p = .1) rates were higher wi th TAD. However, prel iminar i ly there is no

d i f ference in overa l l or complete response af ter hematopoiet ic s tem ce l l t ransplantat ion

(HSCT). Cavo et a l . (449) per formed case match ing to compare pat ients treated wi th

tha l idomide/dexamethasone (TD) or VAD. L ike the HOVON/GMMG tr ia l , h igher induct ion

response rates were seen (76 vs . 52%). Toxic i ty prof i les were di f ferent , wi th more

myelosuppress ion in the VAD-t reated pat ients, but DVT was more common in the TD

pat ients . The number of pat ients who died and who did not make i t to t ransplant were also

comparable. Simi lar numbers of s tem ce l ls were co l lec ted in the TD arm compared to the

VAD arm, 7 .85 versus 10.5 ×106 CD34/kg (p = .4). Th is compar ison is confounded by the

fac ts that this was only a case-match compar ison ( ra ther than a randomizat ion) and that the

TD group received tha l idomide not only during induct ion but a lso dur ing transplantat ion and

post t ransplantat ion.

Though thal idomide/dexamethasone resul ts in h igher response rates compared to melphalan

and prednisone (450) , i t cannot be recommended as induct ion for e lder ly pat ients who are

not dest ined for periphera l blood s tem cel l col lec t ion because of the high toxic i ty ra tes .

Ludwig et al . randomized 350 elder ly pat ients to e i ther thal idomide/dexamethasone or

melphalan and prednisone. Pre l iminary data demonstrate a higher response rate using TD

(52 vs . 35%, p < .05) , but h igher ra tes of neuropathy (25 vs . 8%), psycholog ical toxic i ty (20

vs . 8%), skin toxic i ty (12 vs . 3%), and thrombotic events (8 vs . 3%). The only toxic i ty more

commonly seen in the MP arm was myelosuppress ion.

In contrast , combin ing melphalan, prednisone, and tha l idomide is qui te promis ing in e lder ly

pat ients who are not HSCT candidates, and, based on the resu l ts of two randomized tr ia ls

(436,451) , many would consider this program to be the new s tandard. Palumbo et al .

randomized pat ients to ei ther standard-dose oral melphalan and prednisone (MP) for 6

months or to melphalan and prednisone for 6 months wi th concurrent tha l idomide (MPT) that

is cont inued indef ini te ly (436). Overa l l response rates were s ign i f icant ly h igher wi th the

MPT than the MP (76.0 vs . 47.6%), as were the near-complete or complete response rates

(27.9 vs . 7 .2%) and the 2-year event- free surviva l ra tes (54 vs . 27%, p = .0006) . There was

a t rend toward improved 3-year overa l l surviva l in favor o f MPT (80 vs . 64%). Two cr i t ic isms

of this t r ia l are that 6 months of MP is shor t o f s tandard by about 6 months and that this

t r ia l addresses a maintenance quest ion as much as an induct ion quest ion.

The IFM 99-06 t r ia l bo ls ters the resu l ts o f the Palumbo t r ia l , though i t has not yet been

publ ished in pr in ted form (451) . In the IFM 99-06 s tudy, 436 pat ients were randomized to 1

year o f e i ther MPT or MP or to two sequential min i -autologous per iphera l b lood s tem cel l

t ransplants (MEL100). Higher response rates and longer progression- f ree surviva l (PFS)

were seen for the MPT compared to e i ther the MP or MEL100 groups, wi th respect ive PFS

t imes of 29.5, 17.2, and 19.0 months. W ith a median fo l low-up of 32 months, there is a

s ign i f icant surviva l advantage for the pat ients on the MPT arm, wi th respect ive overa l l

surviva l t imes not reached at 56, 30.3, and 38.6 months (451) . So far , no data have been

provided regard ing the percent o f pat ients in the nonthal idomide arm who received

tha l idomide regimens as salvage therapy.

Though both MPT-versus-MP t r ia ls demonstrated h igher response and surviva l endpoints for

MPT, they a lso had a cons is tent ly h igher toxic i ty prof i le for the three-drug combinat ion

compared to the two-drug combinat ion. In the Palumbo s tudy (436) , the respect ive

percentage of pat ients having grade 3–4 adverse events were as fo l lows: a t least 1 event ,

48 versus 25% (p = .0002) ; thrombosis /embol ism, 12 versus 2%; periphera l neuropathy, 10

versus 1%; in fec t ions, 10 versus 2%; and gastro in tes t ina l events , 6 versus 1%. There was

no s ign i f icant d i f ference in the toxic death ra te between the two arms (8 vs . 5%). The

authors poin t out that the f i rs t 65 pat ients rece ived no DVT prophylaxis , whi le the f inal 64

received enoxapar in ; 13 thromboembol ic events occurred in the f i rst group, but only 2

occurred in second group, and that was after d iscont inu ing the enoxaparin .

Dimopoulos et al . have explored a d i f ferent adminis t ra t ion schedule of tha l idomide a long

wi th melphalan. They treated 50 pat ients 75 years or o lder wi th melphalan, dexamethasone,

and thal idomide. A cycle was 5 weeks in durat ion, and the respect ive doses and schedules

of the three drugs were melphalan 8 mg/m2 days 1 to 4 ; dexamethasone 12 mg/m 2 days 1 to

4 and 14 to 18; and thal idomide 300 mg days 1 to 4 and 14 to 18. A planned course of

t reatment was three cyc les as above, but i f pat ients responded, the next n ine cyc les were

adminis tered wi thout the day 14–18 tha l idomide and dexamethasone. Us ing th is program,

62% of pat ients had a par t ia l response to therapy and 10% had a complete response.

Median t ime to progression was 21.2 months, deep venous thrombosis and peripheral

neuropathy each occurred in 9% of pat ients, and overa l l surviva l was 25 months.

Palumbo et a l . have t reated 50 e lder ly pat ients who were not deemed candidates for HSCT

wi th melphalan, prednisone, and lenal idomide (443) . Pat ients received aspi r in and

c iprof loxac in as prophylaxis . Pre l iminary reports demonstrated an overal l response rate of

70%, inc luding a 10% complete response rate. Th i r ty- f ive percent o f pat ients had grade 3–4

adverse events, includ ing one thromboembol ic event and two dermatologic events . The

major i ty o f adverse events cons is ted of myelosuppress ion.

P.2392

Zervas et a l . (452) treated 39 pat ients wi th thal idomide, v incr is t ine, pegyla ted l iposomal

doxorubic in, and dexamethasone and assessed response after four cyc les . Responses were

seen in 74%, inc luding 10% complete response. Grade 3–4 toxic i t ies included neutropenia

(15%), thrombosis (10%), const ipat ion (10%), rash (5%), and peripheral neuropathy (5%).

Two pat ients suf fered ear ly deaths secondary to in fec t ion. For ty-seven percent of pat ients

went on to s tem cel l co l lec t ion and t ransplantat ion.

Of f idani t reated 50 newly d iagnosed mul t ip le myeloma pat ients >65 years old wi th

tha l idomide (100 mg/day) , dexamethasone (40 mg on days 1 to 4 and 9 to 12), and

pegylated l iposomal doxorubic in (40 mg/m 2 on day 1) every 28 days for a to tal o f f ive to s ix

cyc les . The overa l l response rate was 88% (CR 34%, VGPR/nCR [near complete response]

24%, and PR 30%). Time to progress ion, event- f ree surviva l , and overa l l surviva l pro jec ted

at 3 years were 60, 57, and 74%, respect ive ly. Grade 3–4 infec t ions and thromboembol ic

acc idents were observed in 22 and 14% of pat ients , respect ively (453) .

Hussein et a l . (454) t reated 55 previously unt reated pat ients wi th DVd-T (pegylated

l iposomal doxorubic in, v incr is t ine, decreased-f requency dexamethasone, and tha l idomide)

for a maximum of e ight cyc les , fo l lowed by maintenance wi th maximum tolerated doses of

tha l idomide p lus a l ternate-day ora l prednisone. Though response rates were high (overa l l

93%, wi th CR of 36%), there was substant ial toxic i ty assoc iated wi th the program. Grade 3–

4 toxic i t ies included thromboembol ic events in 25%, per iphera l neuropathy in 22%,

neutropenia in 14%, pneumonia in 12%, palmar plantar erythrodysesthesia in 8%, and

thrombocytopenia in 5%. The median PFS was 28.2 months, and the overal l survival (OS)

was not reached at 50 months. Note that al though the pat ients of Of f idani e t al . (453) were

o lder and received lower doses of tha l idomide and no vincr is t ine, s imi lar response rates and

less toxic i ty were seen.

Hassoun et a l . (455) t reated 45 newly d iagnosed myeloma pat ients wi th doxorubic in and

dexamethasone for 2 or 3 months, fol lowed by tha l idomide and dexamethasone for 2 months

(AD-TD reg imen), wi th prophylact ic ant ibio t ics and dai ly aspi r in (81 mg/day) . Th i r ty-e ight

responded to therapy (84.4%), wi th seven complete responses (15.5%), n ine near-complete

responses (20.0%), and 22 par t ia l responses (48.9%). Pat ients to lerated the t reatment wel l ,

a l though f ive pat ients developed thromboembol ic compl icat ions (11%).

Baz et al . (456) t reated 16 pat ients wi th h igh-r isk , newly d iagnosed myeloma or

re lapsed/ref rac tory d isease wi th arsenic t r ioxide, ascorbic ac id, tha l idomide, and

dexamethasone. Four pat ients ach ieved a par t ia l response, and the PFS was 9.4 months.

Nineteen percent o f pat ients had thromboembol ic events.

Bortezomib as Induction Therapy Thi r ty-e ight to 40% of newly d iagnosed myeloma pat ients respond to s ing le-agent

bor tezomib (324,457) . The addi t ion of dexamethasone resul ts in an overa l l response rate of

67 to 88% (324,458) . A number o f combinat ions have been explored for induct ion.

Mateos et a l . (459) reported on thei r Phase I / I I resu l ts wi th VMP, bor tezomib, melphalan,

and prednisone, in 60 e lder ly pat ients not deemed to be HSCT candidates. Pat ients were

t reated wi th four 6-week cyc les fo l lowed by f ive 5-week cycles . The f ina l dose schedule was

bor tezomib (1 .3 mg/m 2 on days 1, 4 , 8 , 11, 22, 25, 29, and 32), melphalan (9 mg/m 2 on days

1 to 4) , and prednisone (60 mg/m 2 da i ly on days 1 to 4) . The authors exc luded the three

ear ly deaths and four o ther ear ly wi thdrawals f rom the i r response analys is and report the

fo l lowing response rates: overal l response rate 88% (32% CR, 11% VGPR, and 45% PR).

The 16-month event-f ree survival and overa l l surviva l were 83 and 90%, respect ive ly. The

most common adverse events were myelosuppression (>90%), infec t ion (75%), as thenia

(63%), gast ro in tes t inal toxic i ty (>55%), and per iphera l neuropathy (55%). The most common

grade 3–4 toxic i t ies were thrombocytopenia (51%)and neutropenia (43%), peripheral

neuropathy (17%), and diarrhea (16%). Pat ients who were >75 years of age were more

prone to the more ser ious nonhematologic s ide effects (459) .

Oakervee et a l . (460) have t reated 21 previous ly unt reated pat ients wi th PAD (bor tezomib,

doxorubic in, and dexamethasone). Pat ients rece ived four 21-day cycles of bor tezomib 1.3

mg/m 2 on days 1,4, 8, and 11; dexamethasone 40 mg on days 1 to 4 and 15 to 18; and

doxorubic in a t escalat ing doses of 4 .5 or 9 mg/m 2 /day as a cont inuous in t ravenous in fusion

over 4 days. Ninety- f ive percent o f pat ients ach ieved at least a par t ia l response, inc lud ing a

CR in 24% of pat ients. Fi f teen grade 3–4 adverse events occurred in 12 pat ients , wi th the

most common serious adverse events (SAE) includ ing in fec t ions (n = 7) and shing les (n = 3).

Grade 3–4 peripheral neuropathy, postura l hypotension, nausea and vomit ing, at r ia l

f ib r i l la t ion, and hyperglycemia each occurred in one pat ient . Al l but one pat ient proceeded

to stem cel l co l lec t ion and t ransplantat ion. Al though no cardiac toxic i ty was observed,

cardiac biomarker screening for subt le toxic i t ies were not per formed.

Popat e t a l . (461) t reated 19 pat ients wi th previous ly unt reated myeloma wi th four cycles of

LD-PAD (bor tezomib 1 mg/m 2 on days 1, 4 , 8 , and 11; doxorubic in 9 mg/m 2 by in t ravenous

in fus ion on days 1–4, and dexamethasone 40 mg on days 1 to 4 , 9 to 12, and 17 to 20 for

cyc le 1—subsequent courses on ly days 1 to 4) . Th is program d i f fers f rom that o f Oakervee

in that the dose of bor tezomib was reduced by about 25%. Eighteen pat ients were evaluable,

wi th an overa l l response rate of 89% (2 CR. 1 nCR, 4 VGPR, 9 PR). Al l pat ients

successful ly mobi l ized s tem cel ls . Toxic i ty in format ion was not provided.

Wang et a l . (462) t reated 36 previous ly unt reated pat ients wi th VTD ( tha l idomide 50 to 200

mg/day; bor tezomib 1.3 to 1 .9 mg/m 2 days 1, 4 , 8, and 11; and dexamethasone 20 mg on

days 1 to 4 , 9 to 12, and 17 to 20) . Al l pat ients received fu l l ant icoagulat ion. Overal l

response rate was 92%, includ ing a 19% CR rate. There did not appear to be any va lue

added wi th bor tezomib doses >1.3 mg/m2 .

In a Phase I / I I t r ia l , Badros et al . (463) combined escalat ing doses of bor tezomib wi th the

DT-PACE reg imen (dexamethasone, thal idomide, c isplat in , doxorubic in , cyc lophosphamide,

and etopos ide) . Four pat ients had no pr ior therapy, and seven had one prior cycle inc lud ing

DT (n = 4) and DT-PACE (n = 3) . Stem cel ls were col lec ted at a median of 13 days (range

12 to 15 days) in to the cyc le , y ie ld ing a median of 20.6 × 106 CD 34+ s tem cel ls /kg ( range

7.8 to 33.3 × 106 ) . A l l 11 pat ients responded, wi th two CR/nCRs. Grade 3–4 hematologic

toxic i ty, including neutropenic fever requi r ing hospi tal izat ion, was common. There were

three DVTs (despi te enoxapar in) , s ign i f icant ep isodes of hypotens ion, including syncope in

two, and two pat ients wi th grade 3 diarrhea.

Lenalidomide as Induction Therapy In previous ly unt reated pat ients wi th ac t ive myeloma, the combinat ion of lenal idomide and

dexamethasone wi th and wi thout c lar i thromycin y ie lds overa l l response rates of 91 to 95%,

wi th complete response/very good response rates of 32 to 38% (439,464). Rajkumar et a l .

(439) t reated 34 pat ients wi th lenal idomide 25 mg oral ly on days 1 to 21 and

dexamethasone 40 mg on days 1 to 4 , 9 to 12, and 17 to 20, both repeated every 28 days.

Aspir in was g iven as DVT prophylaxis . The overal l response rate was 91%, wi th 6%

achieving a complete response and 32% a very good par t ia l response. Grade 3–4

neutropenia occurred in 12% of pat ients . Forty-seven percent o f pat ients exper ienced grade

3 or h igher nonhemato log ic toxic i ty, most commonly fa t igue (15%). Six percent each had

grade 3–4 muscle weakness, anxie ty, pneumoni t is , or rash.

Niesvizky et al . (465) t reated 40 pat ients wi th c lar i thromycin, lenal idomide, and

dexamethasone. The rat ionale for the c lar i thromycin use is that i t a l ters the hepat ic

metabol ism of both drugs, resul t ing in h igher e ffect ive doses. The lenal idomide schedule

was as above, but dexamethasone was adminis tered only once week ly. Clar i thromycin was

g iven in doses of 500 mg twice dai ly. Aspir in was given as DVT prophylaxis . Pre l iminary

resul ts include a 95% response rate, inc lud ing 25% CR and 18% VGPR. For ty-e ight

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percent o f pat ients developed grade 3 or higher adverse events , inc luding 15% wi th

thromboembol ism, two of which were fa tal . Four of the seven thromboembol isms occurred in

pat ients who had d iscont inued aspi r in .

Risk fac tors for thromboembol ism in pat ients rece iv ing IMiDs include dexamethasone

in tensi ty, erythropoiet in , and other concomi tant chemotherapy (440,442)

Hematopoietic Stem Cell Transplantation

Autologous Transplant To overcome res is tance of the myeloma ce l ls to convent ional -dose chemotherapy, McElwain

and Powles (237) pioneered the use of high-dose melphalan to t reat mul t ip le myeloma and

p lasma ce l l leukemia. The t reatment was compl icated by pro longed myelosuppression.

Bar log ie e t a l . (466) subsequent ly used a regimen combining high-dose melphalan wi th

to tal -body i r rad ia t ion supported by auto logous bone marrow t ransplantat ion in mult ip le

myeloma pat ients re frac tory to VAD. Ten years later , At tal e t a l . publ ished the f i rs t

prospect ive randomized contro l led t r ia l demonstrat ing an improved overal l surviva l for

pat ients undergoing high-dose therapy wi th autologous s tem cel l support compared to

convent ional chemotherapy (245) .

Al though high-dose therapy fol lowed by auto logous s tem cel l t ransplantat ion (ASCT) is not

curat ive, i t improves event- f ree and overal l surviva l (Table 99.10) (245,467,468) Three of

the four “negat ive” s tud ies (469,470,471) are largely “ear ly” versus “de layed” t ransplant

t r ia ls , and the fourth “negat ive” study exc luded f rom randomizat ion those pat ients who did

not respond to induct ion therapy (472) . Response rates wi th ASCT are 75% to 90%, and

complete response rates are 20 to 40% (245,467,468,469,470,471,472) . Antedat ing these

randomized control led t r ia ls, his tor ical comparisons a lso showed conf l ic t ing resul ts . For

example, one histor ical compar ison study from Spain suggested that surviva l in good-r isk

pat ients rece iv ing on ly convent ional chemotherapy was s imi lar to that repor ted in se lected

ser ies of pat ients t reated wi th ASCT (473) . In contrast , the Nordic Myeloma Study Group

(474) prospect ive ly eva luated the ef fec t o f ASCT on survival in myeloma pat ients younger

than age 60 years and compared the surviva l ra tes of t ransplanted pat ients wi th those of

h istor ic controls derived f rom previous Nord ic populat ion-based s tud ies of convent ional -

dose chemotherapy. They found that survival was prolonged wi th the high-dose therapy—44

months for convent ional chemotherapy versus >60 months for pat ients t reated wi th ASCT.

Table 99.10 Conventional Chemotherpay (CCT) versus Single Autologous Hematopoietic Stem Cell Transplantation (ASCT); Randomized Trials

CR/VGPR (%) ORR (%) PFS (mo) OS (mo) SCT (%) N CCT ASCT CCT ASCT CCT ASCT CCT ASCT CCT ASC

T

IFM90 (245,475)

200

13

38a

57

81a

18

28a

44

57a

9 74

MRC7 (467)

401

8 44a

46

86a

19.6

31.6a

42

54a

15

75

MAG91 (469)

190

4 6 56

59

18.7

25.3a

47.6

47.8

22

75

MAG90 (470)

185

57

20

58

78

13

39 64

65 78

98

PEETHMA (472)

164

11

30a

83

82

33

42 61

66 18

90

S9321 (471)

516

17

15

90

93

7 y, 14%

7 y, 17%

7 y, 38%

7 y, 38%

34

82

MMSGb (468)

194

6 25a

66

72

16

28a

42

58+a

39

92

HOVON-24c (477)

303

13

28a

86

90

23

24a

50

55 — —

CR/VGPR, complete response or very good partial response; ORR, any response

greater than or equal to a partial response; PFS, progression-free survival; OS, overall survival; SCT, patients known to receive an autologous hematopoietic stem cell transplant. aSignificant. bTransplant arm is two low-dose (melphalan 100 mg/m2) autologous stem cell transplants. cOften included in “double-transplant” tables because both arms received melphalan 70 mg/m2 × 2 without stem cell support as induction therapy.

Figure 99.10. Conventional chemotherapy versus autologous hematopoietic stem cell transplantation, IFM 90 Trial. (With permission, from Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996;335:91–97. Copyright © 1996 Massachusetts Medical Society. All rights reserved.)

As shown in Table 99.10, the Intergroupe Français du Myélome (245) publ ished the f i rs t

randomized tr ia l comparing high-dose chemotherapy fol lowed by auto logous bone marrow

t ransplantat ion wi th convent ional chemotherapy (F ig. 99.10). Two hundred pat ients wi th

previously unt reated mult ip le myeloma were randomized to receive ASCT or combinat ion

chemotherapy (CCT). The 5-year event- f ree surviva l (28 vs . 10%) and overa l l surviva l ra tes

(52 vs . 12%) were h igher in the t ransplantat ion group. An updated analys is wi th a median

fo l low-up of 7 years conf i rmed that h igh-dose chemotherapy improves event- f ree surviva l

(median, 28 vs . 18 months) as wel l as overa l l surviva l (median, 57 vs . 44 months) (475).

The Medica l Research Counc i l VI I t r ia l was the second publ ished s tudy addressing the

quest ion of CCT versus ASCT (467) . Th is tr ia l inc luded 401 randomized pat ients . The t r ia l

found that the complete response rates (8 vs . 44%), the median event- f ree surviva l (19 vs .

31 months) , and the overa l l surviva l (42 vs. 54 months)

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a l l s igni f icant ly favored the ASCT arm, even though only 75% of the pat ients ass igned to

the transplant group actua l ly rece ived i t and 15% of pat ients in CCT arm received salvage

ASCT.

Three t r ia ls addressed the “ear ly” versus “de layed” t ransplant s t ra tegy (469,470,471) . The

f i rst was the MAG90 t r ia l , in which Fermand et al . demonstrated that among the 185

pat ients randomized to ei ther ear ly or late ASCT, the overal l survival in both groups was 64

months, and the percentages of the respect ive groups actua l ly rece iv ing ASCT were 98 and

78%, respect ive ly (470) . Th is t r ia l was important because i t gave pat ients and physic ians

l icense to opt for t ransplants ei ther up- f ront or on a de layed bas is . Most chose to t ransplant

ear ly, because the t ime wi thout systemic therapy (TW iST) was longer in the ear ly than the

de layed ASCT group, potent ia l ly provid ing better qual i ty o f l i fe for the early- t ransplant

group. The MAG91 t r ia l (469) randomized 190 pat ients under the age of 56 years to CCT or

HSCT, but this t r ia l a lso examined the outcomes of ear ly versus la te t ransplants. Only

pat ients 55 to 65 years of age were included. Event- f ree surviva l (19 vs . 25 months) , but

not overa l l survival (47.6 vs . 47.8 months) , was bet ter in the ASCT arm. Despi te the 120-

month fo l low up, the overa l l surviva l s tat is t ics are confounded by the fac t that only 75% of

the “ASCT” arm received ASCT, and that 22% of the “CCT” arm received an HSCT. The

in tergroup t r ia l (S9321) randomized 510 pat ients age 70 or younger to CCT or HSCT (471) .

W ith a 76-month fo l low-up, 7-year overa l l surviva l was no d i f ferent between the arms;

however on ly 82% of the “ASCT” group received an ASCT and 34% of the “CCT” group

received an ASCT. Remarkably, 7 years af ter a myeloma d iagnosis, 38% of pat ients were

s t i l l a l ive.

The Spanish Cooperat ive Group prospect ive t r ia l was d issimi lar f rom the other randomized

t r ia ls in that on ly those pat ients who responded to therapy were randomized. At enro l lment,

216 pat ients were t reated ini t ia l ly wi th four cyc les of VBMCP and VBAD (vincr is t ine,

carmust ine, doxorubic in , and dexamethasone) (472) , and only 164 were randomized to

receive eight addi t ional courses of chemotherapy or intens i f icat ion wi th h igh-dose therapy

and s tem cel l t ransplantat ion. There was no di f ference between the groups wi th respect to

complete response rates, overal l response rates, progression-f ree survival , or overal l

surviva l . These data d i f fer f rom those of o ther t ransplant t r ia ls. I t is possib le that pat ients

wi th an excel lent response to the induct ion therapy g iven do not requi re consol idat ion wi th

ASCT; or that wi th longer fo l low-up, survival di f ferences wi l l emerge.

The MMSG97 t r ia l was un ique in that i t randomized pat ients aged 50 to 70 years of age to

e i ther melphalan and prednisone or two hal f -dose melphalan t ransplants (468) . Pat ients

receiv ing melphalan and prednisone only had sign i f icant ly worse outcomes. A s igni f icant

d i f ference between two low-dose ASCT and MP was not seen in the IFM 999-06 tr ia l (476).

The Hovon-24 t r ia l is commonly grouped in the “s ing le versus double” transplant category,

though i t is actual ly an “ in tens i f ied chemotherapy wi thout t ransplant” versus “ in tens i f ied

chemotherapy fo l lowed by h igh-dose chemotherapy and a s ing le ASCT” (477) . The most

recent analys is o f th is t r ia l demonstrates a s igni f icant ly higher complete response rate and

event- f ree survival in the h igh-dose t reatment arm. The d i f ferences in event- f ree survival ,

progress ion- f ree survival , and tota l t ime to progression were not seen unt i l the 4-year fol low

up had been reached. The authors repor t that the lack of d i f ference in overa l l surviva l is

l ike ly due to a “high propor t ion” o f pat ients f rom the contro l arm receiv ing HSCT at f i rs t

re lapse.

Table 99.11 Single versus Double Hematopoietic Stem Cell Transplantation, Randomized Trials

Event-Free Survival (mo) Overall Survival (%) Study N FU (mo) Single Double P Single Double P

IFM, 94 (481)

403

75 25 30 .03 48 58 .01

Bologna, 96 (482)

228

~48

21 31 .001

44% at 6 y

63% at 6 y

NS

MAG, 95 (1093)

193

27 41 events

43 events

NS 27 deaths

22 deaths

NS

Single versus Double Transplantation

As the evidence was mount ing that one course of dose-in tens i f ied chemotherapy wi th ASCT

was super ior to convent ional chemotherapy, invest igators began exper iment ing wi th two

consecut ive ASCTs. The concept o f double or tandem t ransplants was promulgated by Dr.

Bar log ie and co l leagues at the Universi ty of Arkansas (331,478,479,480) . These

invest igators repor ted high complete response rates and surviva l (331,478,479,480) . In the

f i rst repor t o f “ to ta l therapy 1, ” which included 231 pat ients wi th newly d iagnosed myeloma,

the overa l l survival wi th th is approach was 68 months (331) .

There have been prel iminary data f rom three randomized t r ia ls that indicate increased

response rates wi th tandem transplantat ion, but on ly two that demonstrate improvement in

event- f ree and overa l l surviva l (481,482,483) (Table 99.11) . In the largest and most mature

s tudy, that is , the IFM 94 s tudy, there was no di f ference in event- f ree or overa l l surviva l

between double and s ingle autologous s tem cel l t ransplants af ter 2 years of fo l low-up (484) ;

however, by 4 years and beyond, a surviva l benef i t was detected (481) . Though the

response rate was not s ign i f icant ly d i f ferent between the two groups (complete response

and very good par t ia l response 42% in the s ing le-t ransplant arm vs. 50% in the double-

t ransplant group, p = .15) , both event- free surviva l (25 vs. 30 months) and overal l surviva l

(48 vs . 58 months) were improved in the double- transplant arm. The respect ive 7-year

overa l l (21 vs . 42%) and event-f ree surviva l ra tes (10 vs . 20%) also s ign i f icant ly favored the

double-t ransplant group (F ig . 99.11). In this t r ia l , four fac tors were assoc ia ted wi th a longer

surviva l : low β2 -microg lobul in leve ls a t diagnos is (p < .01), young age (p < .05) , low lactate

dehydrogenase (LDH) at d iagnosis (p < .01) , and the t reatment arm to which the pat ient was

ass igned (p < .05) . W hen the authors d id an unplanned subgroup analysis , they found that

pat ients who benef i ted most f rom the tandem t ransplant were those who d id not achieve a

very good part ia l response or bet ter a fter thei r f i rs t t ransplant .

Cavo et a l . (482) have made s imi lar observat ions based on prel iminary data, includ ing the

benef i t o f a second t ransplant be ing l imi ted to those pat ients who do not ach ieve a very

good par t ia l response or bet ter a f ter the i r f i rs t t ransplant . Most pat ients under the age of 65

years should have enough s tem cel ls col lec ted for a t least two t ransplants.

Timing of Transplantation

As long as stem cel ls are co l lected early, in the context o f convent ional chemotherapy

versus as s ing le autologous s tem cel l t ransplant , t iming of t ransplant—ei ther as upfront

consol idat ion or salvage at relapse—does not inf luence overal l survival (469,470,471) .

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Because the t ime wi thout chemotherapy is longer in pat ients t ransplanted ear ly in thei r

course, many opt for early t ransplant . The s i tuat ion is less c lear when one int roduces the

concept of double t ransplants , as the relevant data are not yet ava i lable . Many phys ic ians

are act ing on the reasonable premise that t iming of double t ransplants does not mat ter, but

a l l three tandem t ransplant t r ia ls eva luated ear ly, “back to back” t ransplants . There are

emerg ing data—but no randomized t r ia ls—regarding the role a second t ransplant plays as

“sa lvage” therapy af ter re lapse f rom the f i rs t . A l l that can be conc luded f rom these

re t rospect ive analyses is that a second salvage ASCT is a feas ib le opt ion in some pat ients .

Figure 99.11. Single autologous versus double hematopoietic stem cell transplantation, IFM 94 trial. A: Event-free survival. B: Overall survival. (With permission, from Attal M,

Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003;349: 2495–2502. Copyright ©2003 Massachusetts Medical Society. All rights reserved.)

The European Group for Blood and Marrow Transplantat ion Regist ry (EBMTR) analyzed

“p lanned” and “unplanned” second t ransplants among 7,444 pat ients spanning 9 years .

Though the surviva l was shorter a f ter the second t ransplant in the group that had the

“unplanned” and presumably de layed t ransplant , the overa l l survival o f both groups f rom the

t ime of the f i rst t ransplant was s imi lar : 60 months for the planned group and 51 months for

the unplanned group (485) .

Alvares et a l . studied retrospect ive ly the outcomes of 172 pat ients who re lapsed af ter a

s ing le autologous ASCT (486). Eighty- three had a second ASCT at relapse, 7 d ied, and

another 83 had al ternat ive therapies. The median event- f ree surviva l was simi lar in the two

groups at 1 .3 years versus 0.9 years (p = .73) , but there was a t rend toward longer overal l

surviva l in the second t ransplant group (2.9 vs . 1.7 years , p = .07) . The authors caut ioned

that the worse outcome in the la t ter group could potent ia l ly be accounted for by a poorer

per formance s tatus in the group not receiv ing a second t ransplant . Most notable , however,

was the d i f ference in overa l l surviva l between those pat ients who had less than an 18-

month re lapse- f ree surviva l a f ter thei r f i rst t ransplant relat ive to those who had a relapse-

f ree survival of 18 months or longer : The respect ive median overa l l surviva ls were <6

months in the former and near ly 3 years in the lat ter group (p < .00001).

El l ice et a l . (487) analyzed the outcomes of 26 pat ients who had a second t ransplant upon

re lapse after a s ing le t ransplant . From the date of re lapse, the overa l l surviva l o f pat ients

undergoing second t ransplant was 46.9 months, whereas that o f the pat ients rece iv ing

a l ternate sa lvage therapy was 28.3 months. The median overa l l surviva l and event- f ree

surviva l ca lcu la ted f rom the date of second ASCT were 38.1 and 14.8 months, respect ive ly.

Given the smal l numbers of pat ients , the di f ference between the two groups was not

cons idered to be s ta t ist ica l ly s igni f icant .

Mehta et al . repor ted on 42 pat ients a l lograf ted for myeloma af ter not responding to or a f ter

having had progress ion fo l lowing autologous s tem cel l t ransplantat ion (488) . They

compared those cases to 42 pa i r-matched contro ls that underwent sa lvage auto logous stem

cel l t ransplantat ion. The 3-year event- f ree surviva l was simi lar for both groups (20 vs . 25%),

but overa l l survival was s ign i f icant ly h igher a fter autologous t ransplantat ion (29 vs . 54%).

Al though the 3-year probabi l i ty of disease progression was lower af ter a l logeneic

t ransplantat ion (31 vs . 72%), the d i f ference could be at tr ibuted to the high 1-year t reatment-

re lated mortal i ty of 43% in the a l logeneic group. Lee et a l . (489) has shown that pat ients

re lapsing af ter two t ransplants may derive benef i t f rom a thi rd t ransplant as long as they

have favorable prognost ic fac tors.

Long-Term Survival in Myeloma Patients

High-dose chemotherapy wi th auto logous s tem cel l t ransplantat ion has improved outcomes

in pat ients wi th myeloma. Mere ly be ing e l ig ib le for t ransplant is i tse l f a favorable prognost ic

fac tor . In one s tudy, on ly 50% of pat ients who were of t ransplant-el ig ible age were actual ly

t ransplanted. The reasons for not t ransplant ing the other pat ients were poor medica l

condi t ion (25%) and unspeci f ied reasons (25%). Despi te the caveat o f selec t ion,

unprecedented long-term survivals are being seen in populat ions of t ransplanted pat ients .

Moreau et a l . (490) repor ted a 10-year surviva l of 9% percent in pat ients wi th β2 -

microglobul in o f >3 mg/L, compared to 41% for pat ients wi th β2 -microg lobul in o f ≤3 mg/L.

These same groups had median overa l l surviva ls o f 31 versus 73 months. More than one

th i rd o f the pat ients <55 years at diagnos is were a l ive at 10 years . In this re t rospect ive

analys is , the 10-year surviva l was 35% for pat ients who completed a second ASCT,

compared to 20% for those who had only one.

Though long- term surviva l was the focus of the previous paper, 20 to 30% 8-year survivors

have been descr ibed in o ther cohorts (471,491) .

Transplantation for Primary Refractory Myeloma In contrast to the exper ience wi th mal ignant lymphoma, s tem cel l t ransplantat ion appears to

be ef fec t ive for pat ients wi th pr imary res is tant d isease (492,493,494) . Pat ients wi th mul t ip le

myeloma, in whom f i rs t - l ine therapy such as VAD fa i ls , can be sens i t ive to h igh-dose

chemotherapy wi th s tem cel l reconst i tu t ion. Alexanian et a l . (492) repor ted a decrease of

75% in tumor burden in 56% of pat ients and a marked improvement in surviva l compared

wi th matched h is tor ica l controls. Kumar et a l . (494) also looked at s tem ce l l t ransplantat ion

in pr imary ref rac tory d isease and found that though there was a lower complete response

rate (20 vs . 35%) in the pr imary ref rac tory pat ients , the 1-year progress ion- f ree surviva l

was s imi lar to that o f pat ients wi th chemosens i t ive d isease.

Hematopoietic Stem Cell Collection Auto logous per iphera l b lood s tem cel l t ransplantat ion has replaced autologous bone marrow

t ransplantat ion because engraf tment is

P.2396

more rap id and there is less contaminat ion wi th myeloma ce l ls (495,496,497) .

Hematopoiet ic stem ce l ls should be col lected before the pat ient is exposed to alkyla t ing

agents (498,499) , because pro longed melphalan exposure leads to an impai red harvest of

per iphera l b lood s tem cel ls when s tem cel ls are mobi l ized wi th chemotherapy p lus growth

fac tors (500) or growth fac tors a lone (501) . Even af ter four to s ix cyc les of VMCP/VBAP,

which is a reg imen contain ing low doses of melphalan, suf f ic ient s tem cel ls could not be

co l lec ted for t ransplantat ion in ~10% of pat ients (245) . In contrast, successful stem ce l l

co l lec t ion is ach ieved in 95 to 100% of mul t ip le myeloma pat ients treated wi th VAD before

mobi l izat ion wi th h igh-dose cyc lophosphamide (474) . The absolute number o f CD34+

ce l ls/kg is the most re l iab le and pract ica l method for determin ing the adequacy of a s tem

cel l co l lec t ion.

There are many opt ions for mobi l iz ing regimens, f rom single-agent granulocyte colony-

s t imulat ing fac tor (G-CSF) (501) to pegylated G-CSF (502) , to an assor tment o f

chemotherapy-plus-growth fac tor reg imens (503,504,505,506,507). In general ,

chemotherapy mobi l izat ion resul ts in higher CD34 yie lds (503,508,509) . Chemotherapy

mobi l izat ion has been assoc iated wi th lower tumor contaminat ion of the stem cel l product

(503,509) , but no surviva l benef i t has been demonstrated (510) . The CXCR4-antagonis t

AMD3100 has not yet been approved by the U.S. Food and Drug Admin is t ra t ion, but i t has

a l ready shown eff icacy in c l in ica l t r ia ls (511) .

Autologous Hematopoietic Stem Cell Transplantation in Special

Populations

The morta l i ty rate from auto logous stem cel l t ransplantat ion is current ly <5%. Age >65

years a lone is not a contra ind icat ion for t ransplantat ion, al though there are no randomized

data proving or d isproving i ts ut i l i ty in th is age group. Such pat ients are candidates for

t ransplantat ion i f they have good funct ional sta tus and l imi ted comorb idi t ies (512,513) .

Pat ients wi th renal fa i lure, including dia lys is pat ients , can successfu l ly undergo HSCT wi th

melphalan 140 mg/m 2 , wi th s imi lar response rates and progression- f ree surviva l , and a

propor t ion wi l l even have reversal o f the i r renal fa i lure. Treatment- re la ted morb idi ty is

h igher (514) , and thei r overa l l surviva l is in fer ior to that o f thei r dialys is - independent

counterpar ts (515,516) .

Conditioning Therapy and Stem Cell Transplantation

In an effor t to improve auto logous stem cel l t ransplantat ion, var ious preparat ive reg imens

have been used. There has been only one prospect ive randomized contro l led t r ia l

comparing condi t ioning reg imens in pat ients wi th myeloma (517) . Moreau et al . (517)

randomized 282 pat ients to rece ive e i ther melphalan (140 mg/m 2 ) p lus to ta l -body i r radia t ion

or melphalan a lone (200 mg/m 2 ) . There was no d i f ference in response rates or event- f ree

surviva l . Survival at 45 months favored the melphalan-alone arm (65.8 vs. 45.5%, p = .05) .

Toxic i ty wi th melphalan a lone was s ign i f icant ly less . Most invest igators have now

d iscont inued the use of to ta l-body i r rad ia t ion and g ive on ly melphalan (200 mg/m2 ) as the

preparat ive reg imen.

Other reg imens inc lud ing var ious combinat ions of melphalan, busul fan, cyc lophosphamide,

idarubic in , e topos ide, and/or th io tepa have been used (518,519,520,521,522,523) , wi thout

any evidence of super ior i ty o f these regimens over melphalan 200 mg/m 2 , and severa l wi th

s ign i f icant ly more toxic i ty (519,520) and morb idi ty (518) . Innovat ive t r ia ls supplementing

melphalan wi th ske leta l targeted radia t ion [samarium 153-ethylenediaminetet ramethylene

phosphonate (524) and holmium 166-1,4,7,10- te t raazocyclodo-decane-1,4,7, 10-

te t ramethylenephosphonic acid (525) ] have been reported. Others have been s tudying

bor tezomib as a chemosensi t izer for the melphalan (526,527,528) .

Des ikan et a l . ret rospect ive ly compared the ef fect o f d i f ferent condit ion ing regimens used

for the second autologous t ransplant (529) . Outcomes of pat ients t reated wi th melphalan

200 mg/m 2 were bet ter than those condi t ioned wi th melphalan 200 mg/m 2 p lus

cyc lophosphamide 120 mg/m 2 , and melphalan 140 mg/m 2 p lus to ta l -body i r rad iat ion (1 ,125

cGy).

The Role of Purging Vir tua l ly a l l per iphera l b lood cel l products are contaminated wi th mal ignant ce l ls (530,531) .

I t is unclear whether the purging of tumor cel ls f rom the col lec t ion of hematopoiet ic s tem

ce l ls is benef ic ial . Purging marrow wi th cyc lophosphamide der ivat ives (532) or wi th

monoclonal ant ibodies (533,534,535) is feas ib le a l though assoc iated wi th prolonged

myelosuppress ion af ter transplantat ion. CD34+ se lec t ion of per iphera l blood progenitor cel ls

provided ef fec t ive hematopoiet ic support in a group of 55 pat ients wi th advanced mult ip le

myeloma af ter myeloablat ive chemotherapy (536) . However, one large Phase I I I randomized

t r ia l has shown no c l in ica l benef i t to using CD34+ -se lected auto logous per ipheral blood

stem cel ls (537) . Another randomized t r ia l showed an increased rate of infec t ion wi thout

improvement in overal l surviva l (538).

Ear ly work shows that f lowing hematopoiet ic ce l ls through pulsed elec t r ic f ie lds ef fec t ively

purges myeloma ce l ls wi thout sacri f ic ing funct ional s tem ce l ls (539) . This f inding has not

yet made i t in to the c l in ic .

Allogeneic Transplant Al logeneic t ransplantat ion e l iminates the problem of s tem cel l contaminat ion by tumor ce l ls

that is inevi tab le wi th auto logous s tem cel l t ransplantat ion. Fur ther , there is evidence of a

graf t -versus-myeloma effec t wi th a l lograft ing (540). Al logeneic s tem cel l t ransplantat ion

(a l logeneic SCT) can lead to complete response rates of 22 to 67%, including molecular

remiss ions in about one th i rd (495,541,542) , and pro longed d isease- f ree surviva l in

approximately one quar ter to one th i rd o f pat ients (471,495,543) (Table 99.12). The h igh

t reatment- related mortal i ty (10 to 63%) and sign i f icant toxic i ty f rom graf t -versus-host

d isease have l imi ted the ro le o f th is procedure in the treatment o f myeloma (495,544,545) .

Though there are no prospect ive randomized t r ia ls compar ing condi t ion ing regimens in

pat ients rece iv ing al logeneic t ransplants , one retrospect ive mul t icenter analysis o f 139

pat ients undergoing myeloablat ive condit ion ing showed bet ter outcomes in pat ients

receiv ing melphalan/ total -body i r rad ia t ion (TBI) compared to cyclophosphamide/TBI ,

includ ing higher CR rates (65 vs . 47%, p = .085) , lower relapse ra tes (37 vs . 81%, p

< .0001), and longer 5-year overa l l surviva l (44 vs. 28%, p = .06) (546).

A smal l s ing le-center study of 37 myeloma pat ients who underwent myeloablat ive a l logeneic

SCT, but that had a median fo l low-up of 108 months, repor ted that the pat ients ' 5-year

overa l l surviva l , progress ion- f ree survival , and event- f ree surviva l were 40, 54, and 24%,

respect ive ly (547) , despi te a 50% t reatment- rela ted morta l i ty and a median overal l surviva l

o f 28 months. At 10 years , about 30% of the pat ients were al ive. Outcomes were s imi lar for

the a l logeneic t reatment arm in the S9321 In tergroup s tudy (471) .

In another series , on ly 5 o f 80 pat ients were a l ive wi thout evidence of d isease at 4 to 7

years af ter an al logeneic bone marrow t ransplant for mult ip le myeloma (495) . I t must be

emphas ized that the major i ty of these pat ients had chemotherapy-resistant d isease before

t ransplantat ion. Outcomes for a l logeneic SCT have improved over t ime (548) . Of 690

a l logeneic , matched, s ibl ing donor transplants for mul t ip le myeloma repor ted to the

European Group for Blood and Marrow Transplantat ion reg is t ry, 334 were per formed

between 1983 and 1993 (a l l wi th bone marrow) and 356 between 1994 and 1998. The 3-year

overa l l surviva l was 35% for transplant rec ip ients during the ear l ier per iod and 55% for

rec ip ients of bone marrow t ransplants during the la ter per iod. The improvement in survival

s ince 1994 was the resu l t o f a s ign i f icant reduct ion in t ransplant- re lated mortal i ty , f rom 46

to 30% at 2 years (548).

P.2397

Table 99.12 Nonrandomized Comparisons of Autologous and Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Study N TRM (%)

PFS (mo) P OS (mo) P

189 Auto

13 ~22 NS 34 .001 Bjorkstrand et al. (549)

189 Allo

41 ~12 18

24 Auto 12 16.7 NS 33.5 NS Varterasian et al. (550)

24 Allo 25 31 38.6

40 Auto 5 14 — >48 <.001 Couban et al. (551)

22 Allo 27 ~11 7

Auto 35 6 2 y, 30%

NS 2 y, 42%

NS Reynolds et al. (553)

Allo 21 19 2 y, 60%

2 y, 60%

50 Autoa

6 3 y, 67%

NS 3 y, 82%

NS Lokhorst et al. (552)

11 Alloa,b

18 3 y, 67%

3 y, 82%

2 y, 48%

.002 2 y, 74%

.006 166 Auto

13

4 y, 28%

NS 4 y, 41%

NS

Alyea et al. (554)

66 Allo b

24 2 y, 23%

2 y, 51%

4 y, 18%

4 y, 39%

1 y, 67%

NS 1 y, 86%

NS 70 Autoc

6

4 y, 18%

NS 4 y, 50%

NS

1 y, 58%

1 y, 64%

Arora et al. (555)

17 Allo 31

4 y, 32%

4 y, 64%

MS, median survial; NS, not significant; TRM, treatment-related mortality. aChemotherapy-sensitive patients only. bT-cell–depleted allogeneic stem cells. cCyclphosphamide and total-body irradiation conditioning.

Al logeneic t ransplants produce h igher ra tes of complete molecular responses. In a ser ies of

229 myeloma pat ients , al logeneic t ransplants resu l ted in a complete response of 38%,

compared wi th 22% af ter auto logous t ransplantat ion (p < .01) (541) . Among pat ients

achieving a c l in ica l complete response, 50% of the al logeneic t ransplant group had a

molecular complete response, compared wi th only 17% of those who had received an

autologous t ransplant (541) . The median re lapse- f ree survival for those who had a

molecular complete remission was 110 months, compared wi th 35 months for those who d id

not . Moreover, in those wi th a complete molecular remission, the re lapse ra te was only 16%

in the a l logeneic group and 41% in the auto logous group. Th is is s t rong evidence that

molecular complete responses are assoc ia ted wi th a longer re lapse- free surviva l .

There have been seven case-contro l or cohor t-control s tud ies compar ing auto logous to

a l logeneic s tem cel l t ransplants (Table 99.12) (549,550,551,552,553,554,555) . The largest

o f these was by Bjorkst rand et a l . (549) . In thei r re t rospect ive analys is o f data compi led by

the European Blood and Marrow Transplantat ion Group, there was in fer ior survival for

myeloma pat ients t reated wi th al logeneic bone marrow t ransplants compared to case-

matched controls t reated wi th auto logous t ransplants (18 vs . 36 months) (549). The s ix

smal ler s tud ies , which had rela t ive ly shor t fo l low-up, showed mixed resul ts wi th regard to

progress ion- f ree survival and overal l surviva l ; t ransplant- rela ted morta l i ty, however, was

cons is tent ly h igher in the a l logeneic groups (19 to 25%).

Only one repor t favored a l logeneic t ransplantat ion (555) . However, pat ients in the

a l logeneic group were bet ter-prognos is pat ients ; they were s ign i f icant ly younger and less

l i ke ly to have IgA myeloma. Though not reaching s tat is t ical s ign i f icance, there were more

autologous pat ients having the i r t ransplant as sa lvage (37 vs . 23%). In addi t ion,

cyc lophosphamide and to ta l-body i r rad ia t ion were used to condi t ion both the auto logous and

a l logeneic t ransplant pat ients . W ith fo l low-up t imes for the two groups of 24 and 43 months,

respect ive ly, the 1-year overa l l surviva l was 86 and 64%, and the 4-year OS was 50 and

64%.

Two of these studies have evaluated the ro le of T-ce l l deplet ion. Lokhors t e t al . (552)

compared auto logous s tem cel l t ransplants to T-ce l l–depleted a l logeneic s tem cel l

t ransplants . Myeloma pat ients were e l ig ib le i f they had chemotherapy-sens i t ive disease.

Genetic randomizat ion was used. Af ter 44 months ' median fo l low-up, overa l l surviva l had

not yet been reached in e i ther group (Table 99.12) . Transplant- re la ted mortal i ty in the

a l logeneic group was 18%, compared wi th 6% in the auto logous group. In thei r Phase

successor I I I s tudy (HOVON [Dutch-Belg ian Hemato-Oncology Cooperat ive Group] 24) , 53

newly d iagnosed myeloma pat ients wi th an HLA-ident ica l s ib l ing were a l located to a part ia l

T-ce l l–depleted a l logeneic SCT after induct ion therapy (556). The overa l l response rate was

89%, inc luding a 19% complete response. W ith a median fol low-up of 38 months, 33 (62%)

had d ied, 18 f rom t reatment- re lated mortal i ty . The median progression-f ree surviva l f rom

the a l logeneic SCT was 17 months, and median overa l l surviva l was 25 months. Only three

pat ients are in cont inu ing complete response. The authors conclude that the i r data do not

support T-ce l l–depleted myeloablat ive al logeneic SCT as par t o f f i rst - l ine therapy.

Alyea et al . a lso evaluated T-cel l–depleted a l lograf ts, fo l lowed by donor lymphocyte

in fus ions (Table 99.12) . Th is approach appeared to be of l imi ted benef i t , wi th a high

t reatment- related mortal i ty , in fer ior 2-year PFS and OS, but s imi lar 4-year PFS and OS

(554).

Bal len et al . reviewed the National Marrow Donor Program (NMDP) exper ience of

myeloablat ive al logeneic t ransplants (557) . There were 71 consecut ive cases f rom July

1989 to February 2000, wi th a median age of 44 years ( range 22 to 60 years) . Median t ime

to unre la ted donor t ransplant was 17 months. Thi r ty-n ine percent were T-ce l l–depleted. The

2-year survival rate was 27%, and at 5 years only 9% of pat ients were a l ive.

Nonmyeloablative Allogeneic Transplant

In another e f for t to reduce a l logeneic t ransplant-re lated mortal i ty , “nonmyeloablat ive, ”

“ reduced- in tensi ty” or “min i ” s tem ce l l t ransplant reg imens have been s tud ied in pat ients

wi th mul t ip le myeloma. The princ ip le behind th is approach is to harness the improved

complete response rate and re lapse- f ree morta l i ty seen in a s tandard fu l l a l logeneic

t ransplant whi le e l iminat ing the h igh t reatment- rela ted mortal i ty ra tes . The morta l i ty rate for

a l logeneic

P.2398

t ransplantat ion must be reduced before i t can assume a major ro le in the treatment of

mult ip le myeloma. Table 99.13 contains the resul ts f rom the f i rs t studies employing th is

reduced- intens i ty condi t ion ing approach. Many s tud ies inc luded relapsed or re fractory

pat ients , which was thought to account a t least in par t for the poor outcomes. I t a lso

became apparent that th is approach was less usefu l in pat ients who had signi f icant residual

tumor burden at the t ime of the nonmyeloablat ive t ransplant , which led to the concept o f a

p lanned autologous SCT fo l lowed a couple of months la ter by a reduced- in tens i ty a l logeneic

stem cel l t ransplant (RIC SCT). Pre l iminary resu l ts o f th is lat ter approach are summar ized

in Table 99.13.

Table 99.13 Reduced-Intensity Conditioning (RIC) for Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Study N Diagnosis to RIC, mo RIC (range)

Sibling/ MUD Allograft

Age, y (range)

RIC regimena

Median FU, mo

CR/PR, no.

TRM, %

PFS, % (at time in mo)

OS, % (at time, in mo)

Giralt et al. (558)

22

36 (3–135)

13/9

51 (45–64)

FM

15

7/9

41

19% (24)

Med 10 mo

Badros et al. (513,568)

60

NS

49/11

52 (38–68)

Mel 100 or FM-TBI; 26 Auto → RIC

45

18/36

34

26% (60); Med 8 mo

34% (60); Med 9 mo

Gerull et al. (1095)

52

35 (8–233)

32/20

52 (36–68)

F-210 cGy

18

1/8

17

29% (18)

41% (18)

Crawle 2 19 19 5 Va 2 10 2 21 41

y et al. (560)

29

.2 (2–132)

2/37

2 (32–66)

ried

8 /53

2 % (36)

% (36)

Perez-Simon et al. (1096)

70

— — 54 (30–66)

FM; 15 Auto → RIC

19

18/40

24

Med 32 mo

Med 10 mo

Shimazaki et al. (1097)

45

— NS 53 (39–63)

F-based

25

9/24

9 18.8% (36)

38.5% (36)

Galimberti et al. (1098)

20

11 NS 51 (35–66)

Auto → RIC

35

NS

20

51% (24)d

58% (24)d

Maloney et al. (561)

54b

NS

54/0

52 (29–71)

Auto → RIC

22c

25/14

25

55% (24)c

78% (24)c

Kroger et al. (562,5

47

11.2 (4.

24/23

52 (3

Auto →

16

26/13

11

54% (36

70% (36

63,564)

7–57)

1–64)

RIC

) )

ATG, antithymocyte globulin; Bu, busulfan; CR, complete response; F, fludarabine; FC, fludarabine and cyclophosphamide; FM, fludarabine and melphalan; FU, follow-up; Mel, melphalan; MM, multiple myeloma; MMF, mycophenolate; MTX, methotrexate; MUD, matched unrelated donor; RIC, reduced-intensity conditioning; NS, not stated; OS, overall survival; PFS, progression-free survival; PR, partial response; TBI, total-body irradiation; TRM, treatment-related mortality. aAll studies used cyclosporine as part of the graft-versus-host prophylaxis program. bForty-eight percent with relapsed or refractory disease prior to autologous transplant. cTime measured from autologous stem cell transplantation. dTime measured from RIC.

The f i rs t publ ished report o f a RIC series came f rom Gira l t e t a l . , working at the M. D.

Anderson Cancer Center (Table 99.13) . They t reated 22 pat ients , who were predominant ly

re lapsed or ref rac tory, wi th a reduced- intens i ty program inc lud ing f ludarabine and

melphalan. W ith a median fol low-up of 15 months, the median overal l surviva l was 10

months, and 19% were progression- f ree at 24 months (558) . The same group compared

sa lvage auto logous ASCT to RIC SCT for pat ients fai l ing pr ior ASCT. W ith a median fo l low

up of 18 months for the autologous pat ients and 30 months for the al logeneic group, the

respect ive PFS were 6.8 and 7.3 months and the respect ive OS were 29 and 13 months

(559).

Invest igators f rom the Universi ty of Arkansas reported the resul ts o f RIC SCT in 31 poor-

r isk myeloma pat ients (513) . Twenty- f ive were HLA-compat ib le s ibl ings, and 6 of the

rec ip ient -donor pa i rs were unre la ted but matched (Table 99.13) . The condit ioning reg imen

cons is ted of melphalan 100 mg/m 2 for re la ted and melphalan 100 mg/m2 p lus to tal -body

i r radia t ion (250 cGy) p lus f ludarabine for unre la ted al lograf ts. Donor lymphocyte in fusions

were in i t ia l ly given on days 21, 42, and 112 to pat ients wi th no c l in ica l evidence of graf t-

versus-host d isease (GVHD); however, because of high ra tes of lymphocyte- induced GVHD,

donor lymphocyte infus ions were reserved for pat ients who needed to at tain ful l donor

ch imerism or who requi red eradicat ion of residual d isease. Al l but one pat ient had received

one or more than two pr ior auto logous t ransplants . Fi f ty- f ive percent o f the pat ients had

progress ive d isease at the t ime of the al lograf t . Acute GVHD developed in 18 pat ients . Ten

pat ients progressed to chronic GVHD—limi ted in 6 and extensive in 4 pat ients . Two pat ients

fa i led to engraf t even af ter a second a l logeneic per ipheral b lood s tem cel l in fusion. At a

median fol low-up of 6 months, 12 pat ients ach ieved complete remiss ion and another 7 a

near-complete remiss ion, whi le 3 achieved a par t ia l remission. There were 3 treatment-

re lated deaths dur ing the f i rs t 100 days and another 6 a fter 100 days, for an overa l l

t reatment- related mortal i ty o f 28%. Three pat ients died of progressive myeloma. Pat ients

who received t ransplants wi th progressive disease or who had received more than one pr ior

autograft had a sta t ist ical ly h igher morta l i ty ra te. The authors also compared the i r

nonmyeloablat ive t ransplant exper ience to thei r pr ior s tandard a l logeneic exper ience and

found that the nonmyeloablat ive group had a lower mortal i ty during the f i rs t year (p = .09) ,

most notab ly the subset who had received only one prior auto logous t ransplant (p = .05) .

Crawley et al . reported the outcome of 229 pat ients who received an al lograf t for myeloma

wi th reduced- in tensi ty condi t ion ing reg imens f rom 33 centers wi th in the European Group for

Blood and Marrow Transplantat ion (560) (Table 99.13). Ten percent o f pat ients had at least

two pr ior s tem cel l t ransplants, and 26% had never received an ASCT. Seventy-e ight

percent o f pat ients received matched sib l ing t ransplants . Sixteen percent had unre lated

donors . Only 20% received bone marrow s tem cel ls. Condit ion ing reg imens were

heterogeneous, but most were f ludarabine-based and T-ce l l–depleted wi th ant i thymocyte

g lobul in or alemtuzumab. Transplantat ion-rela ted morta l i ty a t 1 year was 22%. The 3-year

overa l l surviva l and progress ion- f ree survival rates were 41% and 21%, respect ive ly.

Adverse OS was associated wi th chemores is tant d isease (re la t ive r isk , 2 .9) , more than one

pr ior t ransplantat ion ( re la t ive r isk , 2 .0), and male pat ients wi th female donors ( rela t ive r isk ,

1 .45). Adverse PFS was associated wi th chemores is tance and alemtuzumab. Grades I I to IV

acute GVHD occurred in 31%. Chronic GVHD was assoc ia ted wi th bet ter OS and PFS and

were 84% and 46% for l imi ted, 58% and 30% for extens ive, and 29% and 12% in i ts absence,

suggest ing that a graft -versus-myeloma effect is important (F ig. 99.12) . The authors

conc luded that reduced-in tens i ty condi t ion ing is feasible , but heavi ly pret reated pat ients

and pat ients wi th progressive disease do not benef i t .

Maloney and co l leagues (561) repor ted resu l ts on 54 newly d iagnosed myeloma pat ients

who were t reated wi th a p lanned tandem auto logous/nonmyeloablat ive a l logeneic s tem cel l

t ransplantat ion (Table 99.13). Af ter induct ion wi th four cyc les of VAD chemotherapy,

fo l lowed by ASCT using melphalan 200 mg/m 2

P.2399

as condit ion ing, pat ients underwent a RIC SCT. The condit ion ing for the second t ransplant

was wi th to ta l -body i r radia t ion (200 cGy). Matched sib l ing donor periphera l blood s tem cel ls

were in fused immediate ly a f ter the to ta l -body i r rad ia t ion. Postgraf t ing immunosuppress ion

included mycophenolate and cyclosporine. Fi f ty- two of the 54 pat ients rece ived the p lanned

RIC SCT, wi th a median t ime between autologous and a l logeneic t ransplants o f 62 days.

The granulocyte and pla te le t nadi rs af ter the nonmyeloablat ive t ransplant were 760 and

95,000 cel ls /µ l , respect ive ly. Acute GVHD was seen in 38% of pat ients and was grade I I in

a l l but four cases. For ty-s ix percent o f pat ients developed chronic GVHD that requi red

therapy. Al l pat ients ach ieved donor engraf tment. F i f ty-seven percent o f pat ients not in

complete response af ter the f i rs t t ransplant ach ieved a complete response af ter the second

t ransplant. W ith a median fol low-up of surviv ing pat ients o f 18 months, 8 pat ients (15%) had

d ied of t ransplant- re lated compl icat ions, 2 o f progress ive myeloma, and 1 of lung cancer .

Figure 99.12. European Blood and Marrow Transplantation Registry data on the role of reduced intensity conditioning allogeneic transplantation regimens. A: Overall and progression-free survival. B: Overall survival relative to presence or absence of graft versus host disease. (With permission, ferom Crawley C, Lalancette M, Szydlo R, et al. Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT. Blood 2005;105: 4532–4539. © the American Society of Hematology.)

Kroger e t a l . (562,563) have appl ied a s imi lar s t rategy, inc lud ing a planned s tandard-

in tensi ty autograft (melphalan 200 mg/m2 ) fo l lowed by a dose-reduced reg imen (f ludarabine

180 mg/m 2 , melphalan 100 mg/m 2 , and ant i thymocyte globul in 10 mg/kg on 3 days) before

a l lograf t ing (Table 99.13) . GVHD prophylaxis inc luded cyclospor ine and min i -methotrexate.

Nine pat ients rece ived al lograf ts f rom re la ted donors and 8 f rom unre la ted donors. Acute

GVHD stage I I to IV occurred in 6 pat ients (38%). Chronic GVHD developed in 40% of the

pat ients , but only 1 pat ient exper ienced extens ive chronic GVHD requi r ing fur ther

immunosuppress ive therapy. The 100-day morta l i ty ra te was 11%, and wi th a median fo l low-

up of 17 months af ter auto logous and 13 months af ter a l logeneic t ransplantat ion, 13

pat ients (76%) are al ive. The rate of complete remission wi th negat ive immunof ixat ion

increased f rom 18% after autograf t ing to 73% after al lograft ing, and 12 remain f ree of

re lapse or progression.

Th is same group has a lso repor ted on th is approach us ing matched unrela ted donors (564).

Twenty-one pat ients wi th advanced mul t ip le myeloma were condi t ioned wi th a reduced-

in tensi ty condi t ioning reg imen consist ing of f ludarabine (150 mg/m 2 ) , melphalan (100 to 140

mg/m 2 ) , and ant i thymocyte globul in (ATG; 10 mg/kg on 3 days) . Al l pat ients had received at

least one pr ior auto logous transplantat ion, in 9 cases as par t o f an auto logous-al logeneic

tandem protocol . Grade I I to IV acute GVHD was seen in 8 pat ients (38%), and severe

grade I I I / IV GVHD was observed in 4 pat ients (19%). Six pat ients (37%) developed chronic

GVHD, but on ly 2 pat ients (12%) exper ienced extensive chronic GVHD. The est imated

probabi l i ty o f nonre lapse morta l i ty a t 1 year was 26%. Af ter al lograf t ing, there was an

overa l l response rate of 90% (40% complete response and 50% part ia l response) . Af ter a

median fol low-up of 13 months, the 2-year est imated overal l and progress ion- f ree survival

ra tes were 74% (95% CI , 54 to 94%) and 53% (95% CI , 29 to 87%), respect ively. A shorter

progress ion- f ree survival was seen in pat ients who had al ready exper ienced relapse to pr ior

autografts (26 vs . 86%, p = .04) .

Table 99.14 Prospective Randomized Trials Comparing Tandem Autologous SCT to Tandem Autologous-HLA Identical Reduced-Intensity Allogeneic SCT

Study N Regimen Age, y (range)

Completed Both SCTs, %

Median FU, mo

Patients in CR, %.

TRM, %

PFS, %

OS, %

219a

Auto mel 200/220 ± IL-6 Ab

58 (28–65)

76 24

33 5 0 at 5 y

44 at 56 mo

Garban et al. (565,566)

65 Auto mel/Allo Bu/Flu/ATG

54 (38–65)

71 28

43 8 0 at 5 y

33 at 5 y

73 Auto mel 200/200

53 (33–64)

75 36

16 4 41 at 3 y

62 at 3 y

Bruno et al (567)

56 Auto mel 200/Allo TBI

54 (34–65)

100 36

46 11 75 at 3 y

84 at 3 y

FU, follow-up; OS, overall survivial; PFS, progression-free survivial; TRM, treatment-related mortality. aHigh-risk patients as defined by the presence of deletion 13 by FISH and β2-microglobulin of >3 mg/L.

Two randomized contro l led t r ia ls compared up- f ront sequent ia l auto logous SCT to

sequent ial autologous SCT, RIC a l logeneic SCT (565) (Table 99.14) .

The f i rs t of these was the IFM9903/9904 tr ia l , in which high-r isk pat ients, as def ined by a

β2 -microg lobul in >3 mg/L and delet ion 13 by FISH, were b io log ical ly randomized to e i ther a

p lanned ASCT fo l lowed by a RIC SCT (n = 65) or two dose- in tensi f ied tandem ASCTs

fo l lowed by t reatment wi th ant i - IL-6 monoc lonal ant ibodies (n = 219) (565,566) . On an

in tent - to- t reat analysis , outcomes of h igh-r isk myeloma pat ients were no d i f ferent between

the groups: median surviva l , 35 versus 41 months; and median event- free survival , 25

versus 30 months, respect ively. There was a t rend toward bet ter overa l l surviva l in the non–

al logeneic SCT arm, 47.2 versus 35 month, p = 0.07, when only pat ients who completed

the ir t reatment assignment were cons idered.

Bruno et a l . (567) have presented in abst rac t form the i r 3-year resul ts o f a prospect ive

randomized tr ia l of double auto logous t ransplants versus tandem auto-RIC. Outcomes were

s ign i f icant ly

P.2400

bet ter in the auto-RIC arm, wi th resu l ts far outs t r ipping those of o ther auto-RIC studies.

So the quest ion remains: W ho should rece ive reduced- in tensi ty condi t ioned SCT? The

answer is not c lear. Some invest igators , includ ing ourselves, have l imi ted the appl icat ion of

RIC SCT to pat ients wi th very h igh-r isk d isease. However, some avai lable data suggest that

pat ients def ined as h igh r isk by FISH delet ion 13 do not seem to do bet ter wi th RIC SCT

than pat ients receiv ing tandem auto logous HSCT (565,566) . Others have quest ioned

whether the RIC, which conta ined ant i thymocyte g lobul in , was too immunosuppress ive and

therefore abrogated a graf t -versus-myeloma ef fec t . Data f rom Lee et a l . show that pat ients

wi th metaphase cytogenet ic abnormal i t ies , which are in par t a surrogate for plasma ce l l

pro l i ferat ion, a lso do worse than the i r counterpar ts wi th normal cytogenet ics (568) . Pat ients

wi th cytogenet ic abnormal i t ies receiv ing RIC SCT had a 36% l ike l ihood of re lapse at 1 year ,

in contrast to 5% for pat ients who lacked cytogenet ic abnormal i t ies go ing in to RIC, even i f

they previous ly had cytogenet ic abnormal i t ies a t an ear l ier date (568).

Unt i l further re f inements are made and addi t ional conf i rmatory studies wi th longer fol low-up

are completed, the ro le o f nonmyeloablat ive a l logeneic stem cel l t ransplantat ion as in i t ia l

therapy in myeloma must be considered invest igat ional . See Table 99.13 for addi t ional

pre l iminary data.

Donor Lymphocyte Infusions A graft -versus-myeloma ef fec t has been noted after the administ ra t ion of donor per iphera l

b lood mononuclear ce l ls for relapse after a l logeneic t ransplantat ion (540,569) . Donor

lymphocyte in fus ion (DLI) has been used in three ways in myeloma pat ients . In i t ia l ly , i t was

used to t reat re lapsed or residual d isease after a fu l l myeloablat ive a l logeneic s tem cel l

t ransplant (540,569). Subsequent ly, i t was used to supply T ce l ls to pat ients who had

received an a l logeneic T-ce l l–depleted graft (570,571). Most recent ly, i t has been used in

RIC programs to t reat mixed ch imer ism, as wel l as for previous ly es tabl ished ind ic t ions

(572,573,574) .

In the largest DLI ser ies for relapsed myeloma (n = 54) (575) , 52% of pat ients responded to

donor lymphocyte in fus ions, 35% wi th a part ia l response and 17% wi th a complete response.

The most common s tar t ing T-cel l dose was 1 ×107 ce l ls /kg, wi th a range of 1 × 106 to 5 ×108

ce l ls/kg. Fi f ty- four pat ients rece ived a to ta l o f 95 DLI courses ( range, 1 to 7 courses) for a

median of 20 months (range 4 to 90 months). Retreatment was prompted by a lack of

response or lack of GVHD by 3 months. The major i ty o f pat ients rece ived some

chemotherapy before DLI . Progression- f ree and overa l l surviva l were 19 and 23 months,

respect ive ly. Rates of overa l l acute GVHD and of grade I I I to IV acute GVHD were 57 and

20%, respect ive ly. Rates of overa l l chron ic GVHD and of extens ive GVHD were 47 and 30%,

respect ive ly. Acute and chronic GVHD fo l lowing DLI were the s t rongest pred ic tors for

response (575) .

The best s tart ing dose for DLI has not yet been estab l ished. Ini t ia l repor ts suggested that a

T-ce l l dose of more than 1×108 cel ls /kg, response to re induct ion therapy, and

chemotherapy-sens i t ive d isease before a l logeneic t ransplantat ion (576) were predict ive of

best outcomes, but these data have not yet been conf i rmed by s tud ies wi th larger sample

s izes and fur ther fo l low-up (573,575,577) .

Von Donk et a l . reviewed the i r exper ience wi th donor lymphocyte in fusions given for

re lapsed (n = 48) or persis tent (n = 15) myeloma fo l lowing RIC SCT (574) . Acute and

chronic GVHD occurred in 38% and 43% of pat ients , respect ively. There were seven

t reatment- related deaths. Th i r ty-e ight percent o f pat ients responded, wi th ha l f achieving a

par t ia l response and hal f a complete response. Wi th a median fol low-up of 14 months,

overa l l surviva l a f ter DLI was 23.6 months (1 .0 to >50.7 months) : 23.6 months for

nonresponders and not yet reached for responders . In responders , progression-f ree surviva l

a f ter DLI was 27.8 months (1 .2 to >46.2 months). The only s igni f icant prognost ic factors for

response to DLI were the occurrence of acute and chronic GVHD.

Maintenance Therapy

Strateg ies for maintenance therapy can be d iv ided into two broad categories : (a) cont inued

induct ion therapy ad in f in i tum, and (b) addi t ion of a novel therapy af ter induct ion therapy.

The former s t ra tegy was prevalent unt i l recogni t ion of the r isk o f developing a lkylator-

induced myelodysplast ic syndromes and leukemia (578,579,580,581,582,583) . The la t ter

s t rategy has mainly used immune modulators , including prednisone, in ter feron, ce l lu lar

therapies, and, more recent ly, thal idomide and lenal idomide. To date, the benef i ts o f

maintenance therapy have been margina l a t best, but for severa l o f these agents , addi t ional

s tud ies are requi red. No benef i t has been observed wi th maintenance levamisole (271,369) ,

azath ioprine (584) , or bac i l lus Calmet te-Guérin (BCG) (387).

Maintenance Chemotherapy Through the 1970s and 1980s, severa l randomized s tudies estab l ished that alkyla tor-based

maintenance therapy does not produce a survival benef i t

(225,253,278,280,364,384,584,585,586) . In genera l , pat ients not receiv ing maintenance had

s imi lar to s l ight ly shor ter remiss ion durat ion than those receiv ing maintenance

(225,364,384,584,586,587) but had h igher ra tes of a second remiss ion (586,587) . Some

s tud ies showed a t rend toward longer surviva l in the former group (278,280,585) .

Induct ion therapy is commonly d iscont inued after p lateau is reached, def ined as no change

in M protein o f >25% for 4 to 6 months (225,278,588) . W ith a lkyla tor-based therapy, the

ab i l i ty to achieve a pla teau is as important as the degree of response achieved

(225,588,589,590,591,592) . No benef i t has been documented for treatment beyond 12

months (364) , a l though i t has been suggested—but not va l idated—that pro longed primary

chemotherapy may be benef ic ia l in pat ients ach ieving less than a par t ia l response, i .e . , a

minimal response or s tab le d isease (593) .

Alkylator-unmaintained remiss ions tend to last about 12 months (584). Pat ients who re lapse

of f alkyla tor-based chemotherapy have response rates of 25 to 80% wi th resumpt ion of the

or iginal reg imen (225,387,586,587) . Second response rates are lower in pat ients who

progress or relapse during maintenance than in those who relapse wi thout maintenance

therapy in the case of alkyla tor-based therapy (584,587) and IMiD-based therapy (594) . In a

s tudy of 115 newly d iagnosed pat ients t reated wi th VBMCP for ~1 year , an in i t ia l response

rate of 82% was achieved, wi th a median durat ion of response of 22 months. Af ter a f i rs t

re lapse, 26 of 38 pat ients (68%) responded again and had a median durat ion of response of

11 months. After a second relapse, 7 o f 16 pat ients (44%) responded, wi th a durat ion of

response of 3 .5 months (595) .

Corticosteroids as Maintenance Therapy Four s tud ies deal wi th cor t icostero ids as maintenance therapy. None just i f ies a

recommendation of prednisone as a s tandard maintenance reg imen for a l l pat ients .

The most recent s tudy (SW OG 9210) compared prednisone 10 mg every other day to

prednisone 50 mg every other day in pat ients who had responded (SW OG PR or bet ter) to 6

to 12 months of a VAD-based program, that is , a cor t icosteroid- in tens ive program. From the

t ime of randomizat ion to the two di f ferent al ternate-day prednisone schedules, the median

progress ion- f ree survival for the h igher-dose prednisone arm was 14 months, compared to 5

months for the lower dose (p = .003). Survival also was marginal ly bet ter , a t 37 and 26

months (p = .05) (596) . Al though the more dose-in tensive cor t icosteroid maintenance

s t rategy does provide a longer progress ion- f ree surviva l in cor t icosteroid-respons ive

pat ients , these data cannot be general ized. By compar ison, af ter a lkylator-based therapy

the median unmainta ined progression- f ree surviva l is 12 months in responding pat ients

(584).

P.2401

An ear l ier randomized s tudy, which compared dexamethasone maintenance to in ter feron

maintenance after induct ion wi th melphalan and dexamethasone, demonstrated equiva lence

to in fer ior i ty o f dexamethasone compared wi th inter feron. Pat ients rece ived maintenance

t reatment wi th in ter feron-α (3 MU 3 t imes a week) or dexamethasone (20 mg/m 2 oral ly da i ly

for 4 days repeated month ly) unt i l re lapse. Remission durat ion was ident ica l (10 months);

however, s igni f icant ly more pat ients responded upon re ins t i tut ion of the melphalan and

dexamethasone at d isease re lapse in the in ter feron group than in the dexamethasone group

(82 vs . 44%, p = .001) (597) .

The CALGB 7461 s tudy addressed this issue less di rec t ly. Pat ients were t reated ini t ia l ly

wi th a lkyla tor therapy and were randomized to observat ion or v incr ist ine and prednisone as

maintenance. Survival and response rates were s ign i f icant ly longer and h igher in the

v incr is t ine–prednisone maintenance group who had received up- front melphalan (median,

35.3 vs . 27.0 months; p = .003) but not in pat ients who had received up-f ront BCNU or

CCNU (269) .

F inal ly, SW OG 8624, which evaluated the in f luence of cor t icosteroid dose in tens i ty on

response and surviva l , ind i rec t ly provided data on cor t icostero id maintenance. Higher

object ive response rates and median survival were observed in pat ients who received

pro longed administ ra t ion of glucocort ico ids (prednisone 50 mg every other day) between

chemotherapy courses. Pat ients given VMCP/VBAP wi th and wi thout al ternate-day

prednisone had median overa l l surviva ls of 40 versus 31 months, respect ive ly (p = .02) . The

surviva l advantage may have been confounded by the complexi ty o f the study; di f ferent

t reatment p lans were ass igned after 12 months of induct ion therapy, determined by tumor

response (402) . Moreover , one could argue that the cor t icosteroid was a par t o f the

induct ion ra ther than the maintenance program.

Interferon as Maintenance Therapy

After Conventional Chemotherapy

The in i t ia l posi t ive f indings by Mandel l i et al . (598) in 1990 demonstrated a super ior

d isease- free and overa l l surviva l in chemotherapy-respons ive pat ients randomized to

maintenance inter feron-α . Subsequent studies have yie lded d ivergent resu l ts . Ludwig and

Fr i tz (431) analyzed 1,615 pat ients in 13 maintenance t r ia ls

(374,419,422,598,599,600,601,602,603,604,605,606,607,608) ; the Myeloma Tr ia l is ts '

Col laborat ive Group (432) used the ind iv idual data of 1 ,543 pat ients enrol led in 12

randomized tr ia ls (374,402,419,422,426,599,601,605,609,610,611). Results were s imi lar in

that the f i rs t group found a 4.4-month pro longat ion of re lapse- free surviva l (p < .01) and a

7.0-month increase in overa l l surviva l (p < .01) (431) . The lat ter group repor ted a 3-year

progress ion- f ree survival o f 27 versus 19 months (p < .00001) in favor o f the in terferon

maintenance group. Inter feron-α prolonged the overa l l surviva l by ~7 months (p = .04) (432)

(F ig . 99.10). Survival t ime f rom progress ion to death was s ign i f icant ly worse in the

in ter feron group than in the contro l group (odds rat io 1 .21, p = .007) . No analyzed fac tors

predic ted for the in terferon benef i t ( i .e . , pret reatment hemoglobin, calc ium, β2 -M, creat in ine,

sex, per formance s tatus, or immunoglobul in isotype). The level of response (complete

response, part ia l response, s tab le disease) or in ter feron dose in tensi ty (<12 vs . ≤12

MU/week) a lso d id not pred ic t for in ter feron ef fec t (432) . In 2000 the cost o f the 1-year

surviva l benef i t in pat ients t reated wi th inter feron as maintenance was $US 18,968,

assuming a dose of 11.6 MU/week (431) .

In Combination with Corticosteroids

Cort icostero ids have been added to maintenance in ter feron in an at tempt to intens i fy the

program. Smal l numbers of pat ients have been t reated wi th s tandard maintenance in ter feron

and e i ther dexamethasone (612) or prednisone (401,612) . In one smal l randomized s tudy,

the progress ion-f ree surviva l was longer in the cor t icostero id-p lus-inter feron arm than in the

in ter feron-only arm, a l though median surviva l was not di f ferent (401). The combinat ion can

a lso induce further par t ia l remiss ions in more than ha l f o f responding pat ients so t reated

(612) and may a lso pro long the durat ion of a second remiss ion (613) .

Interferon after High-Dose Chemotherapy with Stem Cell Support

Fewer data are avai lab le about the ut i l i ty o f in ter feron af ter autologous s tem cel l

t ransplantat ion. There is one smal l randomized t r ia l o f 85 pat ients (610) and a larger

re t rospect ive analys is o f regis t ry data by the European Group for Blood and Marrow

Transplantat ion (614) . The use of in ter feron in this sett ing cannot be recommended outs ide

of c l in ica l t r ia ls .

Cunningham et a l . (610) randomly ass igned 85 pat ients to in ter feron at 3 MU/m 2 three t imes

week ly or to observat ion. The median progression- f ree surviva l in the 43 pat ients

randomized to in ter feron-α was 46 months, compared wi th 27 months in the contro l pat ients

(p < .025) . Al though there was a s ign i f icant surviva l advantage at 54 months, a t which t ime

12% of pat ients in the inter feron group and 33% of pat ients in the no-in ter feron group had

d ied (p = .006), th is surviva l advantage was no longer evident a t a median fo l low-up of 77

months.

The data f rom the European Group for Blood and Marrow Transplantat ion reg is t ry included

473 pat ients who had received maintenance and 419 who had not . Unfor tunate ly, the two

groups were poor ly matched. The pat ients who did not receive in terferon had s igni f icant ly

more pr ior therapy, a higher s tage at diagnos is , and a longer t ime to t ransplantat ion. They

were a lso s ign i f icant ly o lder , and a h igher percentage had received to ta l -body i rradia t ion–

conta in ing condi t ion ing reg imens (614) . Al though these fac tors were “s tat is t ical ly corrected

for” in the survival analys is , the imbalance makes in terpretat ion of th is ret rospect ive

co l lec t ion of reg is t ry pat ients prob lemat ic . Prognost ic fac tors such as β2 -M, C-react ive

protein , cytogenet ics , and PCLI were not inc luded in the analys is . Overal l survival was

s ign i f icant ly bet ter in the pat ients who received inter feron (78 vs . 47 months, p = .007) .

Paradoxica l ly, there was a more prominent surviva l benef i t in those pat ients who achieved a

par t ia l response (97 vs . 46 months for in ter feron vs . no inter feron, p = .03) ra ther than a

complete response (64 vs . 51 months, p = .1) , and the par t ia l - response group had a better

overa l l surviva l than the complete-response group.

Thalidomide as Maintenance Therapy Severa l t r ia ls are evaluat ing the tolerabi l i ty o f tha l idomide as maintenance (615,616,617) ,

but very few Phase I I I data are evaluable at th is t ime, and therefore tha l idomide

maintenance cannot be recommended as standard therapy of f -s tudy. The two completed

t r ia ls that approach the quest ion are the IFM 99-02 (618) and Total Therapy 2 studies (594).

IFM 99-02 evaluates the va lue of maintenance tha l idomide versus no tha l idomide in low-r isk

myeloma pat ients who have undergone tandem ASCT. Though the 3-year event- f ree survival

(36 vs . 52%, p < .009) and the 4-year overal l surviva l (75 vs . 87%, p = .04) favored the

tha l idomide maintenance arm, there are severa l caveats to this t r ia l . The f i rs t is that median

fo l low-up is short at 39 months. The second is that on ly 65% of the pat ients on the no-

maintenance arm actua l ly received thal idomide at re lapse. The thi rd is that fewer of the no-

maintenance pat ients rece ived modern salvage therapy wi th lenal idomide or bor tezomib at

re lapse than d id the maintenance group (15 vs. 38%). W ith such a modest survival benef i t ,

i t is poss ib le that th is f ind ing wi l l not survive the tes t o f t ime.

The Tota l Therapy 2 t r ia l was a complex reg imen in which al l pat ients received in tensive

induct ion, tandem t ransplantat ion, and consol idat ive chemotherapy; pat ients were then

randomized to receive ei ther no thal idomide throughout or tha l idomide a long wi th a l l

therapies and cont inued as maintenance. Because of the intens i ty o f the program, i t is

d i f f icu l t to make sweeping genera l izat ions about the role that tha l idomide p layed as

maintenance therapy, but a few observat ions are worthy of note: Though response rates and

event- f ree survival ra tes were s ign i f icant ly

P.2402

bet ter in the group receiv ing tha l idomide, the overa l l surviva l ra tes were no di f ferent . Th is

t r ia l a lso i l lus t ra tes the danger o f concentrat ing too much on event-f ree and progression-

f ree endpoints in the context o f maintenance tr ia ls . Final ly, the quest ion that u l t imately

needs to be addressed is whether sa lvage therapy wi l l be as good as maintenance therapy.

Immunotherapy as Maintenance Therapy

Dendritic Cell-Based Vaccination

In an effor t to prolong durat ion of response and, hopeful ly, surviva l , id iotype- t reated

dendr i t ic cel l vacc ines are being explored as a therapeut ic modal i ty for myeloma pat ients .

B-cel l mal ignanc ies, includ ing mul t ip le myeloma, are un ique in the i r expression of

immunoglobul in (272). The immunoglobul in on mal ignant cel ls can be d is t inguished f rom

that on normal B cel ls or p lasma cel ls by v i r tue of speci f ic id io typ ic determinants . Dendr i t ic

ce l ls are the on ly known natura l cel ls that can present ant igen to naive T ce l ls (619).

Ant igen-pulsed dendr i t ic ce l ls can successful ly induce both humora l and cytotoxic ce l lu lar

immune responses.

Id iotyp ic vacc inat ions a lone have met wi th l imi ted success in human t r ia ls (620,621,622) .

However, vaccinat ion wi th pr imed dendr i t ic ce l ls appears to be a more potent way to induce

ant i tumor immuni ty than vaccinat ion wi th pept ide a lone (623,624,625) . Tr ia ls are now

explor ing the use of dendr i t ic cel l–based vacc inat ions in mul t ip le myeloma (626) .

Management of Relapsed or Refractory Disease

Relapsed and ref rac tory myelomas have dist inc t b iologies but are commonly grouped

together in d iscussions of chemotherapy regimens and tr ia ls. Di f ferent ia t ion between

re lapses occurr ing on therapy and of f therapy should be made, wi th the former having a

poorer prognosis. Simi lar ly, pr imary re f rac tory—the condi t ion in which the d isease has not

responded to in i t ia l therapy—and secondary re f rac tory (or resistant ) disease—should be

d ist inguished f rom each other. Final ly, wi th the growing l is t o f ac t ive agents now avai lable ,

the c lass of agents or the t reatment modal i ty to which the pat ient is ref rac tory should be

spec i f ied.

Before the in t roduct ion of h igh-dose chemotherapy wi th s tem cel l support , IMiDs, and

proteosome inhib i tors , t reatment gu ide l ines were more s t raight forward. I f the re lapse

occurred dur ing an unmaintained remiss ion, resumption of the pat ient 's or ig ina l therapy was

a good ru le (587) . F i f ty to 60% of pat ients responded to repeat t reatment i f re lapse occurred

af ter unmainta ined remiss ions (387,586,587,627) , wi th a median surviva l of about 10

months (587,628). The myeloma ce l l doubl ing t ime and durat ion of response tend to

decrease wi th each subsequent course of therapy (195,304,595). In the case of pr imary

re f rac tory d isease or acqui red res is tance on therapy, the mainstays of t reatment had been

c l in ical t r ia ls—anthracycl ine-based, cort icostero id-based, and a lkyla tor-based reg imens.

Table 99.15 Conventional Combinations for Relapsed, Refractory Disease

Author Regimen N ORR (%)

DOR (mo)

OS (mo)

de Weerdt, 2001 (637)

Continuous low-dose CTX; Pred

42 38 — —

Trieui, 2005 (1099) Weekly CTX; Pred 66 41 — 28.6

Lenhard, 1994 (638) CTX IV; Pred 48 29 — 8.6

Petrucci, 1989 (379) IV Mel 25 mg/m2 34 34 16 8

Tsakanikas, 1991 (376)

IV Mel50-70 mg/m2

18 50 — 11.5

Barlogie, 1984 (391)

VAD 29 59 >12 —

Dimopoulos, 1996 (657)

HyperCVAD 58 40 8 15

Finnish Leukaemia Group, 1992 (1100)

MOCCA 80 49 22 31

Lee, 2003 (672) DT-PACE 148 32 — —

Barlogie, 1989 (286)

EDAP 20 40 — 4.5

Bonnet, 1982 (645) VBAP 151 25 — 7.6

CTX, cyclphosphamide; pred, predisone; mel, melphalan; DOR, duration of response; DT-PACE, dexamethasone, thalidomine, cisplatin, doxorubicin, cyclophosphamide, etoposide; EDAP, etoposide, dexamethasone, doxorubicin, cisplatin; hyperCVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; mo, months; MOCCA, melphalan, vincristine, cyclophosphamide, lomustine, doxorubicin; N, number of patients; ORR, overall response rate (partial response or better); OS, overall survival; VAD, vincristine, doxorubicin, dexamethasone; VBAP, vincristine, carmamustine, doxorubicin, prednisone.

The current landscape, however, is more compl icated. New combinat ions incorporat ing the

new and the o ld agents are be ing tested wor ldwide, leaving c l in ic ians wi th an assor tment o f

opt ions but l i t t le guidance on how to proceed. Does one use a ser ies of s ing le agents ,

adding addi t ional drugs as the s impler regimen fa i ls? And i f so, which agent does one use

f i rst? Or does one bet on synergy and star t wi th a mul t iagent program at f i rs t re lapse? So

far , there are no answers to these quest ions, and pat ient and physic ian preference guide

the dec is ion-making process ra ther than data. Moreover, as we review salvage therapies,

one must remember that response rates for o lder sa lvage regimens were based

predominant ly on a lkyla tors and cor t icostero ids sa lvaging a lkyla tor and cor t icosteroid

fa i lures. One would, for ins tance, expect the cyclophosphamide prednisone sa lvage rate to

be higher for thal idomide and dexamethasone fa i lures than melphalan and prednisone

fa i lures, a l though this hypothesis has not yet been examined in any formal s tudies .

Unt i l myeloma is a curable disease in a l l pat ients, c l in ica l t r ia ls wi l l p lay a cr i t ica l role in

the treatment o f these pat ients . They wi l l ass is t in def ining a better c lass i f icat ion system for

the d isease, c lar i fy which t reatments of fer the most value, and br ing new ef fec t ive agents

in to s tandard c l in ica l pract ice. The subject of chemotherapy for re lapsed or re fractory

d isease wi l l be d iv ided in to four sect ions: a lkylator-based reg imens, anthracycl ine-based

reg imens wi th or wi thout dose- in tensi f ied cor t icostero ids , novel therapies, and other

t reatment modal i t ies.

Alkylator-Based Regimens for Relapsed or Refractory Disease

(Table 99.15) There is c ross-resistance among the a lkyla tors , but th is is not absolute and may be

c i rcumvented by increasing dose in tensi ty. W ithout s ign i f icant dose in tens i f icat ion, 5 to 20%

of pat ients wi th melphalan-res is tant disease respond to cyc lophosphamide or BCNU as

s ing le agents or in combinat ion wi th prednisone (628,629,630,631,632,633,634) . Response

rates as high as 30 to 38% can be obta ined i f prednisone is administered wi th the

cyc lophosphamide (635,636,637) . Higher doses of cyc lophosphamide (e.g. , 600 mg/m2

in t ravenously for 4 consecut ive days) resu l t in response rates of 29 to 43% (254,638). Both

response durat ion and overa l l surviva l

P.2403

tend to be shor t , ~3 and 9 months, respect ive ly (254,638) . Consol idat ing the chemotherapy

in to a 1-day schedule rather than a 4-day schedule does not improve response rates but

does increase toxic i ty (639) . Simi lar ly, administ rat ion of 3 .6 g/m2 over 2 days wi th

prednisone appears to produce comparable responses (640) .

Dose intens i f icat ion of melphalan can also be qu i te e ffec t ive and is the bas is for high-dose

therapy wi th stem cel l support (237) . Selby et a l . (243) repor ted that 66% of pat ients wi th

res is tant d isease t reated wi th 140 mg/m 2 wi thout s tem cel l support responded, but median

response durat ion was on ly 6 months, a l l pat ients relaps ing wi thin a year. Median t imes to

leukocyte and p la tele t recovery were 42 and 37 days, respect ive ly, and the regimen-re la ted

toxic i ty was 13%. Doses of 50 to 70 mg/m2 resul t in a 50% response rate and leukocyte and

p la te le t recovery t ime of 20 and 16 days, respect ive ly (376,377) . Fur ther reduc ing the

in tensi ty to 30 mg/m2 every 2 months resul ts in response rates of 38% and a progress ion-

f ree survival of 10 months (380) .

VBMCP ( the M-2 reg imen) or MOCCA provides responses in 20 to 30% of re f ractory pat ients

(246,363,641) wi th a median surviva l o f about 11 months (246). Combinat ions of c isp la t in

wi th BCNU, cyclophosphamide, and prednisone have produced responses in heavi ly

pret reated pat ients (330); however, the addi t ion of c ispla t in and bleomycin to VBAP d id not

appear to produce bet ter outcomes than s tandard VBAP (286,329,330) .

Dimopoulos et al . (642) exp lored a combinat ion of high-dose cyclophosphamide (3 g/m 2 )

and etopos ide (900 mg/m 2 ) fo l lowed by granulocyte-macrophage colony-s t imulat ing fac tor .

Of the 52 pat ients wi th advanced and ref ractory mult ip le myeloma t reated, 42% responded.

Median t ime to granulocyte recovery was 19 days, and the median durat ion of remission

was 8 months.

Anthracycline-Based Regimens for Relapsed or Refrac tory

Disease Var ious permutat ions of doxorubic in-containing chemotherapy regimens—doxorubic in and

cyc lophosphamide (AC) (386); doxorubic in , BCNU, cyclophosphamide, and prednisone

(ABC-P) (643) ; CAP (644) ; VCAP (387) ; VBAP (645,646) ; and BAP (644) have been t r ied in

pat ients wi th re lapsed and ref rac tory d isease, resul t ing in response rates of 7 to 28%

(387,643,644,645). Response durat ion and surviva l tend to be shor t—<6 and 12 months,

respect ive ly. Responding pat ients tend to l ive 7 to 10 or even 22 months longer than

nonresponders (644,645,646) . Pat ients who have re lapsed d isease, ra ther than res is tant or

re f rac tory d isease, have h igher response rates ( i .e . , c lose to 30%).

Af ter s tudying high-dose cytos ine arabinos ide, c isp la t in , and etopos ide as s ing le agents ,

Bar log ie e t al . (331) did pre l iminary s tud ies wi th DAP (dexamethasone, cytos ine arab inos ide,

and c ispla t in) and la ter EDAP (etopos ide and DAP). In pat ients wi th ref rac tory disease,

response rates wi th these t reatments were 7, 14, 17, 0 , and 40%, respect ive ly. Median

surviva l in pat ients t reated wi th EDAP was 4.5 months. Th is regimen is myelosuppress ive,

wi th more than hal f of t reated pat ients requi r ing p la te le t t ransfus ions and 80% requi r ing

hospi ta l izat ion for neutropenic fever . In the f i rs t month, t reatment- re la ted morta l i ty was 15%.

In the complex Tota l Therapy 2 program, in which th is reg imen was used as par t o f

induct ion, the respect ive incrementa l objec t ive and complete response rates went f rom 55

and 9% to 65 and 15% af ter EDAP therapy (331).

Another approach to t reat ing relapsed or re f ractory myeloma is by augment ing anthracycl ine

and vincr ist ine wi th h igh-dose cor t icosteroids . Alexanian et al . (247) descr ibed VAP (bolus

v incr is t ine 1.5 mg on day 1, doxorubic in 35 mg/m 2 on day 1, and prednisone 45 mg/m 2 for 5

days repeated every 8 days for three cort icostero id pulses) ; response rates accord ing to

SW OG response and improvement cr i ter ia were 47%. Bar log ie et al . (391) publ ished thei r

exper ience wi th VAD, and numerous var iants have fol lowed. The overa l l response rate wi th

VAD in 29 pat ients who had ref rac tory or resistant disease was 59% accord ing to SW OG

cr i ter ia . In the 20 pat ients who had not rece ived pr ior doxorubic in , the response rate was

70%. VAD di f fered f rom VAP in that the former inc luded cont inuous- in fus ion v incr is t ine and

doxorubic in and a s ixfo ld cort icostero id dose intens i f icat ion (391) . The act iv i ty o f VAD has

been substant ia ted by others (647,648,649) . In fec t ion is the most important compl icat ion,

wi th 38% of pat ients having fever and 28%, a documented in fec t ious agent (391) . Ear ly

in t ravenous catheter removal may occur in ~16% of pat ients as a resul t o f thrombosis or

in fec t ion (258) .

Var iants o f VAD include reg imens that al ter the type or dose of cor t icostero id, schedule of

adminis t ra t ion, type of anthracycl ine used, as wel l as the addi t ion of o ther drugs. The

ef fec t iveness of VAMP (methylpredniso lone in p lace of dexamethasone) appears

comparable to VAD, wi th a response rate and overa l l surviva l o f 36% and 20 months,

respect ive ly, in pat ients wi th resis tant disease (260) . Browman et a l . (650) eva luated m-

VAD, in which a l l of the v incr is t ine and doxorubic in was g iven on day 1 over 2 hours and the

dexamethasone on days 1 to 4 and 15 to 18 on ly; the overal l response rate was 27% (95%

CI , 14 to 40%) wi th a median surviva l o f 7 .6 months. The authors expressed concern that

th is reg imen might be less ef fec t ive than s tandard VAD, but the conf idence interva ls o f the

response rate were large. In fac t , the same bolus schedule was used by Dimopoulos et a l .

(a lbe i t in newly d iagnosed pat ients) as one arm of a randomized t r ia l compar ing bo lus VAD

to DVD (VAD, but wi th l iposomal doxorubic in) . Outcomes were ident ical between the two

arms (406) .

Al ternat ive anthracycl ines have been t r ied, inc luding mitoxantrone (NOP or mitoxantrone,

v incr is t ine, and dexamethasone [MOD]) (651,652,653), which have resul ted in response

rates of 25 to 40% (651,653) epi rubic in (399,654) , and l iposomal doxorubic in (400). In one

randomized s tudy, pla teau durat ion was s ign i f icant ly longer in the VAD group than in the

MOD group, but there was no d i f ference in overal l survival (653) . Several invest igators have

added other drugs to the VAD base wi thout measurable benef i t . Concurrent in terferon

(427,655) adds nothing to response rate or overal l survival . In s ing le-arm s tud ies, there

does not appear to be any advantage to the addit ion of cyclophosphamide to VAD, VAMP, or

v incr is t ine, ep i rub ic in , and dexamethasone (VED) to y ie ld CVAD, hyperCVAD, C-VAMP, or

VECD (257,260,399,656,657) .

Novel Therapies for Relapsed or Refractory Disease

Thalidomide-Based Therapy for Relapsed or Refractory Disease

As has been ment ioned, s ing le-agent tha l idomide can induce a response in 25 to 58% of

re lapsed/ref rac tory pat ients (295,297,298,299,300,301,302,303,304) .There appears to be

synergy between thal idomide and dexamethasone (308,658). Response rates of 41 to 55%

(658,659,660,661) have been observed in pat ients wi th res is tant myeloma (Table 99.16) .

Doses of dexamethasone have ranged f rom 4 mg as a da i ly cont inuous dose (661) to 40 mg

on days 1 through 4 of each month (658,660). Dimopoulos et a l . (658) administered

dexamethasone for an addi t ional 8 days (days 9 to 12 and 17 to 20) in the f i rs t month only.

W ith these combinat ion reg imens, tha l idomide dose leve ls have ranged between 100 and

400 mg/day, wi thout any c lear dose–response effec t . Pat ients who are resis tant to

dexamethasone-based (658,659) or tha l idomide-based (662) reg imens may respond to the

combinat ion of these two agents . Coleman et a l . (663) described a 100% response rate for

re lapsed or ref rac tory d isease t reated wi th c lar i thromycin, low-dose tha l idomide, and

dexamethasone. These resul ts have yet to be substant ia ted by other invest igators, and

c lar i thromycin alone is not an effec t ive t reatment (350,351,352).

Invest igators have combined thal idomide wi th alkylators ei ther wi th

(664,665,666,667,668,669) or wi thout cor t icostero ids (670,671) , achieving overal l response

rates as high as 79%, inc lud ing complete response rates as h igh as 26%. Others have

added tha l idomide to anthracyc l ine-based therapies (452,454,672,673) .

Typica l ly, thal idomide is adminis tered once night ly, but Dimopoulos et a l . (665) have taken

a d i f ferent approach by combining cyclophosphamide (150 mg/m 2 by mouth twice da i ly, days

P.2404

1 through 5) , tha l idomide (400 mg PO once dai ly, days 1 through 5 and 14 through 18) , and

dexamethasone (20 mg/m 2 PO once dai ly, days 1 through 5 and 14 through 18). Th is was

repeated every 28 days for three courses; and in subsequent courses drugs were

adminis tered on days 1 through 5 on ly. The only grade 3–4 toxic i ty noted was

myelosuppress ion. Two percent o f pat ients developed phleb i t is and 4% grade 1 neuropathy.

Grade 1 const ipat ion and somnolence were each seen in about one thi rd o f pat ients . Median

t ime to progress ion was 8.2 months, and median overa l l surviva l was 17.5 months.

P.2405

Table 99.16 Novel Combinationations for Relapsed, Refractory Disease

Author Regimen Phase N CR (%)

VGPR (%)

PR (%)

OR (%)

PFS/EFS, (mo)

OS (mo)

Thalidomide-based

Singhal, 1999 (43,310)

Thalidomide

2 169

— — — 30

2 y, 20%

2 y, 48%

Dimopoulos, 2001 (658)

Thal-Dex 2 44 — — 55

55

4.2 12.6

Offidani, 2003 (670)

Mel-Thal 2 27 12

0 48

60

2-y PFS, 61%

2-y OS, 61%

Palumbo (retrospective), 2005 (1101)

Low-dose Thal-Dex

Retro

43 0 — 47

47

20 NR

Hovenga, 2005 (671)

CTX Thal 2 38 11

0 64

75

30 20

Garcia-Sanz, 2004 (664)

CDT 2 71 2 0 53

55

2-y EFS, 57%

2-y OS, 66%

Dimopoulos, 2004 (665)

CDT 2 53 5 0 55

60

TTP 8.2

17.5

Kropff, 2003 (666)

CDT 2 60 3 0 65

68

11 19

Kyriakou, 2005 (667)

Low-dose CDT

2 52 17

0 62

79

— —

Sidra, 2006 (668)

CDT 2 47 0 19

63

83

— —

Palumbo, 2006 (669)

MPT IV 2 24 0 13

29

42

9 —

Zervas, 2004 (452)

T-DVD 2 39 10

10

64

84

— —

Hussein, 2006 (454)

T-DVd 2 49 20

24

31

75

15.5

39.9

Offidani, 2006 (673)

TDD 2 50 26

12

38

76

17 NR

Bortezomib-based

Richardson (SUMMIT), 2006 (321)

Bortezomib

2 193

4 6 18

28

7 17

Bortez-Dex (1.0 mg/m2)

2 27 0 19

19

37

TTP 10.9

26.7

Jagannath, 2004 (322)

Bortez-Dex (1.3 mg/m2)

2 26 0 4 46

50

TTP 7.0

NR

Bortezomib

3 315

6 7 25

38

6 1 y, 80%

Richardson, (APEX) 2005 (320)

Dex 3 312

1 1 16

18

— 1 y, 66%

Kropff, 2005 (1102)

Bortez-Dex 2 15 7 — 67

74

— —

Musto, 2006 (1103)

Bortezomib

2 21 10

0 33

43

— —

Orlowski, 2002 (44,677)

Bortez-pegylated dox

1 22 23

14

36

72

— —

Chanan-Khan, 2005 (1104)

Bortez-pegylated dox-thal

Pilot

6 33

— 17

50

— —

Jakubowiak, 2005a (1105)

Bortez-pegylated dox-Dex

2 20 33

— 22

55

— —

Berenson, 2006 (683)

Bortez-MP 1/2 34 6 9 32

47

8 —

Ciolli, 2006 (681)

Low-dose bortez-thal-dex

2 18 11

— 33

44

— —

Zangari, 2005a (679)

Bortez-Thal-Dex

2 85 0 — 55

55

9 22

Popat, 2005a (461)

Bortez-IV Mel

2 16 — — 75

75

— —

Reece, 2005a* (682)

CTX-Bortez - Pred

2 16 6 — 25

31

— —

Kropff, 2005a (1106)

CTX- Bortez -Dex

2 50 10

— 66

76

10 NR at 10 mo

Palumbo, 2005a (685)

Bortez-MP-Thal

1/2 20 10

10

35

55

— —

Terpos, 2005a (684)

Bortez-MD-Thal

2 25 8 — 48

56

— —

Teoh, 2006a (680)

Bortez-Thal-Dex

2 14 43

21

29

93

— —

Lenalidomide-based

Richardson, 2006 (316)

Lenalidomide

1 102

0 0 13

17

— —

Lenalidomide/dex

3 351/2

14

44

58

TTP 13.3

— Dimopoulos (MM-010), 2005a (688)

Dex 3 351/2

4 18

22

TTP 5.1

—

Lenalidomide/dex

3 177

59

TTP 11

— Weber (MM-090), 2006a (689)

Dex 3 177

21

TTP 4.7

24

Richardson, 2005a (317)

Lenalidomide

2 222

0 0 25

25

TTP 5.1

>15

Richardson, 2005 (693)

Bortez-Lenalid

1 19 5 5 42

53

— —

Gerecke, 2005a (692)

Lenalid-pegylated dox-Dex

1/2 6 100

— —

Baz, 2005a (691)

Pegylated dox-vincristine-Dex-Lenalid

1/2 45 13

11

35

59

— —

Other

Munshi, 2002 (327)

ATO 2 14 0 0 7 7 — —

Hussein, 2004 (328)

ATO 2 23 0 0 0 33b

— —

Abou-Jawde, 2006 (694)

ATO-Dex-AA

2 20 — — — 30

10.4

—

Berenson, 2006 (696)

MAC 2 65 2 0 23

26

7 19

Wu, 2005a (695)

ATO-Dex 2 20 0 0 13

13

— —

Berenson, 2006a (697)

ATO-Bortez-AA

1/2 22 9 0 9 18

— —

Baz, 2006a (456)

Dex/ATO/Thal/AA

2 16 0 0 25

25

9.4 —

AA, ascorbic acid; ATO, arsenic trioxide; Bortez, bortezomib; CDT, cyclophosphamide, dexamethasone, thalidomide (several different schedules); CR, complete response; Dex, dexamethasone; EFS, event-free survival; IFN, interferon; Lenalid, lenalidomide; MAC, melphalan, ATO, AA; MD, melphalan, dexamethasone; mo, months; MP, melphalan, prednisone; MPT IV, intravenous melphalan, prednisone, thalidomide; N, number of patients; NR, not reached; OR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; Retro, retrospective analysis; TDD, thalidomide, pegylated doxorubicin, dexamethasone; T-DVD, thalidomide, pegylated doxorubicin, vincristine, dexamethasone; T-DVd, T-DVD, but low dose dexamethasone; Thal, thalidomide; TTP, time to progression; VGPR, very good partial response; y, years. aAbstract only. bMinimal response.

Most programs a lso include cort icostero ids . Two except ions are the protocols o f Hovenga et

a l . (671) and Of f idani (670) . Hovenga et al . (671) t reated 38 pat ients wi th cont inous low-

dose cyc lophosphamide (100 to 150 mg) and thal idomide (maximum dose of 400 mg).

Median doses of thal idomide and cyclophosphamide were 100 and 95 mg/day, respect ively.

Sixty- four percent of pat ients achieved a response (wi th 11% CR). W ith a median fol low-up

of 22 months, median PFS and OS were 30 and 20 months, respect ive ly. The most common

s ide ef fec ts were drowsiness, neurotoxic i ty, and const ipat ion wi th grade 3–4 rates in 20, 16,

and 13% of pat ients , respect ive ly. One pat ient developed a DVT. Two pat ients died af ter

grade 4 in fect ions. One pat ient developed secondary acute myeloid leukemia. Of f idani e t a l .

(670) t reated 27 pat ients wi th n ight ly thal idomide (100 to 600 mg) and melphalan 0.2

mg/kg/day for 4 days every 28 days unt i l maximum response or toxic i ty. Overa l l response

rate was 60%, includ ing 12% complete responses. At a median fo l low-up of 15 months, both

the 2-year PFS and OS were 61%. The main s ide ef fects were const ipat ion (82%),

somnolence (41%), fa t igue (22%), sensory per ipheral neuropathy (56%), deep venous

thrombosis (11%), and grade 3 leukopenia (30%). However, no severe in fec t ions occurred.

Moehler e t a l . added etoposide to tha l idomide, cyc lophosphamide, and dexamethasone and

reported a 68% response rate in relapsed and ref ractory pat ients (674); th is program was

associated wi th a 36% rate of severe infec t ions.

DT-PACE is a combinat ion of f ive drugs (Table 99.3) and is an in tegral par t of Tota l

Therapy 2 and 3, p i lo ted by Bar log ie and col leagues at the Univers i ty o f Arkansas. Lee et a l .

(672) descr ibed thei r exper ience using this combinat ion in 236 previously t reated pat ients

pr ior to s tem cel l col lect ion. Near ly two th i rds (n = 148) had shown progressive disease

af ter the i r pr ior therapy. Af ter two to four cyc les of DT-PACE, of the 229 evaluable pat ients ,

21 pat ients ach ieved a CR, 29 pat ients a nCR, and 44 pat ients a PR. Response was not

a f fec ted by chemosensi t iv i ty to preceding chemotherapy. The most common grade 3–4

toxic i t ies were myelosuppress ion (39%), neutropenic fever (9%), nausea and vomit ing (6%),

stomati t is (4%), and thromboembol ism (5%). Treatment- rela ted mortal i ty was 4%. Of note,

before rout ine thrombosis prophylaxis , thromboembol ic events occurred in 37% of cyc les

(one th ird o f which were l ine-associa ted thromboses) .

Of f idani e t a l . (673) t reated 50 previously unt reated pat ients wi th ThaDD, a combinat ion of

tha l idomide (100 mg dai ly) , pegyla ted l iposomal doxorubic in (40 mg/m2 on day 1 every 28

days) , and dexamethasone (40 mg PO on days 1 to 4 and 9 to 12) . Twenty-s ix percent o f

pat ients ach ieved a complete response, 6% a near-complete response, 6% a very good

par t ia l response, and 38% a par t ia l response, for an overa l l response rate of 76%. The

median event- f ree surviva l was 17 months, and the median overa l l surviva l has not been

reached. Grade 3 nonhemato log ic toxic i ty occurred in 12% of pat ients , thromboembol ic

d isease in 12%, and severe in fec t ion in 16%.

Hussein et a l . (454) t reated 55 pat ients wi th DVd-T (same as Of f idani , except that

dexamethasone was g iven on only 4 days per cycle) for a maximum of eight cycles , fo l lowed

by maintenance wi th maximum tolerated doses of thal idomide plus al ternate-day oral

prednisone. Though response rates were high (OR 75%, wi th 20% CR), there was

substant ia l toxic i ty assoc iated wi th the program. Grade 3–4 toxic i t ies included

thromboembol ic events in 25%, per iphera l neuropathy in 22%, neutropenia in 14%,

pneumonia in 12%, palmar/plantar erythrodysesthesia in 8%, and thrombocytopenia in 5%.

The median PFS was 15.5 months, and the OS was 39.9 months.

Bortezomib-Based

Therapies for Relapsed or Refractory Disease. Single-agent response rates in

re lapsed/ref rac tory myeloma range f rom 28 to 38%, wi th a median response durat ion of 8

months (319,320,321,322) (Table 99.16) . In v i t ro, there is s igni f icant synergy between

bor tezomib and both chemotherapy (675) and ioniz ing radia t ion (676) . Cl in ica l t r ia ls

exp lo i t ing th is synergy are beginn ing to emerge and are described in the fo l lowing.

Or lowks i e t a l . (44,677) treated 24 pat ients in thei r Phase I t r ia l of bor tezomib plus

l iposomal doxorubic in. Sixty-seven percent of thei r pat ients achieved a PR or bet ter , wi th a

CR rate of 21%. Grade 3 or 4 adverse events seen in a t least 10% of pat ients included

thrombocytopenia (43%), lymphopenia (40%), neutropenia (17%), fat igue (14%), pneumonia

(14%), per iphera l neuropathy (12%), febr i le neutropenia (10%), and d iarrhea (10%).

Zangar i e t a l . (678,679) have pre l iminari ly reported the i r exper ience wi th bor tezomib,

tha l idomide, and dexamethasone (VT + D). In a Phase I t r ia l wi th a 2 ×2 des ign, they

escalated bor tezomib and tha l idomide doses. I f no part ia l response was seen af ter three

cyc les of VT, dexamethasone was added (20 mg the day of and af ter bortezomib dosing) .

The overa l l response rate was 55%; EFS and OS were 9 and 22 months, respect ive ly.

Myelosuppress ion was the most common grade 3–4 toxic i ty. Per iphera l neuropathy

worsened above basel ine in 5 to 9% of these heavi ly pret reated pat ients . In another s tudy

presented in abst rac t form, addi t ion of bor tezomib to thal idomide and dexamethasone

increased the complete response rate f rom 7.7 to 42.9% (680) .

Cio l l i e t al . (681) exp lored the reg imen LD-VTD (Velcade/bor tezomib 1.0 mg/m 2 on days 1, 4,

8 , and 11 every 28 days; dexamethasone 24 mg on days 1, 2 , 4 , 5 , 8 , 9, 11, and 12; and

tha l idomide 100 mg each evening) for up to e ight cyc les . Pat ients rece ived therapeut ic

warfar in as DVT prophylaxis . The overal l response rate was 41%, wi th 11% of pat ients

achieving a CR. After a median fol low-up of 11 months, 6 pat ients had died.

Reece et a l . (682) have treated 16 pat ients wi th bor tezomib, cyc lophosphamide, and

prednisone as par t o f an ongoing Phase I s tudy. Pre l iminary in format ion suggests that there

is ac t iv i ty wi th th is program. So far , the overal l response rate is 31%, including one pat ient

wi th a near-complete response.

Berenson et a l . (683) have t reated 35 pat ients wi th relapsed, re f rac tory myeloma in a Phase

I / I I t r ia l combin ing bor tezomib and melphalan. Thei r maximum to lerated dose is a maximum

of eight 28-day cyc les of bor tezomib 1.0 mg/m2 o n days 1, 4 , 8, and 11, and melphalan 0.1

mg/kg on days 1 through 4. The overal l response rate was 47%, includ ing a combined

CR/VGPR rate of 15%. The authors emphasize that f ive of the s ix pat ients t reated had a

response to therapy. The main s ide ef fects were severe myelosuppress ion, fat igue, and

per iphera l neuropathy. Pat ients have suf fered f rom nausea, vomit ing, d iarrhea, const ipat ion,

fever , and rash.

Terpos et al . (684) have t reated 31 pat ients wi th re lapsed or ref rac tory myeloma wi th VMDT,

a combinat ion of bor tezomib (1 .0 mg/m 2 on days 1, 4 , 8 , and 11) , melphalan (0.15 mg/kg on

days 1 to 4) , dexamethasone (12 mg/m 2 on days 1 to 4 and 17 to 20, and tha l idomide (100

mg dai ly) . Pat ients were t reated for up to eight 28-day cycles . In thei r pre l iminary repor t on

25 of these pat ients , 56% achieved an ob ject ive response, inc luding 8% wi th a complete

response. Adverse events included fa t igue (56%), thrombocytopenia (12% grade 3/4) ,

neutropenia (8% grade 3/4) , anemia (8% grade 3), neuropathy (48% grade 1/2, no grade 3/4

observed) , infec t ions (36%, including two herpes zoster cases) , and hyponatremia (12%).

No pat ient exper ienced a DVT, whi le two pat ients died as a resu l t o f seps is .

In a Phase I s tudy, Palumbo et a l . (685) t reated 20 pat ients wi th VMPT, a combinat ion of

ora l melphalan (6 mg/m 2 on days 1 to 5), prednisone (60 mg/m2 on days 1 to 5) , and

tha l idomide (100 mg cont inuous ly) wi th dose escalat ions of bor tezomib (dose levels ranging

f rom 1 to 1.6 mg/m 2 admin is tered on days 1, 4 , 15, and 22 of each 5-week cyc le). A fu l l

course was def ined as s ix cyc les . Ten pat ients had a response, including two complete

responses, one near-complete response, and seven part ia l responses. Herpes zoster was a

common compl icat ion wi thout acyc lovir prophylaxis .

Other in terest ing combinat ions being explored inc lude samarium Sm153 lexidronam (a

bone-seeking rad ionuc l ide) and bortezomib (686) ; and the combinat ion of bor tezomib,

melphalan, and pegylated doxorubic in (687).

P.2406

Lenalidomide-Based Therapy for Relapsed or Refractory Disease

. Us ing lenal idomide as a s ingle agent , ~18 to 25% of re lapsed or re f rac tory pat ients

achieved a par t ia l response, and the median durat ion of response for responding pat ients

was 20 months (316,317) (Table 15). In a randomized Phase I I t r ia l of lenal idomide, the

addi t ion of dexamethasone (40 mg on days 1 to 4 and 15 to 18) for pat ients not responding

to 2 months of lenal idomide resul ted in part ia l response rates in an addit ional 22% of

pat ients (316) . The combinat ion of lenal idomide and dexamethasone has been studied in

two large Phase I I I t r ia ls (688,689) . The resul ts of the two t r ia ls were comparable, wi th 59%

of pat ients responding to the combinat ion, inc lud ing a 14% complete response rate. Th is

was s ign i f icant ly bet ter than what was observed wi th s ing le-agent dexamethasone (PR

22.5% and CR 2%). In addi t ion, both t ime to progress ion (11 to 13 months vs . ~5 months)

and overal l survival (not reached vs . 24 months) were super ior in the

lenal idomide/dexamethasone arm. A subgroup analysis was per formed to assess the effec t

o f pr ior therapy wi th thal idomide (690). Regardless of whether thal idomide had been used

previously, the lenal idomide/dexamethasone arm outper formed dexamethasone on al l

metr ics . However, there was a t rend toward bet ter lenal idomide/dexamethasone

per formance in pat ients who had not rece ived prior tha l idomide: CR (17.6 vs . 8.1%); and

TTP (13.6 vs . 8 .5 months) .

Baz et al . (691) have t reated 45 re lapsed, ref rac tory pat ients who were evaluable for

response wi th DVd-R (s tandard DVd plus lenal idomide 10 mg dai ly) for four to s ix cyc les ,

fo l lowed by lenal idomide and prednisone. Six had a CR (13%), 5 had a nCR (11%), and 16

had a PR (35%). Most common toxic i t ies were myelosuppression, in fec t ion, and

thromboembol ic events. W ith a median fo l low-up of 7 .3 months, 23 pat ients progressed and

16 died.

A number o f combinat ions are be ing explored, including lenal idomide, doxorubic in , and

dexamethasone (692) ; and lenal idomide, bor tezomib, and dexamethasone (693) . Both

combinat ions are showing evidence of ac t iv i ty.

Arsenic Trioxide Combinations for Relapsed or Refractory Disease

As a s ingle agent , arsenic t r ioxide (ATO) resu l ts in part ia l response rates of about 7%

(327); i f 25% reduct ion in the M-prote in concentrat ion is inc luded as “ response,” the rates

are as h igh as 33% (328) (Table 99.15). The combinat ion of dexamethasone, ATO, wi th and

wi thout ascorb ic ac id , resu l ted in response rates of 30 (694) and 13% (695) , respect ive ly.

Melphalan, ATO, and ascorbic ac id (MAC) provided a 26% response rate (696). Early

resul ts wi th other combinat ions are shown in Table 99.16 (456,697) .

Other Agents for Relapsed or Refractory Disease In terferon has been shown to modulate the mult idrug res is tance phenotype and to re induce

chemosensi t iv i ty in pat ients wi th chemores is tant mult ip le myeloma. In one s tudy,

nonresponding pat ients received the same chemotherapy to which they were res is tant ,

preceded by a 5-day course of in ter feron. An ob ject ive response was achieved in 4 of 14

pat ients (28.6%) (698) .

Severa l invest igators have combined in terferon wi th dexamethasone (402,699) or

methylpredniso lone (700) as therapy for pat ients wi th re lapsed or re f rac tory d isease. W ith

response rates of 29 to 66% (699,700) i t is d i f f icu l t to iso late the cort icosteroid and

in ter feron ef fec ts . There is no c lear evidence that the response rate or the survival t ime

improved compared wi th s imi lar treatments wi thout in terferon (655).

Because pat ients wi th mul t ip le myeloma ref rac tory to a lkylat ing agents f requent ly express

P-g lycoprote in , which is associated wi th the mult idrug res is tance phenotype, cyc losporine, a

mult idrug res is tance reversal agent , has been combined wi th VAD in pat ients wi th ref rac tory

or progress ive d isease. No benef i t was observed (701,702) . As a resul t of the f indings of a

Phase I / I I t r ia l in pat ients wi th myeloma (703) , PSC 833, a mul t idrug-res is tance glycoprote in

modulator , has been incorporated in to a smal l Phase I I I study of VAD versus VAD and PSC

833 in the re lapsed/ref rac tory sett ing (704). There was no d i f ference in response rate,

progress ion- f ree survival , or overa l l survival in the PSC 833 arm, though there was more

toxic i ty.

The human ant i -CD20 ant ibody has demonstrated some ef fec t in pat ients wi th myeloma.

About 20% of pat ients wi th myeloma have CD20 express ion on the i r plasma ce l ls . In one

s tudy, 1 o f 19 pat ients had a part ia l response to therapy; an addit ional 5 had s tab le disease

(705).

Because vascular endothel ia l growth factor has been shown to be involved in myeloma

pathogenes is (706), severa l invest igators have evaluated d i f ferent ant i -VEGF therapeut ic

s t rategies. Somlo et al . (707) have explored the ro le o f the ant i -VEGF ant ibody rhuMAB

bevacizumab versus bevac izumab and thal idomide in a randomized Phase I I t r ia l . Twelve

pat ients have been enro l led. Median t ime to progress ion for the 6 pat ients t reated wi th

bevacizumab a lone was 2 ( range 1 to 4) months. Progress ion- f ree survival for the 5

evaluable pat ients t reated wi th bevac izumab and thal idomide was 6 +, 7, 8 +, 10, and 30 +

months, wi th 2 pat ients st i l l on study and in response. Zangar i e t a l . have evaluated

SU5416, a smal l -molecule VEGF receptor-2 inhibi tor , in 27 pat ients wi th myeloma in a

mult icenter Phase I I s tudy (708) . Grade 3/4 toxic i t ies were rare ly observed; the most

f requent was thrombocytopenia (12%). There were three thromboembol ic ep isodes and f ive

cases of new-onset hyper tens ion. There were no ob ject ive responses, and overa l l median

surviva l was 42 weeks ( range, 3 to >92 weeks) . A decrease in median VEGF p lasma leve ls

was observed in pat ients wi th s tab le disease (n = 7) compared to pat ients wi th progressive

d isease (n = 5) .

The Hsp 90 chaperone inh ib i tor 17-AAG is showing promise in combinat ion wi th bor tezomib

in myeloma pat ients . In a Phase I t r ia l , Chanan-Khan et a l . t reated 20 pat ients (709) . Of the

12 bor tezomib-ref rac tory pat ients , one pat ient had a near-complete response and another

f ive had a 25% reduct ion in thei r serum M prote in.

Radiation Therapy As ear ly as the mid-1920s there was recogni t ion that externa l -beam radiat ion therapy could

promote immediate rel ief o f pa in , heal ing of patho log ic f rac tures, and resolut ion of

ext ramedul lary p lasmacytomas (25,710,711) . Unt i l the 1950s, radia t ion therapy was the only

e f fec t ive t reatment avai lab le for the management o f plasma ce l l tumors. W ith the advent o f

sys temic chemotherapy, indicat ions for i r rad ia t ion were pr imar i ly pa l l ia t ion of bone pain and

so l i tary p lasmacytomas. Concern for mainta ining bone marrow reserve a lso constrains the

use of radia t ion in pat ients wi th mul t ip le myeloma. Sykes et al . (712,713) showed that

rad ia t ion has long-term ef fec ts on the bone marrow; the major i ty o f pat ients rece iv ing

concentrated local doses of 3,500 cGy or more showed pers is tent loca l ized marrow aplasia .

One must admin is ter enough radia t ion to provide pa l l iat ion, wi thout jeopard iz ing

opportun i t ies for fur ther systemic therapy. In a ret rospect ive review, Norin (714) has found

that objec t ive improvement was lacking when the tumor dose was below a cumulat ive dose

(s ing le-dose equivalent ) o f 1 ,000 cGy. For pa l l ia t ion, the recommendat ion is therefore a

cumulat ive dose of 1 ,500 cGy, corresponding to a tumor dose of 3 ,400 cGy, in 10 to 15

f ract ions (714,715) . Leigh et a l . (716) recommended a to tal cumulat ive dose of 1 ,000 cGy in

these same pat ients. There is controversy as to whether the durat ion of response corre la tes

wi th the radia t ion dose in myeloma pat ients (716,717).

In contrast , the convent ional wisdom has been that pat ients wi th sol i tary p lasmacytoma of

bone should rece ive h igher doses in an at tempt a t cure. Al though the opt imal dose has not

been estab l ished by randomized control led tr ia ls, 4 ,000 to 5 ,000 cGy encompass ing a l l

disease wi th a marg in of normal t issue is recommended by most exper ts (718,719,720). A

recent s tudy of 203 pat ients wi th so l i tary plasmacytoma of bone has brought this pr inc iple

in to quest ion (721). These authors found that therapeut ic doses >3,000 cGy had no bear ing

on loca l control .

P.2407

Radiat ion can often spare pat ients f rom undergoing surgery (722) . In a recent ret rospect ive

analys is of 35 cases of pat ients wi th cervica l les ions and sp ina l ins tab i l i ty , i t was found that

19 of the 20 pat ients exper ienced resolut ion of pain , 15 of whom received rad ia t ion a lone.

Of the 10 pat ients wi th suf f ic ient fol low-up data, none showed c l in ical progress ion of

instabi l i ty .

Sequential Half-Body (Hemibody) Irradiation The f i rs t report of us ing whole-body i r rad ia t ion to t reat myeloma was by Medinger and

Craver (723) in 1942. Par t ia l or complete re l ie f o f pa in was noted in the majori ty o f pat ients .

Once ef fec t ive systemic chemotherapy came in to wide use, th is approach became less

popular unt i l 1971, when Bergsagel (724) postu lated that sequential hemibody rad ia t ion

could be a means of debulk ing tumor. He suggested that i f a dose of ~725 cGy were g iven

to the upper ha l f o f the body and 1,000 cGy to the lower ha l f , a theoret ical 3- log k i l l cou ld

be achieved and surviva l prolonged. Af ter a ser ies of re trospect ive s tudies

(606,725,726,727,728,729,730,731,732) and a randomized study (390,733) eva luat ing i ts

ro le in the ear l ier phases of myeloma, hemibody i r radia t ion has once again fal len out o f

favor . In pat ients who have end-s tage d isease, wi th poor pa in control , th is t reatment may

s t i l l be important.

The majori ty o f ser ies invo lv ing hemibody or sequential hemibody radia t ion are

re t rospect ive and inc lude pat ients who were ei ther res is tant to or relaps ing f rom a lkylator-

based therapy. Signi f icant rel ie f of bone pain occurred in 80 to 90% of pat ients

(606,725,726,727,728,729,730,731,732) , and the median durat ion of surviva l was 5 to 11

months (715,727) Object ive b iochemica l response occurred in 25 to 50% of pat ients

(606,727,734) . Pain rel ief typ ica l ly occurred 1 to 2 days after ins t i tu t ion of therapy, wi th a

maximal response in 1 to 2 weeks (725) . The most common s ide ef fec ts were moderate

myelosuppress ion, pneumoni t is , nausea, vomit ing, diarrhea, and s tomat i t is (715,725) . I f an

ora l lead shie ld was not used, mucos i t is a lso occurred (715) . Nadirs occurred wi thin 3

weeks (727), and whi te ce l l count and pla te le t count recovery occurred by about 6 weeks

(715,727) . Decrements in pulmonary funct ion occurred in about ha l f o f the t reated pat ients

(715). The most serious compl icat ion was radia t ion- induced pneumoni t is , which was seen in

14% of pat ients (727) . The opt ion of sequent ia l ha l f -body rad ia t ion therapy must be

ba lanced against unpredic tab le and varying degrees of pancytopenia and a l ternat ive

t reatment opt ions (734).

Bergsagel 's postu late (724) and prel iminary data f rom several smal l s tud ies (726,730,731)

led two cooperat ive group s tudies (SW OG 8229 and CALGB 8003) to incorporate systemic

rad ia t ion therapy as consol idat ion therapy (390,733) . Nei ther s tudy demonstrated a

meaningful advantage to pat ients rece iv ing ad juvant hemibody rad ia t ion (390,733) , and

hemibody rad iat ion is used only for pa in pal l ia t ion in end-stage chemotherapy-ref ractory

myeloma pat ients .

Pathogenesis, Pathophysiology, and Prognosis Pathogenesis and prognos is wi l l be covered together, because in many ins tances there is

an in t imate re la t ionship between them. To date no single molecular defect can account for

the pathogenes is o f mult ip le myeloma, though us ing s ing le-nuc leot ide polymorphisms and

gene express ion prof i l ing, several candidate genes have been ident i f ied as be ing d i f ferent

between MGUS and MM (735,736) . Mal ignant plasma ce l ls are long-l ived ce l ls, typ ical ly

wi th low pro l i ferat ive ra tes and label ing ind ices (199,737) . A postgerminal ce l l o f or ig in is

indicated by the i r somat ica l ly hypermutated, rearranged immunoglobul in genes (738) . A

mult i tude of abnormal i t ies has been ident i f ied in s ignal ing pathways, apoptot ic mechanisms,

the bone marrow microenvi ronment , and the ce l l cyc le . Factors including the leve l o f gene

express ion, prote in express ion, and gene product phosphoryla t ion s ta tus of ce l l -cycle

molecules may al l be re levant for the propagat ion of the mal ignant p lasma ce l ls .

Ext race l lu lar s ignal ing a l terat ions inc lude changes in st romal ce l l , os teoblast , os teoclas t ,

vessel endothel ia l cel l , and immune ce l l in teract ions. These changes may in turn resu l t in

ac t ivat ion, adhes ion, and cytok ine product ion that fue l myeloma ce l l pro l i ferat ion and

surviva l (F ig . 99.13) .

Figure 99.13. Putative pathogenic mechanisms in myeloma. IGF, insulinlike growth factor; IL, interleukin; MIP, macrophage inflammatory factor; MMP, metalloproteinase; NCAM,

neural cell adhesion molecule; TNF, tumor necrosis factor; VEGF, vascular-derived endothelial growth factor; VLA, very late antigen.

Bone Marrow Microenvironment There is a synerg is t ic , patholog ic rela t ionship between myeloma ce l ls and the ce l ls

compr is ing the bone marrow microenvironment , inc luding f ibroblasts , os teoblasts, and

osteoc lasts . The s t romal cel ls in the marrow of myeloma pat ients produce h igh leve ls of

in ter leukin-6 ( IL-6) in v i t ro (739) . The IL-6 serves as a growth and survival fac tor for benign

and mal ignant plasma cel ls, which produce IL-1β (740,741) , VEGF, and macrophage

in f lammatory protein-1α (MIP-1α ) (742,743) . In turn, IL-1β and MIP-1α regulate and act ivate

osteoc lasts (740,744,745) .

A cel l adhesion molecule be longing to the immunoglobul in super family, CD56 (N-CAM), is

s t rongly expressed in most p lasma cel ls of myeloma pat ients (746) and is be l ieved to p lay a

ro le in myeloma homing and cel l adhesion to the marrow. Increased levels o f the adhes ion

molecules lymphocyte funct ion–associated ant igen (LFA)-3 (212) , LFA-1 (CD11a) (747) , and

very la te ant igen-4 (VLA-4) are expressed on the myeloma ce l ls in the major i ty o f pat ients .

VLA-4 may act to b ind myeloma ce l ls to f ibronect in in bone marrow (748) , which under

appropr ia te condi t ions can s ign i f icant ly increase IL-6 product ion by s t roma (749) . Cel l–ce l l

contact between marrow s t romal ce l ls and myeloma cel ls v ia VCAM-1 and α4β1 - in tegr in

enhances product ion of os teoc las t -s t imulat ing act iv i ty (750) . Hyaluronan, a

g lycosaminoglycan component of the bone marrow ext race l lu lar matr ix, appears to be a

surviva l and pro l i ferat ion factor for myeloma ce l ls (751) . Notch receptors are expressed in

ear ly hematopoiet ic s tem ce l ls , and Notch l igands are expressed on bone marrow s tem cel ls

(BMSCs). Myeloma cel ls expressing Notch receptors are act ivated by the BMSC Notch

l igand, protect ing the myeloma cel ls f rom drug- induced apoptos is . In addi t ion, th is

in teract ion also act ivates Notch s ignal ing in BMSCs, leading to secret ion of IL-6, VEGF, and

IGF-1 (752).Cel l -adhes ion drug resis tance (CAM-DR) is a wel l - recognized ent i ty (753) .

The endothel ia l microvascular environment has a lso been shown to be important in mult ip le

myeloma b io logy (201) . There

P.2408

is a high correla t ion between the extent of bone marrow angiogenes is , eva luated as

microvessel area, and the prol i ferat ing (S-phase) f rac t ion of marrow p lasma cel ls in pat ients

wi th mul t ip le myeloma and in those wi th MGUS (201,754,755) . VEGF plays an important role

in angiogenes is by act ing as a potent inducer o f vascular permeabi l i ty as wel l as serving as

a spec i f ic endothel ia l ce l l mi togen. Plasma cel ls in the bone marrow f rom mult ip le myeloma

pat ients express VEGF (756,757) , which can thereby interact wi th the Fl t -1 and KDR high-

af f in i ty VEGF receptors that are h igh ly expressed on bone marrow myelo id and monocyt ic

ce l ls surrounding the tumor (754) .

Invest igators are beginning to unders tand the complex in teract ions between osteoclasts ,

os teoblasts, and myeloma ce l ls . The receptor act ivator of NFκB (RANK), which is found on

osteoc lasts , in teracts wi th RANK l igand (RANKL) found on osteoblasts and bone marrow

s t romal ce l ls. These in teract ions contr ibute to bone destruc t ion (758) . Myeloma cel ls also

prevent d i f ferent ia t ion of os teoblasts through secret ion of the Wnt-s ignal antagonist DKK1

(759). MIP-1a is produced by myeloma cel ls and serves as an inducer o f os teoc las t

format ion (760) . In turn, os teoc las ts produce a number of fac tors that s t imulate myeloma

ce l ls, including IL-6 (141) .

Cytokines and Cell Signaling The search for a growth fac tor for myeloma ce l ls cu lminated in the ident i f icat ion of IL-6,

former ly known as B-cel l growth fac tor or hybridoma growth fac tor (761). IL-6 is among the

most important prol i ferat ion and surviva l fac tors in myeloma (762). Predominant ly produced

by bone marrow s tromal ce l ls—macrophages, f ibrob lasts , osteoblasts , osteoclas ts , and

monocytes (F ig. 99.13) (763)—it serves as a growth fac tor and as an ant iapoptot ic fac tor

(764,765,766,767). In the majori ty of cases, myeloma ce l ls and cel l l ines are capable of

producing IL-6 and the IL-6 receptor , resu l t ing in autocrine st imulat ion (764,765,766,767) .

IL-6 t ransmi ts messages in t race l lu lar ly through the s ignal - t ransduc ing prote in gp130, which

can act ivate two pathways: the JAK-STAT pathway (768) and the Ras-MAP k inase pathway

(769). Through the former pathway, which inc ludes JAK-2 and STAT3, the ant iapoptot ic

proteins Mcl -1 (768) and Bc l -XL (770) are up-regulated; through the la t ter pathway,

t ranscrip t ion fac tors such as ELK-1, AP-1, and NF-IL-6 (768) are up-regulated. NF-κB (771)

and IL-6 (772,773) may a lso mediate the observed increase in the ant iapoptot ic proteins

Bc l -2 (774,775), Mcl -1 (772) , and Bcl -XL (772,773,776,777) . The overal l e f fec t o f these

pathways is prevent ion of apoptosis and enhancement o f mul t ip le myeloma prol i ferat ion. In

addi t ion, the const i tu t ive act ivat ion of STAT3 may a lso be important in the pathogenesis o f

mult ip le myeloma, independent o f IL-6 (778) . Moreover , CD40 act ivat ion of myeloma cel ls

can a l ter the cel l sur face phenotype, t r iggering autocr ine IL-6 secret ion regulat ing myeloma

ce l l cyc le in a p53-dependent fashion (779) .

Other cytokines and growth fac tors produced by myeloma and st romal ce l ls that maintain

myeloma growth (780) inc lude IL-1β (781,782,783) , VEGF, insul in l ike growth fac tor ( IGF)

(784,785,786,787,788,789) , and tumor necros is fac tor-α (790,791). Aberrant expression of

IL-1β may be a cr i t ical s tep in the trans i t ion of MGUS to mul t ip le myeloma (740,783). IL-1β

up-regulates product ion of IL-6, changes expression of cel l adhesion molecules, and has

been shown to have osteoc last -ac t ivat ing fac tor ac t iv i ty. A l though IL-1β does not st imulate

myeloma ce l l prol i ferat ion d irect ly, by v i r tue of i ts e ffec t on s t romal ce l ls in the marrow i t

induces product ion of IL-6 (741) and IL-8 (792) . Myeloma ce l ls are capable of express ing

and secret ing VEGF and responding to the cytok ine in an autocr ine fash ion (742,743).

Moreover , s t romal and microvascular endothel ia l ce l l exposure to VEGF induces an

increase in IL-6 secret ion (742) , which then fur ther st imulates myeloma ce l ls . The prec ise

ro le that basic f ibroblast growth fac tor (bFGF), another potent angiogenic factor , p lays in

the growth of myeloma ce l ls is under ac t ive invest igat ion (793). Higher bFGF leve ls have

been found in more advanced s tages of mul t ip le myeloma (793) . IGF, which is bel ieved to

s ignal through the phosphat idyl inos i to l -3 ′-k inase (PI-3K) pathway (784) , is capable of

d i rec t ly s t imulat ing myeloma ce l l growth and enhancing myeloma cel l respons iveness to IL-

6 through mi togen-act ivated prote in k inase (787) and a lso inhibi t ing apoptos is by increasing

express ion of BAD (784).

Cell Cycle Regulatory s ignals underly ing prol i ferat ion of myeloma ce l ls inc lude increased cycl in D1

express ion, hypermethyla t ion of the cyc l in-dependent k inase (CDK) pathway regulatory

gene p16 (794), mutat ions of the ras oncogene (795,796) , loss of p53 (795,796) , and

poss ib ly overexpression of c-myc in progressive d isease (797) .

Approximate ly one–thi rd o f myeloma pat ients have up-regulat ion of cyc l in D1 by

immunohis tochemis t ry; the plasma ce l ls o f these same pat ients tend to have h igher

pro l i ferat ive ra tes (798) . The t (11;14) (q13;q32) translocat ion, which juxtaposes the

immunoglobul in heavy-chain promoter and the cyc l in D1 gene, is seen in ~25% of mul t ip le

myeloma pat ients (799,800,801,802,803) . Bergsagel et a l . have postula ted that ac t ivat ion of

one of the three cyc l in D genes is an in i t ia t ing event in myeloma (804) .

Both p15 and p16 are important cel l cycle inhib i tors that suppress cel l pro l i ferat ion through

inhib i t ion of CDK4 or CDK6 or both, thereby prevent ing the phosphoryla t ion of the

re t inoblastoma gene (RB) . A l though large de let ions of p15 and p16 are rare in myeloma (0

to 12% of cases) (805,806,807) , se lec t ive methyla t ion of these genes, a form of

t ranscrip t ional inact ivat ion, occurs in as many as 67 and 75% of cases, respect ive ly

(808,809,810) . Most data, including our own (811,812) suggest that hypermethyla t ion of p16

or p15 is assoc ia ted wi th d isease progression (811,812) .

K- and N- ras mutat ions have been descr ibed in 25 to 100% of newly d iagnosed mul t ip le

myeloma pat ients (796,813,814) , depending on the technique used for detect ion. A p53

tumor-suppressor gene delet ion is present in less than one th i rd of plasma cel ls f rom newly

d iagnosed myeloma pat ients (815), and mutat ions are even less common (816,817,818,819).

The c-myc protein and c-myc RNA are overexpressed in ~25% of mult ip le myeloma pat ients

(820,821) . Rearrangements of c -myc gene are present in ~15% of pat ients wi th mult ip le

myeloma or pr imary PCL (822) . Dysregulat ion of c -myc appears to be caused pr incipa l ly by

complex genomic rearrangements that occur dur ing la te s tages of mul t ip le myeloma

progress ion (797) .

Prognosis and Staging Surviva l o f mult ip le myeloma pat ients var ies f rom months to more than a decade (589,823).

There are no precise methods of ident i fy ing the subset o f newly d iagnosed pat ients who are

best served by s tandard-in tensi ty therapies, by maintenance therapies, by novel therapies,

or by more intens ive regimens such as hematopoiet ic stem ce l l t ransplantat ion. Prognost ic

fac tors are needed for pat ient counsel ing, therapeut ic dec is ion making, and c l in ical t r ia l

s t rat i f icat ion.

Stag ing is one form of prognost ic model ing. The Dur ie-Salmon system (Table 99.17) , which

unt i l recent ly was the most widely accepted mult ip le myeloma s tag ing system, separates

pat ients predominant ly by tumor burden and renal funct ion (28) . As the b io logy of myeloma

is bet ter understood, novel markers ref lec t ing myeloma cel l k inet ics , s ignal ing, genet ic

aberrat ions, and apoptosis have ecl ipsed the prognost ic s ign i f icance of tumor burden as a

predic tor o f surviva l .

A l though the Durie-Salmon system has some prognost ic u t i l i ty (28) , o ther b iolog ic var iab les

appear to be more va luable (388,824,825,826,827,828,829,830) . At the t ime of i ts incept ion,

the Dur ie-Salmon s taging system was an elegant system that incorporated information about

immunoglobul in product ion and hal f - l i fe, hemoglob in, ca lc ium, creat in ine, and extent o f

bone disease to der ive

P.2409

mathematica l ly the to ta l myeloma ce l l burden (28) . Quant i f icat ion of bone lesions used in

th is staging system, however, is not a lways rel iab le as a prognost ic factor (827) in that

pat ients c lass i f ied as s tage I I I so le ly on the basis o f bone lesion cr i ter ia do not have a

poorer prognosis.

Table 99.17 Durie-Salmon Staging System

Criterion Measured Myeloma Cell Mass (cells× 1012/m2)

Stage I

All of the following: Hemoglobin >100 g/L Serum calcium <12 mg/dl On radiograph, normal bone structure (scale 0)a or solitary bone plasmacytoma only Low M-component production rates IgG <50 g/L IgA <30 g/L Urine light-chain M component on electrophoresis <4 g/24 hours

<0.6 (low)

Stage II

Fitting neither stage I nor III 0.6–1.2 (intermediate)

Stage III

One or more of the following: Hemoglobin <85 g/L Serum calcium >12 mg/dl Advanced lytic bone lesions High M-component rates High M-component rates IgG >70 g/L IgA >50 g/L Urine light-chain M component on electrophoresis >12 g/24 h

>1.2 (high)

Subclassification

A: Serum creatinine <2 mg/dl B: Serum creatinine ≥2 mg/dl

aScale of bone lesions: normal bones, 0; osteoporosis, 1; lytic bone lesions, 2; and extensive skeletal destruction and major fractures, 3. From Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975;36:842–854.By permission of the American Cancer Society.

Other variables , inc lud ing pat ient age, per formance s tatus, serum a lbumin, immunoglobul in

isotype, and bone marrow p lasma ce l l in f i l t ra t ion, have long been recognized to pred ic t

surviva l (831,832), and subsequent models have incorporated these fac tors

(253,589,830,833) (Table 99.18). Myeloma b io logy is better addressed by increased

concentrat ions of serum β2 -M, C-react ive protein , c i rcula t ing plasma ce l ls by per iphera l

b lood label ing index, o ther serum markers , bone marrow PCLI , and chromosomal

abnormal i t ies (388,824,825,828,829,830) . W hen designing a new s tag ing system, one must

choose between readi ly ava i lab le , inexpens ive markers , which f requent ly descr ibe the host

more than the int r ins ic propert ies of the myeloma, or more esoter ic , expens ive markers,

which ref lec t the int r insic bio logy of the indiv idual pat ient 's myeloma ce l ls . Each of these

systems has value, but the goal is to reach a consensus and to s tandard ize d iscuss ions and

comparisons among c l in ica l t r ia ls and outcomes. An internat ional consensus panel has

addressed this issue and developed the In ternat ional Stag ing System ( ISS) for mul t ip le

myeloma; i t incorporates serum a lbumin levels and β2 -microglobul in (491) . Though this

s tag ing system sat isf ies the former condit ion—it is inexpensive and readi ly ava i lab le—it

does not get to the hear t o f myeloma ce l l b io logy as genet ic changes do. Invest igators in

the myeloma communi ty have preferred severa l genet ic c lassi f icat ion systems; the next s tep

wi l l be to arr ive at a consensus system for th is as wel l . W ith these basic concepts in mind,

var ious prognost ic markers wi l l be d iscussed independent ly, and Tables 99.18 and 99.19

summarize severa l invest igators ' e f for ts to in t roduce more meaningfu l s tag ing systems.

Individual Prognostic Markers

β2-Microglobulin β2 -M concentrat ion is the s trongest and most re l iab le prognost ic fac tor for mul t ip le myeloma

that is rout ine ly ava i lable (Table 99.18) . I t depends not only on tumor burden but a lso on

renal funct ion. Elevated β2 -M va lues predict ear ly death (825,828,834) . Formulas to correct

the β2-M concentrat ions for the ef fec ts of renal insuf f ic iency have not improved i ts

predic t ive va lue (835) ; the β2 -M va lue is st i l l prognost ic in myeloma pat ients wi th normal

renal funct ion (824). β2 -M va lue a lso predicts h igh-dose therapy outcome ( i .e . , event- f ree

and overal l survival ) (245,837,838,839,840,841) . However, the Br i t ish Medica l Research

Counci l has shown that a f ter 2 years of survival , the ini t ia l β2 -M concentrat ion loses i ts

prognost ic va lue (836) .

C-Reactive Protein French invest igators f i rs t showed that C-react ive protein was usefu l as a un ivaria te and

mult ivar ia te (828) prognost ic marker in mul t ip le myeloma (Table 99.18) . These f ind ings

were substant ia ted in groups of pat ients f rom the Mayo Cl in ic (825) . C-react ive protein

va lues also predic t h igh-dose therapy outcome (803). However, C-react ive prote in

concentrat ion does not appear to be usefu l as a marker o f d isease s ta tus (842) .

Lactate Dehydrogenase Increased lac tate dehydrogenase va lues ident i fy a group of pat ients wi th poor prognos is

and aggressive d isease, sometimes a lymphomal ike d isease character ized by tumor masses

and ret roperi toneal adenopathy wi th a shor t c l in ica l course (843,844,845) . Only 7 to 11% of

pat ients wi th newly d iagnosed myeloma have an increased concentrat ion of LDH (132,845) .

Bone Marrow Plasma Cell Number and Morphology The quant i ty, growth patterns, and morpholog ic features of bone marrow p lasma cel ls have

been evaluated as prognost icators for pat ients with myeloma wi th var iab le resu l ts

(833,846,847,848,849) . Al though the est imat ion of percent bone marrow p lasmacytos is is

not a lways reproducible (846,847) , invest igators have repor ted prognost ic s ign i f icance

(833,849) . Bar t l e t a l . (833) constructed an int r icate s tudy of bone marrow character is t ics o f

myeloma pat ients (Table 99.18) . The archi tec tural pat tern of growth—inc lud ing in ters t i t ia l ,

in ters t i t ia l /sheets , in terst i t ia l /nodular , nodular , and packed—correla tes wi th survival

(833,849) , as does the plasma ce l l morphology (833). Accord ing to Bar t l e t al . (833),

myeloma ce l l h is to log ic features can be c lass i f ied in to s ix types: (a) Marschalko type—

predominant ly normal-appearing p lasma ce l ls wi th a mean s ize of 21 µm; (b) smal l cel l

type—smal l , round, and lymphoplasmacyto id wi th a mean size of 13 µm; (c) c leaved type—

notched, c leaved, or even convoluted nucle i o f var iab le s ize; (d) po lymorphous type—

marked ce l lu lar po lymorphism and mult inuclear i ty, wi th in terspersed giant p lasma cel ls and

cytoplasmic inc lusions; (e) asynchronous type—marked asynchronous maturat ion of the

nucleus and cytop lasm, large eccentr ic nuc lei , f requent nucleol i , and a pronounced

per inuc lear “hof ”; and ( f) b las t ic type—plasmablasts wi th large nuc le i , prominent centra l ly

located nucleol i wi th a moderate r im of basophi l ic cytoplasm, and a fain t per inuclear hof

(Table 99.18) . Nei ther o f these morpholog ic features—archi tec ture or p lasma cel l

phenotype—has been appl ied widely.

Other invest igators have demonstrated the powerfu l prognost ic s ign i f icance of immature or

p lasmablast ic plasma cel ls (199,200,826,845,850,851,852,853,854) . Plasmablast ic

morphology is assoc ia ted wi th a h igh PCLI , a higher leve l o f s IL-6R, and ras mutat ions

(826).

P.2410

Elect ron microscopy conf i rms that immature nuclear morphology and nuc lear cytoplasmic

asynchrony corre la te wi th one another and wi th poor prognos is (855) . Nuclear immaturi ty

and three cytoplasmic abnormal i t ies—scattered pat terns of mi tochondr ia, s ing le-sac

loopl ike s t ructures, and numerous in trami tochondr ial granules—have been associa ted wi th

poor outcome.

Table 99.18 Noncytogenetic Prognostic and Staging Systems in Newly Diagnosed Multiple Myeloma Patients (Standard-Intensity Chemotherapy Unless Stated

Otherwise)

Study No. of Patients

Risk or Stage Patients (%)

Features OS (mo)

Durie and Salmon, 1980 (28,1107)

150 IA IIA & IIB IIIA IIIB

11 27 50 13

Defined in Table 4.17

61 54 30 15

Low 22 BUN ≤8 mM and Hb >100 g/L

>48

Intermediate 56 Not meeting other criteria

~34

MRC, 1980 (253)

485

High 22 BUN >10 mM and Hb ≤75 g/L

~24

Low grade 71 Marschalko and small PCa

40

Intermediate grade

28 Cleaved, polymorphous asynchronous PC

20

Bartl et al., 1987 (833)

674

High grade 2 Plasmablastic PC

8

Low 30 PCLI <0.4% and β2-M <4 mg/L

48

Intermediate 25 PCLI ≥0.4% or β2-M ≥4 mg/L

29

Greipp et al., 1988 (824)

100

High 45 PCLI ≥0.4% and β2-M ≥4 mg/L

12

Low 50 β2-M and CRP <6 mg/L

54

Intermediate 35 β2-M or CRP ≥6 mg/L

27

Bataille et al., 1992 (828)

162

High 15 β2-M and CRP ≥6 mg/L

6

Low 14 PCLI <1% and β2-M <2.7 mg/L

71

Intermediate 54 PCLI ≥1% or β2-M ≥2.7 mg/L

40

Greipp et al., 1993 (825)

107

High 32 PCLI ≥1% and β2-M ≥2.7 mg/L

17

Ib 26 REb <6 or SM: ((a–d)=0

>80

II 52 6 ≤ RE ≤ 8.5 or SM: 0 > ((a–d)≤ 3

36

San Miguel et al., 1995 (830)

120

III 22 RE >8.5 or SM: ((a–d) ≥4

9

I 61 Hb ≥100 g/L and BMPC <70%

57

II 25 Hb <100 g/L or BMPC ≥70%

45

Finnish Leukaemia Group, 1999 (589)

324

III 14 Hb <100 g/L and BMPC ≥70%

25

I 13 β2-M <2.5 mg/L 53

II 43 β2-M ≥2.5 but <5.5 mg/L

41

III 33 β2-M ≥5.5 mg/L and alb >3 g/dl

24

Crowley et al., 2001 (388)

1,026

IV 11 β2-M ≥5.5 mg/L and alb <3 g/dl

16

I 29 β2-M <3.5 mg/L and alb ≥3.5 g/dl

62

II 38 Not stage I or III 45

International Staging System (491)

8,056

III 33 β2-M ≥3.5 mg/L 29

Alb, albumin; β2-M, β2-microglobulin; BMPC, bone marrow palsma cells; BUN, blood urea nitrogen; CRP, C-reactive protein; ECOG, Eastern Cooperative Oncology Group; MRC, Medical Research Council Working Party on Leukaemia in Adults; OS, overall survival; PC, plasma cells; PCLI, plasma cell labeling index; SWOG, Southwest Oncology Group. aSee text for details. The Bartl staging system is a plasma cell (PC) morphology–based staging system. bFrom risk equation (RE) and simplified model (SM): RE: (2.2 * %S phase PC) +(0.8 (β2-M) +(1.2 * ECOG) + (0.9 * age). SM: (a) S phase ≥ 3% (+2); (b) β2-M ≥ 6 µg/ml (+1); (c) ECOG ≥ 3 (+1); (d) age ≥ 69 (+1); absence of each (+0).

Plasma Cell Labeling Index The PCLI of bone marrow p lasma ce l ls is a reproducible and powerful prognost ic factor in

mult ip le myeloma (824,825,830,856) (Table 99.18) . The PCLI is determined f rom an

immunof luorescence sl ide-based assay (199) . Cel ls in DNA S phase of the ce l l cycle

incorporate bromodeoxyur idine, which can be recognized by us ing a monoc lonal ant ibody.

S-phase cel ls are then marked wi th a second ant ibody, and p lasma cel ls are recognized by

morphology and react iv i ty wi th ant ihuman immunoglobul in κ and λ l ight chains. An increased

PCLI pred ic ts a shor t remission and surviva l but does not predict response to therapy. Al l

la rge studies publ ished to date have conf i rmed the independent prognost ic va lue of the

PCLI for surviva l a f ter t reatment wi th convent ional chemotherapy (824,826,851,857) or

h igh-dose therapy (838) . Other methods for determining pro l i ferat ion inc lude Ki67

immunohis tochemica l s ta ining (858,859) , and determinat ion of S phase by f low cytometry

(830,860,861) . W itz ig et a l . (862,863) have also demonstrated the prognost ic va lue of the

per iphera l b lood label ing index.

Immunophenotype of Myeloma Cells As discussed previously, the phenotype of mal ignant p lasma cel ls is diverse

(205,206,207,210,211,213,214) and potent ial ly dynamic (864,865) . Invest igators have

demonstrated that sur face express ion of CD45, CD56, and CD117 por tends a better

prognos is (207,209) and expression of CD28 and CD44, a worse prognos is (207,866).

Pat ients wi th the t (11;14) t rans locat ion are more l ike ly to have sur face express ion of CD56,

and CD117. Pat ients wi th nonhyperd ip loid myeloma have increased express ion of both

CD20 and CD28 in the absence of react iv i ty for CD56 and CD117—al l poor prognost ic

f indings (207) .

Cytogenetics, Fluorescence in Situ Hybridization, a nd Other

Genetic Abnormalit ies The f i rs t cytogenet ic abnormal i t ies in myeloma were documented near ly 30 years ago (F ig.

99.14) . In the past decade i t has become increas ing apparent that cytogenet ic tes t ing is an

in tegral element of es tabl ish ing prognos is and a treatment plan for a l l newly d iagnosed

myeloma pat ients . Near ly a l l myeloma pat ients have abnormal chromosomes by

f luorescence in s i tu hybrid izat ion (FISH), includ ing dele t ions, aneuploidy, and

t rans locat ions (867,868), al though abnormal karyotypes are seen in only 18 to 30% of cases.

Th is apparent d iscrepancy is exp la ined by the general ly low pro l i ferat ive ra te of myeloma

ce l ls and the requi rement o f obta ining plasma ce l ls (and not just the rap idly d iv iding normal

myeloid

P.2411

precursors) in metaphase to generate convent ional cytogenet ics (869,870,871). Therefore,

any abnormal i ty in convent ional cytogenet ics ident i f ies a group wi th a higher pro l i ferat ive

ra te (872) and a par t icular ly poor prognos is . There is an excel lent correlat ion between

abnormal convent ional cytogenet ics and a h igh plasma ce l l prol i ferat ive ra te (873,874) . W ith

in terphase FISH, several chromosomal abnormal i t ies , such as immunoglobul in heavy-chain

t rans locat ions and delet ion of chromosome 13, are observed at equal f requenc ies among

the spectrum of p lasma pro l i ferat ive d isorders f rom MGUS to mul t ip le myeloma to PCL

(875,876) .

Figure 99.14. History of cytogenetic discovery.

Severa l “molecular c lassi f icat ion” systems have been proposed based on gene express ion

prof i l ing (877,878,879,880) ; however, though these systems may unravel the pathogenes is

o f myeloma, they are not ready for general c l in ical appl icat ion. In contrast , cytogenet ic

c lass i f icat ion systems are eas i ly appl ied in the c l in ic at present. There is d ispute as to

which genet ic tes ts should be done. Metaphase cytogenet ic and FISH test ing each has i ts

own advantages and d isadvantages. The added va lue of metaphase cytogenet ics is

addi t ional negat ive prognost ic in format ion provided by the abi l i ty to generate a plasma ce l l

karyotype—i.e. , i t captures pro l i ferat ion in addi t ion to in format ion about p loidy sta tus and

spec i f ic st ruc tura l abnormal i t ies. The d isadvantage is that cer tain in terst i t ia l abnormal i t ies

and t rans locat ions may be missed. In contrast , a s tandard myeloma FISH panel wi l l conta in

probes for the common translocat ions and st ruc tura l abnormal i t ies and wi l l detect them

regard less of the pro l i ferat ive ra te of the p lasma ce l ls; plo idy s ta tus can also be est imated

by the t r isomy index. FISH, however, provides no in format ion on the prol i ferat ive index of

the myeloma ce l ls . Ideal ly, both metaphase cytogenet ics and FISH should be done for al l

newly d iagnosed pat ients , but i f the cost is proh ib i t ive, the test that is more readi ly

ava i lab le should be performed.

Monoal lel ic loss of chromosome 13 (de l 13) or i ts long arm (de l 13q) , when determined by

metaphase cytogenet ics , is a powerfu l adverse prognost ic fac tor in pat ients t reated wi th

s tandard chemotherapy (356,829,881) or wi th high-dose chemotherapy and hematopoiet ic

stem cel l t ransplantat ion (331,480,803,882,883) (Table 99.18) . Approximate ly 50% of newly

d iagnosed mul t ip le myeloma pat ients have del 13 or de l 13q by FISH (874,876,884) . Our

group has shown that del 13q is assoc ia ted wi th spec i f ic bio logic features, inc lud ing a

h igher frequency of λ - type mul t ip le myeloma, s l ight female predominance, h igher PCLI , and

a h igher f requency of a serum M component o f <10 g/L (356) . Pat ients wi th the de let ion by

FISH have worse overa l l survival wi th s tandard chemotherapy (356,829,874) , h igh-dose

therapy (884,885), and in ter feron t reatment (356) . The absence of abnormal i t ies o f

chromosome 13 and 11 by convent ional cytogenet ics is associa ted wi th longer complete-

response durat ion, event- f ree survival , and overal l survival in pat ients t reated wi th high-

dose therapy (331) . The prognost ic s ign i f icance of del 13q by FISH is less than that for de l

13 by convent ional cytogenet ics , because the la t ter tes t incorporates both the chromosomal

abnormal i ty and a h igh ra te of plasma ce l l pro l i ferat ion, whereas the former captures on ly

the chromosomal abnormal i ty.

Hypodiploid myeloma has a worse prognos is than d ip lo id or hyperdiplo id myeloma. This has

been demonstrated by f low cytometr ic methods (881,886,887) and metaphase cytogenet ics

(883,888,889,890,891) . Controversy exis ts about whether the dele t ion 13q adds any

addi t ional prognost ic in format ion to a hypodiploid karyotype (888,891,892) .

Up to 75% of pat ients wi th mul t ip le myeloma have t ranslocat ions invo lv ing the heavy-chain

gene on chromosome 14. These t ranslocat ions inc lude i l legi t imate swi tch recombinat ions of

the variable regions of the immunoglobul in heavy-chain gene at 14q32. Par tners o f the

t rans locat ions into the IgH swi tch region on chromosome 14 include chromosomes 11, 4, 6 ,

and 16 (893) . The most common t rans locat ion in mul t ip le myeloma is t (11;14) (q13;q32)

(870,892) , which increases expression of cycl in D1 (802) , a protein involved in ce l l -cycle

progress ion. The prevalence of t (11;14) (q13;q32) is 20% in mult ip le myeloma

(870,892,894) . Previous publ icat ions had suggested that th is t rans locat ion was assoc ia ted

wi th an adverse outcome in mul t ip le myeloma (803,829) , but more recent data re fu te this

hypothesis (894) . The t (6 ;14) (p21;q32) is also associa ted wi th a neutra l prognos is (895) .

The t (4 ;14) (p16.3;q32) is present in 15% of mul t ip le myeloma pat ients

(896,897,898,899,900) . Th is t rans locat ion resul ts in the up-regulat ion of f ibrob last growth

fac tor receptor 3 (FGFR3) and in the hybr id t ranscrip t IgH/MMSET (896,897) . The t (14;16)

(q32;q23) is a lso seen in a smal l subset (~5%) of pat ients wi th mul t ip le myeloma (892,897) .

Both convey a very poor prognos is . In one s tudy there was a t ight assoc iat ion of de l 13

abnormal i t ies and h igh β2 -M va lues wi th the unfavorable t (4 ;14) and t(14;16) abnormal i t ies

(822).

P.2412

The f requency of h igh β2-M or de l 13 was one hal f that in pat ients wi th the t (11;14)

abnormal i ty. Th is suggests that the poor prognos is associa ted wi th del 13 may be because

of o ther nonrandom, assoc ia ted chromosomal abnormal i t ies. Fonseca et a l . (901) have

recent ly demonstrated that three d is t inc t s tag ing groups can be def ined by the presence of

t (14;16) (q32;q23) , t (4;14) (p16.3;q32) , dele t ion 17p13, and del 13q by FISH (Table 99.19) .

Table 99.19 Genetic-Based Prognostic and Staging Systems in Newly Diagnosed Multiple Myeloma Patients (Patients Treated with Standard-Intensity Chemotherapy

Unless Stated Otherwise)

Study N Risk or Stage Patients (%)

Features OS (mo)

Low 36 No F-∆ 13q and β2-M ≤4 mg/L

102

Intermediate 40 F-∆13q or β2-M >4 mg/L

46

Konigsberg et al., 2000 (829)

88

High 24 F-∆13q and β2-M >4 mg/L

11

Low 39 Absence of F-∆13q, t(4;14), t(14;16), and F-∆ 17p13

50

Intermediate 37 F-∆ 13q 42

Fonseca, 2003 (901)

275

High 24 t(4;14), t(14;16), or ∆ 17p13

25

Low 35 β2-M ≤3 mg/L and nonhypodiploidb

52

Intermediate 42 β2-M >3 mg/L or hypodiploidb

30

Smadja et al., 2001a (888)

159

High 23 β2-M >3 mg/L and hypodiploidb

11

Low 76 Absence of M-∆13q, and M-∆11qb

>48

Intermediate 17 M-∆13q OR M-∆ 11qb

>50

Tricot, 1995c (803)

155

High 3 M-∆13q AND M- 12

∆11qb

Low 20 No FISH del 13q and β2-M <2.5 mg/L

>111

Intermediate 50 F-∆13q or β2-M ≥2.5 mg/L

47

Facon et al., 2001d (884)

110

High 30 F-∆13q and β2-M ≥2.5 mg/L

25

Low 67 No karyotypic abnormality

51

Intermediate 16 Not hypodiploid, but karyotypic abn other than M-∆13q

36

Fassas 2002c (1108)

1,475

High 17 Hypodiploid or M-∆13q

19

Low 53 no F-∆13q NR

Intermediate 26 F-∆13q only 29

High 18 F-∆13q + poor IgHt OR F-∆ p53

20

Chieccio 2006a(1109)

470

Very high 3 F-∆13q + poor IgHt AND F-∆ p53

13

β2-M, β2-microglobulin; F-∆, fluorescence in situ hybridization deletion; IgHt, poor prognosis IgH translocation; M-∆, metaphase cytogenetic deletion; NR, not reached; OS, overall survival. aPatients received either standard chemotherapy or high-dose chemotherapy with

transplant. bMetaphase cytogenetics. cTandem transplant study, rather than conventional chemotherapy. dHigh-dose melphalan, single transplant, or tandem transplant.

Another new cytogenet ic prognost ic marker is the gain of 1q21 in myeloma. Abnormal i t ies o f

both the shor t and long arms of chromosome 1 have been noted s ince the f i rs t cytogenet ic

s tud ies of myeloma (869,903) (F ig . 99.14) . More recent ly, Hanamura et al . demonstrated

that the f requency of 1q21 ampl i f icat ions increases from monoc lonal gammopathy of

undetermined signi f icance (0%), to overt mul t ip le myeloma (43%), and f inal ly to re lapse

(72%). Ampl i f icat ions of 1q21 are concurrent wi th dysregulated express ion of c -MAF,

MMSET/FGFR3, or dele t ion 13 (902). Candidate genes for the molecular mechanism of

prognos is imparted by the 1q21 ampl icat ion include CDS1B, BCL-9, or RAB25, but this has

not been conf i rmed by others (736) .

Tr isomy is common by FISH and inc ludes chromosomes 3, 6 , 9 , 11, and 15 (904) . In another

s tudy, t r isomy of 3 , 7 , and 11 accounted for >50% of the hyperdiplo id cases (905) .

Tr isomies of chromosomes 6, 9, and 17 were assoc ia ted wi th pro longed surviva l (906).

Mutat ions of ras have been noted in 30 to 50% of MM pat ients , wi th increas ing prevalence

in the advanced stages of the disease (795,813) and shor ter surviva l (K-ras ) (796) .

Mutat ions of ras were f i rs t observed in fu lminant d isease (907) but have also been observed

in 27 to 39% of newly d iagnosed cases (795,796) . Pat ients wi th ras mutat ions had a median

surviva l o f 2 .1 years , versus 4 years for pat ients wi th wi ld- type ras (796) .

The inact ivat ing mutat ion of p53 , locus 17p13, is rare in f reshly exp lanted myeloma cel ls

but is common in human myeloma ce l l l ines and in pat ients wi th a terminal phase of

myeloma (907) . Such mutat ions have been observed in ~5% of cases of ear ly mul t ip le

myeloma, versus 20 to 40% of cases of PCL (816,817,818,819) . Delet ions of p53 as

detected by FISH are present in 9 to 33% of pat ients wi th newly d iagnosed myeloma

(815,908) and confer a poorer median survival (15.9 vs. >38 months) (815) .

Epigenet ic phenomena, such as methylat ion of the p16 (Met-p16 ) promoter reg ion, have

been associa ted wi th progress ion in the p lasma ce l l dyscras ias (794,909,910,911) . Met-p16

is uncommon in MGUS/smoldering mul t ip le myeloma, increases in f requency wi th advancing

s tages of the disease (811,911) , and is common in ext ramedul lary mul t ip le myeloma,

includ ing PCL.

Zhan et a l . (735,912) s tud ied the gene express ion of 74 myeloma pat ients by us ing h igh-

dens i ty o l igonucleot ide microarrays in terrogat ing about 6 ,800 genes. On h ierarch ical

c lus ter ing analys is , four d ist inc t subgroups of myeloma (MM1, MM2, MM3, and MM4) were

ident i f ied. The expression pat tern of MM1 was s imi lar to normal PCs and MGUS, whereas

MM4 was s imi lar to MM cel l l ines. Cl in ical var iables l inked to poor prognos is , includ ing

abnormal karyotype and h igh serum β2 -M leve ls , were most prevalent in MM4.

Overexpress ion of genes invo lved in DNA metabol ism and ce l l -cycle contro l were observed

in MM4. Novel candidate MM disease genes have been ident i f ied.

Angiogenesis Severa l s tud ies have demonstrated the prognost ic s ign i f icance of increased microvessel

dens i ty ( i .e. , angiogenesis) in mul t ip le myeloma (201) . The f i rst descr ip t ion was a

comprehens ive study of mult ip le myeloma and MGUS that showed a s t rong associa t ion wi th

d iagnos is and wi th an increased S-phase f rac t ion of p lasma cel ls measured by the PCLI

(201). Th is f inding was corroborated in a prospect ive c l in ica l t r ia l (913) . Median surviva ls

were 4.4 and 2 years in pat ients wi th low, intermediate, and high microvessel dens i ty,

respect ive ly. However, in this s tudy of only 74 pat ients there was no independent

prognost ic s ign i f icance for angiogenes is in a model that included PCLI , β2 -M, and the

percentage of marrow p lasma cel ls (913) . In another s tudy, angiogenes is fa i led to predict

surviva l (771) . I t is not known whether leve ls o f angiogenic

P.2413

cytokines such as VEGF, bFGF, or hepatocyte growth factor are assoc ia ted wi th poor

surviva l , a l though concentrat ions are reduced dur ing ef fect ive chemotherapy (793) .

Lymphocyte Subsets Low numbers of CD4 (helper T) ce l ls a t d iagnosis are assoc ia ted wi th worse prognos is

(914,915) ; the prognost ic importance of CD4 T ce l ls is present throughout the course of

d isease, inc lud ing af ter the complet ion of chemotherapy and at relapse (916) .

In the post t ransplantat ion set t ing, the number o f c i rcu la t ing lymphocytes appears to be an

important prognost ic fac tor . Porrata et a l . (917) demonstrated lower relapse ra tes and

pro longed survival for pat ients wi th h igher absolute lymphocyte counts a f ter auto logous

s tem cel l t ransplantat ion, suggest ing an ear ly graf t -versus-tumor ef fec t. The median overa l l

surviva l and progress ion- f ree survival for myeloma pat ients were s ign i f icant ly longer in

pat ients wi th an absolute lymphocyte count o f ≥500 ce l ls/µ l on day 15 than for pat ients wi th

an absolute lymphocyte count <500 ce l ls /µ l (33 vs . 12 months; 16 vs . 8 months) .

Researchers at the Univers i ty o f Arkansas made a s imi lar observat ion. In a t r ia l des igned to

eva luate the ro le of more intense condi t ion ing, lymphocyte recovery, evaluated as a

surrogate for immune recovery, was in fer ior in more in tensive ly t reated pat ients . Despi te

ident ical complete remiss ion rates, event- free surviva l and overa l l surviva l were

s ign i f icant ly decreased among pat ients rece iv ing more intens ive condi t ioning (529).

Other Prognostic Factors Other factors that have adverse prognost ic va lue include decreased sta in ing of bone

marrow p lasma ce l ls for ac id phosphatase (918) , increased ci rcu la t ing p lasma ce l ls as

measured by the per iphera l b lood label ing index (863) , apoptot ic index (218) , increased s IL-

6R (826,919) , serum neopterin (366), α1 -ant i t rypsin (920), C- terminal te lopept ide of type I

co l lagen (921,922) , serum bone sia loprotein (923) , B1 2 -b ind ing prote in (924) , soluble CD56

(925), so lub le Fc receptor (CD16) (926) , solub le syndecan or CD138 (927) , and serum IL-6

leve ls (920,928,929) . Al though IL-6 is known to have a major ro le in myeloma pathogenesis,

C-react ive prote in leve ls corre la te wel l wi th th is more expensive and less readi ly avai lab le

prognost ic tes t. There are mixed resul ts on the prognost ic va lue of serum thymid ine k inase

(930,931) .

Drug Resistance One form of drug res is tance is marked by mul t idrug res is tance-1 express ion on plasma ce l ls

as demonstrated by immunocytochemis t ry (932). The presence of th is P-glycoprotein in the

ce l l membrane of p lasma cel ls o f pat ients wi th mul t ip le myeloma is assoc ia ted wi th a poor

prognos is . Drug res is tance measured by immunocytochemica l detect ion of lung resistance

protein is highly corre la ted wi th fa i lure of response to melphalan and poor subsequent

surviva l (933) .

Significance of the Extent of Response after Therapy

Significance of Response after Standard-Intensity C hemotherapy Response is o f ten used as a measure of e ff icacy, and i t is of ten assumed that complete

remiss ions are a prerequis i te for cure. Indeed, pat ients t reated wi th s tandard- in tensi ty

chemotherapy wi th respons ive d isease tend to l ive a median of 18 months longer than do

pat ients wi th resistant disease (38,238,591) . However, tumor response may speak more to a

pat ient 's tumor bio logy than i t does to the therapy in quest ion. Most s tandard-in tens i ty

chemotherapy s tudies suggest that the degree of response does not corre la te wi th survival

(591,593,934,935,936) . Rather, the ab i l i ty to achieve a p la teau of a t least 6 months '

durat ion is as important, i f not more important , than the degree of response to therapy

(588,589,590) . The data f rom only three (251,368,369) o f 27

(233,277,354,359,362,363,366,385,937) randomized induct ion t r ia ls suggest that the

observed h igher response rate t rans lates in to longer overa l l surviva l (Table 99.6) .

The importance of response kinet ics is a lso a controvers ia l topic . Some data support the

premise that those wi th the most rap id responses to alkyla tor-based therapy have a shor ter

remiss ion durat ion and surviva l (586), whereas other data contradic t th is assumption (591) .

Significance of a Complete Response after High-Dose Therapy I t is unclear whether the achievement o f a complete response as def ined by the

d isappearance of the M protein by immunof ixat ion of the serum and ur ine af ter high-dose

therapy wi th hematopoiet ic s tem cel l support is of prognost ic va lue. Mul t ip le s tud ies have

produced incons is tent resu l ts (245,479,544,938,939,940,941) . Severa l o f these s tudies

(245,544,939) d id not use the more s t r ingent def in i t ion of “complete response”; they rel ied

on the absence of an M protein on an e lec trophoret ic pat tern ra ther than immunof ixat ion

negat iv i ty. These s tudies should be in terpreted wi th caut ion because they do not inc lude

several of the most powerful determinants o f prognos is—PCLI and cytogenet ics

(331,803,824,825,830) .

One of these is a re t rospect ive study of 344 pat ients wi th mul t ip le myeloma t reated wi th

h igh-dose chemotherapy fo l lowed by auto logous s tem cel l t ransplantat ion. Pat ients were not

t reated un i formly. The 5-year overal l surviva l was 48% in those who had no M prote in on

immunof ixat ion and 21% in those wi th a pers is tent M protein (940) . In another study,

Rawston et al . reported bet ter overa l l surviva l in pat ients ach ieving a complete response

e i ther by immunofixat ion or by f low cytometry (942). In yet another study, Davies and

co l leagues (941) reported a series of 96 pat ients who received h igh-dose therapy and were

assessed for the ef fec t of response on surviva l . Al though there was a trend toward

improved progression- f ree surviva l among pat ients wi th an immunof ixat ion-negat ive

complete response compared wi th pat ients wi th a part ia l response (49.4 vs . 41.1 months, p

= .26) , there was no improvement in overa l l surviva l . A lexanian et a l . (943) repor ted on a

ser ies of 68 pat ients t reated wi th dexamethasone-based induct ion therapy fo l lowed by ear ly

h igh-dose therapy; resu l ts were compared to those of 50 pat ients who were unable to

receive high-dose therapy because of socioeconomic reasons. Pat ients who achieved an

immunof ixat ion-negat ive complete response by ei ther means ( i .e. , h igh-dose or s tandard

chemotherapy) had super ior overa l l survival compared to pat ients who achieved a par t ia l

response or less . The impl icat ion of these data is that a complete response may be an

important surrogate marker o f long surviva l and less aggress ive myeloma b iology. In yet

another s tudy, Rajkumar et al . (944) repor ted a complete response in 33% of 126 mul t ip le

myeloma pat ients who underwent s tem cel l t ransplantat ion. There was no d i f ference in the

overa l l surviva l or progress ion- f ree survival between pat ients who achieved a complete

response and those who d id not; rather, overa l l surviva l was s ign i f icant ly in f luenced by the

leve l o f the PCLI (493) .

Special Cases of Myeloma

Nonsecretory Multiple Myeloma

Nonsecretory mul t ip le myeloma accounts for 1 to 5% of myeloma cases

(130,945,946,947,948,949) . W ith more sensi t ive tes t ing such as immunof ixat ion (950) and

f ree l ight -chain assays (21) , a major i ty o f these “nonsecretory” pat ients are found to be low

secretors or o l igosecretory. Immunoperoxidase or immunofluorescence s tud ies should be

per formed for al l pat ients in whom nonsecretory myeloma is suspected. More than 85% of

cases have a cytoplasmic monoclonal prote in ; in the remainder, no monoclonal prote in can

be detected in the cytop lasm (948,949,951) . Indiv iduals in this lat ter group are re ferred to

as “nonproducers . ” From a cl in ica l s tandpoint, both are termed “nonsecretory. ”

At presentat ion, hypercalcemia and anemia may be present. A reduct ion in background

immunoglobul ins is common (948,949) . There is minimal to no r isk o f myeloma k idney

(946,948) . Lyt ic bone d isease is present in most pat ients (945,946,947,948) . Median

P.2414

surviva l o f these pat ients is at least as good as for those wi th secretory myeloma

(945,947,948) . Response is di f f icul t to document, but wi th the new serum assays,

quant i ta t ion of f ree l ight chains is poss ib le in about two thi rds of these pat ients (21) .

Immunoglobulin D Myeloma IgD myeloma accounts for about 2% of a l l cases of myeloma (952) . The presence of a

monoclonal IgD in the serum usual ly ind icates myeloma, but three cases of IgD MGUS have

been documented (946). Pat ients wi th IgD myeloma general ly present wi th a smal l band or

no evident M sp ike on serum prote in elec t rophores is . Their c l in ica l presentat ion is s imi lar to

that o f pat ients wi th Bence Jones myeloma ( l ight-chain myeloma) in that both have a h igher

incidence of renal insuf f ic iency and coinc ident amylo idos is as wel l as a higher degree of

proteinur ia than in IgG or IgA myeloma (952) . IgD myeloma pat ients , however, appear to

have a h igher f requency of monoclonal λ l ight chains than κ l ight chains (952) . W ith an

incidence of 19 to 27%, ext ramedul lary involvement is more prevalent in pat ients wi th IgD

myeloma (953,954,955) . Surviva l wi th IgD myeloma has been repor ted to be in fer ior to that

wi th o ther forms of myeloma, wi th a median of 12 to 17 months (953,954,955). In the Mayo

Cl inic series , however, median surviva l was 31 months in pat ients diagnosed af ter 1980

(946,956) .

Immunoglobulin E Myeloma

IgE myeloma is a rare form of myeloma. A dispropor t ionate number of cases are PCL,

a l though the sample s ize is smal l , wi th only about 40 cases of IgE myeloma repor ted in the

l i terature (957,958) .

Plasma Cell Leukemia PCL is a rare form of plasma ce l l dyscras ia . Between 2 and 4% (904,959,960) o f mal ignant

p lasma ce l l dyscrasia cases are PCL. By def ini t ion, there are >20% plasma ce l ls in the

per iphera l b lood, wi th an absolute p lasma cel l count o f >2 × 109 /L . Some authors accept the

d iagnos is wi th on ly one of these cr i ter ia (946) . The presentat ion may be pr imary, de novo,

or secondary, evolv ing f rom an exis t ing case of myeloma as par t o f the terminal phase of

the d isease. About 60 to 70% of cases are pr imary (959) .

Al though there is overlap, the phenotype of p lasma cel ls f rom pat ients wi th pr imary PCL is

d i f ferent f rom those of myeloma pat ients . PCL plasma cel ls more f requent ly express the

CD20 ant igen (904) than those of mul t ip le myeloma (50 vs. 17%), and they of ten lack CD56

ant igen (210,904), which is present on the majori ty o f myeloma cel ls (904) . CD56 is

cons idered important in anchoring p lasma cel ls to bone marrow s t roma, and i ts absence is

associated wi th a poor prognosis (211,212) . CD28 is more f requent ly expressed on

mal ignant plasma ce l ls in secondary than in pr imary PCL, which is consistent wi th an

observat ion made in myeloma, i .e. , that acquis i t ion of the CD28 ant igen on p lasma ce l ls

appears to correla te wi th an increased pro l i ferat ive ra te and d isease progress ion (961) .

PCL p lasma cel ls have higher pro l i ferat ive ra tes (904)and more complex karyotypes than

myeloma p lasma cel ls (960) . By comparat ive genomic hybr idizat ion and by FISH techniques,

losses on 13q (962,963) and monosomy 13 (904) exis t in >80% of PCL pat ients (962,963) .

Losses on chromosome 16 also occur in ~80% of cases (963). Gains in 1q are present in

about ha l f o f the pat ients by FISH (904) , but in al l by comparat ive genomic hybrid izat ion

(963). In addi t ion, PCL pat ients have un ique losses of 2q and 6p (963) . Overexpress ion of

PRAD1/cycl in D1, which p lays an important role in contro l o f the cel l cycle , has a lso been

observed in PCL (964).

The c l in ical presentat ion of pr imary PCL is more aggress ive than that o f mult ip le myeloma,

wi th a h igher present ing tumor burden and h igher f requenc ies of ext ramedul lary invo lvement ,

anemia, thrombocytopenia, hyperca lcemia, renal impai rment (904,959,960,965), increased

leve ls o f serum lac tate dehydrogenase and β2 -M, and p lasma cel l pro l i ferat ive act iv i ty (904) .

The inc idence of ly t ic bone lesions is s l ight ly lower than that usual ly observed in mul t ip le

myeloma (904,966) .

Though the c l in ica l and laboratory features of pr imary and secondary PCL are s imi lar

(966,967) , the response to therapy and overa l l surviva l in pr imary and secondary PCL go

f rom poor to worse (959,960,966,967) . Higher response rates can be achieved wi th

mult iagent chemotherapy ra ther than s ing le-alkyla tor programs (47 to 66% vs. 8 to 13%)

(904,959,960,966). Regimens such as VMCP/VBAP, VAD, and combinat ion

cyc lophosphamide and etopos ide have resul ted in median survivals o f 18 to 20 months,

compared wi th 2 to 6 months when s ing le-agent therapy is used (904,959,960,966) .

Response and surviva l ra tes wi th secondary PCL remain low (966,967). When tha l idomide

and dexamethasone are used, responses are poss ible (968,969) (personal observat ion) ,

which is not surpr is ing g iven the high response rates observed in pat ients wi th h igh PCLIs

in our thal idomide t r ia l (970) . There are anecdota l reports o f ac t iv i ty of bor tezomib in these

pat ients (971,972,973) . Some pat ients der ive excel lent responses and 2- to 3-year d isease-

f ree survivals a f ter auto logous s tem cel l t ransplantat ion (974,975,976,977,978) . Saccaro et

a l . (979) repor ted on the cumulat ive outcomes of PCL pat ients undergoing hematopoiet ic

s tem ce l l t ransplantat ion repor ted in the l i terature. Median surviva l post–autologous HSCT

was 36 months, whereas i t was on ly 12 months after al logenic HSCT. Two authors have

independent ly noted the presence of an increased number of c i rcu la t ing large granular

lymphocytes af ter stem ce l l t ransplantat ion (974,980) ; d isappearance of these ce l ls in one

pat ient co inc ided wi th relapse (974) . The s igni f icance and impl icat ion of these observat ions

are yet to be determined.

Osteosclerotic Myeloma (POEMS Syndrome) Osteosclerot ic myeloma is a rare variant o f myeloma (≤3.3% of cases) (981) . There is a

s t raight os teosc lerot ic var iant that is s imi lar to mult ip le myeloma in that anemia, s ign i f icant

bone marrow p lasmacytos is , hyperca lcemia, and renal insuf f ic iency occur (143) . Surviva l in

these pat ients is comparable to that o f c lass ic mul t ip le myeloma pat ients. There is , however,

a more in terest ing form, which is known as Crow-Fukase syndrome, PEP (p lasma ce l l

dyscrasia , endocr inopathy, polyneuropathy) syndrome, Takatsuk i syndrome, and POEMS

syndrome (polyneuropathy, organomegaly, endocr inopathy, M prote in, and sk in changes)

(982,983,984,985). Th is var iant is associa ted wi th mul t ip le paraneoplast ic phenomena, and

i ts natural history is not s imi lar to that o f c lass ic mult ip le myeloma. The acronym POEMS

captures severa l o f the dominant features of the syndrome, but i t omi ts the sclerot ic bone

lesions, Cast leman disease, papi l ledema, per iphera l edema, asc i tes , polycythemia,

thrombocytos is , fa t igue, and c lubbing commonly observed in the d isorder. Not al l features

are requi red to make the d iagnosis ; a t a minimum, however, a pat ient must have: (a)

per iphera l neuropathy, (b) os teosc lerot ic myeloma ( i .e . , a c lonal plasma ce l l dyscras ia and

at least one sc lerot ic bone lesion) or Cast leman d isease, and (c) at least one of the other

previously ment ioned features (985) . The peak inc idence of POEMS syndrome is in the f i f th

and s ixth decades of l i fe, and there is a male predominance (983,985,986) .

Al though the precise mechanism of POEMS syndrome is unknown, VEGF appears to be a

dr iv ing fac tor in th is disorder (987,988,989) . Despi te the presence of os teosc lerot ic bone

lesions, which microscopical ly conta in c lonal plasma cel l in f i l t ra tes , bone marrow aspira te

and b iopsy of the i l iac crest typ ica l ly y ie ld on ly ~5% monoclonal lambda plasma ce l ls

(982,985,987) .

Treatment for th is disorder is far f rom s tandardized. Most agree that for an iso la ted

p lasmacytoma, i rradia t ion is the preferred t reatment (990,991,992,993) . Radiat ion therapy

produces substant ial improvement o f the neuropathy in more than hal f o f the pat ients

P.2415

who have a s ingle les ion or mult ip le les ions in a l imited area. I f there are widespread

lesions, chemotherapy and, potent ia l ly , per iphera l blood s tem cel l t ransplantat ion should be

cons idered (994). Responses of sys temic symptoms and sk in changes tend to precede those

of the neuropathy, wi th the former beginning to respond wi th in a month and the la t ter wi thin

3 to 6 months.

The most common causes of death are cardiorespi ratory fai lure, progressive inani t ion,

in fec t ion, capi l lary leak–l ike syndrome, and renal fa i lure (982,985). The neuropathy may be

unrelent ing and contr ibute to progress ive inani t ion and eventual card iorespi ratory fai lure

and pneumonia. St roke and myocard ia l in farct ion, which may or may not be rela ted to the

POEMS syndrome (985) , are a lso observed causes of death. Pat ients do not d ie o f c lass ic

myeloma ( i .e . , progressive bone marrow fai lure or hypercalcemia) .

Treatment of Complications and Supportive Care

Pharmacologic Therapy of Myeloma Bone Disease Myeloma bone d isease is a s igni f icant contr ibutor to morb idi ty, and there is expanding

in format ion about the re la t ionships between bone turnover and p lasma cel l growth and

surviva l (142,758,995,996,997) . Local ly ac t ing osteoc lastogenic and resorpt ive factors by

both osteoblasts and st romal ce l ls are dependent on a number o f in teract ions between them

and the myeloma ce l ls. Th is neoplast ic un i t releases in f lammatory and eros ive cytok ines,

such as IL-1β , IL-3, IL-6, IL-11, TNF-α , and a parathyro id hormone-rela ted prote in ,

hepatocyte growth fac tor, bas ic f ibrob last growth fac tor , meta l loproteases, and macrophage

in f lammatory protein-1α (142,997) .

The s tandard method of fo l lowing pat ients is wi th periodic (every 6 to 12 months) skele ta l

rad iographs; the use of more sophist icated imaging modal i t ies has been descr ibed in a

previous sect ion. Cross-l inked N-te lopept ides of type I co l lagen, which can be measured in

the serum or ur ine, appear to be a sens i t ive indicator o f bone turnover (922,998) , and

ur inary levels show a s trong pos i t ive correlat ion wi th the dynamic histomorphometr ic indices

of bone resorpt ion (999). Serum leve ls of bone metabol ism markers such as osteocalc in ,

MIP-1α , RANKL, and osteopetegr in have been s tud ied and shown to be aberrant ly

expressed in pat ients wi th ac t ive myeloma (142). Despi te carefu l moni tor ing, pat ients are at

r isk for skele ta l events . Bes ides t reat ing the under ly ing disease wi th chemotherapy,

b isphosphonates have been the mainstay of pharmacolog ic therapy of myelomatous bone

d isease. Other drugs, such as bone-seek ing radionuc l ides (524,686,1000) and inh ib i tors o f

the receptor ac t ivator o f nuclear fac tor κB (RANK) s ignal ing known as osteoproteger in

(1001), are be ing tes ted.

Month ly in t ravenous admin is t ra t ion of pamidronate has been shown to reduce the l ike l ihood

of a ske le tal event by a lmost 50% in pat ients wi th mul t ip le myeloma (1002).

Bisphosphonates inhib i t d issolu t ion of the hydroxyapat i te crys ta ls and down-regulate the

major os teoc las t funct ions. Af ter interna l izat ion, the n i t rogen-conta in ing b isphosphonates

in ter fere wi th the b iosynthet ic mevalonate pathway by inhib i t ing farnesyl diphosphonate

synthase, wi th the resu l t ing inabi l i ty o f os teoc lasts to form the ru ff led borders of the i r

membrane needed to act ivate bone resorpt ion. In th is s tudy, 392 pat ients wi th s tage I I I

myeloma and at least one lyt ic lesion received e i ther p lacebo or pamidronate, 90 mg

in t ravenously admin is tered as a 4-hour in fus ion month ly for 21 cyc les (F ig . 99.15B).

Skeletal events (patho log ic f rac ture, radia t ion or surgery, and spinal cord compress ion) and

hyperca lcemia were assessed monthly. At 12 months, there were fewer ske le tal - rela ted

events in the pamidronate group than in placebo-t reated pat ients (28 vs . 44%; p < .001)

(1002,1003). W ith longer fo l low-up of 21 months, the d i f ference between groups persisted

but narrowed s l ight ly, to 28% in the pamidronate group versus 51% in the p lacebo group (p

< .015) (1004). Th is prospect ive s tudy subsequent ly led the U.S. Food and Drug

Admin is t ra t ion (FDA) to approve the use of the drug in th is set t ing.

Figure 99.15. Bone risk in multiple myeloma. A: Natural history of bone events in patients with newly diagnosed myeloma (1945 to 2001) without bisphosphonate support. (With permission, from Melton LJ 3rd, Kyle RA, Achenbach SJ, et al. Fracture risk with multiple myeloma: a population-based study. J Bone Miner Res 2005;20:487–493.) B: Pamidronate versus placebo in newly diagnosed myeloma patients. (With permission, from Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol 1998;16:593–602.)

Equivalency of pamidronate and zo ledronic ac id has been demonstrated in two randomized

c l in ical t r ia ls , a randomized Phase I I t r ia l (1004) and a randomized Phase I I I t r ia l (1005) . In

the Phase I I I t r ia l , pat ients wi th mul t ip le myeloma or breast cancer , who had lyt ic d isease,

were t reated wi th zo ledronic ac id (4 or 8 mg per dose) or pamidronate (90 mg) every 3 to 4

weeks. The infus ion t ime for zoledronic acid was increased f rom 5 to 15 minutes during the

t r ia l because of an increase in creat in ine occurr ing more f requent ly among pat ients

receiv ing the rap id in fus ion. Renal problems cont inued to occur more of ten among pat ients

randomized to 8 mg zo ledronic acidum, and the ir dose was subsequent ly reduced to 4 mg.

The sample s ize was based on showing noninfer ior i ty of zo ledronic ac id to pamidronate. A

to tal of 1 ,648 pat ients were enrol led; 510 had mul t ip le myeloma and the remainder had

metastat ic breast cancer. The por t ion of pat ients wi th any SRE af ter 13 months d id not

d i f fer among the three treatments and did not d i f fer between the breast cancer and mult ip le

myeloma pat ients . In February 2002, the FDA approved an expanded ind icat ion for

zo ledronic acid for the t reatment o f pat ients wi th bone metastases that inc luded i ts use in

mult ip le myeloma.

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Despi te the fac t that the longest fo l low-up of pat ient in these s tud ies was 24 months, the

recommendation of the Amer ican Soc iety of Cl in ica l Oncology was to cont inue these agents

indef in i te ly a t month ly interva ls (1006). The rat ionale for pract ice was not data-driven, but

based on severa l theoret ical benef i ts . The f i rs t was that pat ients have cont inued bone

d isease throughout the course of the i r d isease. The second was predicated on the in v i t ro

and in v ivo (mur ine) data that bisphosphonates exert ant i tumor act iv i ty (995) .

In the shor t term, the drugs were wel l to lerated—occas ional episodes of mi ld pyrexia , renal

funct ion impai rment , myalgias , and hypocalcemia occurred. However, by 2003, avascular

os teonecrosis o f the jaw (ONJ) had been descr ibed as a new compl icat ion associated wi th

the ir use (1007,1008,1009,1010,1011,1012,1013,1014,1015,1016,1017,1018).

Bisphosphonate-assoc ia ted ONJ has been descr ibed in various mal ignancies, including

mult ip le myeloma, breast cancer , and prostate cancer. A management a lgor i thm for ONJ

has recent ly been publ ished (1019). I t has been seen in both the mandible and the maxi l la

but is more frequent in the former. The et io logy of ONJ is unc lear , but i t is l ike ly

mult i fac tor ia l in or ig in. Al though most pat ients who develop ONJ have had recent dental or

ora l surg ical procedures (70%), the remainder develop spontaneous ONJ (1012). Proposed

mechanisms include that inhibi t ion of os teoc las t act iv i ty reduces bone turnover and

remodel ing and that bisphosphonates prevent re lease of bone-speci f ic fac tors that promote

bone format ion (1020). In addi t ion, bisphosphonates, par t icu lar ly zo ledronic ac id, may have

ant iangiogenic e f fects, and impai red b lood supply has been impl icated in the development

o f ONJ. F ina l ly, heal ing of an open bony oral wound is chal lenged by bacter ia l insu l t f rom

ora l microf lora.

Table 99.20 Mayo Clinic Consensus Statement for Bisphosphonate Use in Patients with Multiple Myeloma

Clinical Scenario Guideline

MM and lytic disease evident on plain radiographs

Intravenous bisphosphonates should be administered monthly.

No lytic disease evident on plain radiographs, but osteopenia or osteoporosis on bone mineral density studies

It is reasonable to start intravenous bisphosphonates in these patients.

Smoldering MM Not recommended outside context of a clinical trial.

Duration of bisphosphonate Patients should receive infusions of bisphosphonates monthly for 2 y. After 2 y: If the patient has achieved remission and is in stable plateau phase off treatment, the bisphosphonates can be discontinued. If the MM still requires active treatment, the frequency of bisphosphonate infusions can be decreased to every 3 mo.

Choice of bisphosphonate In patients with newly diagnosed MM, we favor use of pamidronate over zoledronic acid.

Dental evaluation and follow-up of patients taking bisphosphonates

Encourage patients to have comprehensive dental evaluation before receiving any bisphosphonate treatment. Undergo invasive dental procedures before starting bisphosphonate treatment. See a dentist at least annually and maximize preventive care; report oral/dental symptoms promptly. Manage new dental problems conservatively and avoid dental extractions unless absolutely necessary. See an oral and maxillofacial surgeon if surgery is required. Practice good dental hygiene. Encourage physicians to Withhold bisphosphonate treatment for at least 1 mo before the procedure and do not

resume until the patient has recovered from invasive dental procedures.

Source: Lacy MQ, Dispenzieri A, Gertz MA, et al. Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 2006;81:1047–1053.

The t rue inc idence of this compl icat ion is hard to es t imate. Durie and co l leagues (1015)

per formed a W eb-based survey of 1 ,203 pat ients wi th myeloma and breast cancer and found

an incidence of 6.8% in pat ients wi th MM and 4.4% in pat ients wi th breast cancer. The data

a lso suggested that the inc idence was higher in pat ients t reated wi th zoledronic acid than in

those treated wi th pamidronate (1015).

In another s tudy, Bamias et al . est imated inc idence rates in myeloma pat ients o f 9 .9%

(1014), and found that the t ime of exposure was st rongly associa ted wi th development o f

ONJ, and that ra tes were h igher in zo ledronic acid–treated pat ients. Pat ients who

developed ONJ received a median number of 35 in fus ions ( range, 13 to 68) , compared to 15

in fus ions ( range, 6 to 74) for pat ients wi th no ONJ. Median t ime of exposure to

b isphosphonates was 39.3 months for pat ients wi th ONJ (range, 11 to 86 months) ,

compared wi th 19 months (4 to 84.7) for pat ients wi th no osteonecros is . The l ike l ihood of

develop ing ONJ was 1% in the f i rs t year o f t reatment , increasing to 21% at 3 years of

t reatment for zo ledronic ac id–t reated pat ients, whereas in the non-zo ledronic ac id–t reated

pat ients the ra tes were 0 the f i rs t 2 years and 7% af ter 4 years of t reatment .

These observat ions prompted the Mayo Cl in ic Myeloma Group to prof fer a Consensus

Guidel ine Statement (Table 99.20) (1020). The recommendation is o f 2 years of monthly

therapy for pat ients wi th myelomatous bone disease, fo l lowed by e i ther cessat ion of therapy

in pat ients who are of f ac t ive t reatment for the i r myeloma, or cont inuat ion of

b isphosphonate therapy every 3 months for those who are rece iv ing ongoing therapy for

the ir myeloma. These recommendat ions are bo ls tered by two recent observat ions. The f i rs t

is the natural history o f myeloma bone

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d isease in the days before bisphosphonate use; the per iod wi th the h ighest ra tes of bone

d isease is the f i rs t 2 years (1021). The second is a repor t by the IFM group that

pamidronate use after tandem t ransplant for low-r isk pat ients does not provide any

s ign i f icant reduct ion in ske le tal events (618) .

Nonpharmacologic Treatment of Myeloma Bone Disease When lyt ic lesions are d iscovered in long bones, the r isk o f f racture has been demonstrated

to be very high i f pain is aggravated by funct ional use of that l imb or i f the les ion occupies

more than two th i rds of the diameter of that bone. Such lesions should be s tab i l ized by

in ternal f ixat ion (1022). Endostea l resorpt ion of one hal f the cort ica l width of the femur

weakens the bone by 70%. Surg ical t reatment should be cons idered for these lesions as

wel l (1023) . Once a bone has fractured, heal ing can occur , especial ly i f proper interna l

f ixat ion is performed and i f pat ients have an ant ic ipated survival of >6 months. Much of the

data regarding mal ignant bone disease are derived f rom pat ients wi th carcinoma rather than

mult ip le myeloma. In pat ients wi th carc inoma metastat ic to bone, modest postoperat ive

rad ia t ion doses (≤3,000 cGy) as adjuvant therapy are associa ted wi th better heal ing (1024),

but the ro le of ad juvant rad ia t ion therapy in mul t ip le myeloma pat ients is less c lear . Mul t ip le

myeloma is o ften chemotherapy-sensi t ive; adjuvant systemic chemotherapy in mul t ip le

myeloma pat ients may be more appropria te than ad juvant radia t ion therapy. In general ,

rad ia t ion therapy should be used for pa in rel ief in chemotherapy-ref rac tory d isease,

because i t re l ieves pain in 80 to 90% of pat ients wi th bony metastases (1025), long-term in

55 to 70% (1026).

Percutaneous vertebroplasty is occas ional ly an opt ion for pat ients wi th ver tebra l body

compress ion f rac ture. Pain re l ie f is genera l ly apparent wi th in 1 to 2 days af ter in jec t ion and

persists for a t least severa l months and up to severa l years (1027). Compl icat ions are

re lat ive ly rare, a l though some s tud ies repor ted a h igh incidence of c l in ica l ly ins ign i f icant

leakage of bone cement in to the paraver tebra l t issues. Compression of spinal nerve roots or

neura lgia as a resu l t o f the leakage of po lymer and pulmonary embol ism have also been

reported. Percutaneous kyphoplasty is a lso an opt ion (1028). To date, there are no

randomized tr ia ls to in form c l in ic ians as to which procedure is more ef fect ive.

Spinal Cord Compression In a paper publ ished in 1979, i t was est imated that near ly 10% of pat ients wi th myeloma

e i ther present wi th sp inal cord compress ion or that i t develops during the course of the

d isease (1029); wi th h igher awareness of myeloma and bet ter imaging technology, the

incidence is l ikely lower now. Cord compress ion, however, remains an important and

emergent subject . The usual s tandard t reatment is high-dose cort icostero ids and radia t ion

therapy (1030,1031,1032,1033). On rare occasions, surgica l decompress ion may be

cons idered. Because most myelomatous les ions ar ise f rom the ver tebral body, an anter ior

surgica l approach is genera l ly used, which may contr ibute addi t ional morbid i ty. One smal l

randomized tr ia l addressing the quest ion of rad iat ion versus laminectomy and radia t ion

showed no benef i t a t t r ibutable to laminectomy (1031); s imi lar ly, a larger re t rospect ive

ser ies found no benef i t (1030) . I f the def ic i t is a resul t o f compress ion by the p lasma cel l

tumor ( ra ther than a bone f ragment re t ropulsed by a pathologic compression f racture),

outcomes wi th rad ia t ion therapy are probably equal (or super ior) to surg ica l intervent ion in

a radiosensi t ive tumor such as myeloma (1030,1031).

High-dose cor t icosteroids may provide immediate pa in rel ie f and improvement in neurolog ic

funct ion (1032,1033). The opt imal cor t icostero id dose has not been establ ished, but

common dose schedules for metastat ic d isease inc lude dexamethasone in an ini t ia l bolus of

10 mg in t ravenously or 100 mg in t ravenously fol lowed by 4 mg oral ly 4 t imes da i ly (1034);

or a 100-mg in t ravenous bo lus fol lowed by 96 mg in 4 div ided doses for 3 days fo l lowed by

tapering doses (1032,1033).

Hypercalcemia

Pat ients wi th mult ip le myeloma are at r isk o f severe hypercalcemia that can prec ip i ta te

acute renal fa i lure, hyper tens ion, nausea, vomi t ing, pancreat i t is , card iac arrhythmia, coma,

and death. The ext racel lu lar vo lume deplet ion assoc iated wi th hypercalcemia should be

corrected by v igorous hydrat ion (727,1035) fol lowed by an ant i resorpt ive agent such as

in t ravenous b isphosphonate. Serum calc ium va lues usual ly dec l ine rap idly, reaching the

normal range wi thin 2 to 3 days in >80% of cases. I t occas ional ly goes be low normal at the

nadi r . Cor t icostero ids can a lso reduce serum calc ium concentrat ion in ~60% of pat ients wi th

hyperca lcemia (1036).

Gal l ium n i t ra te , mi thramycin, and ca lc i tonin are in terest ing f rom a his tor ica l perspect ive.

Since the advent o f b isphosphonates, they are not o ften used. Gal l ium n i t ra te therapy had

been shown to be superior to maximal ly approved doses of ca lc i tonin for acute control o f

cancer-re la ted hyperca lcemia (1037).

Hematologic Complications Including Anemia, Seconda ry

Leukemia, Hyperviscosity, and Cryoglobulinemia

Anemia

The anemia of mul t ip le myeloma can resul t f rom many fac tors . W hen the anemia is due

so le ly to myelomatous bone marrow in f i l t ra t ion, chemotherapy remedies the problem. Other

pat ients have a rela t ive erythropoiet in def ic iency re la ted to renal in jury due to the myeloma

or to age-rela ted changes. In these pat ients , as in any pat ient wi th renal insuf f ic iency,

modest doses of recombinant erythropoiet in are ef fect ive. For pat ients wi th chemotherapy-

induced anemia, recombinant erythropoiet in may be ef fec t ive at h igher doses (150 to 300

IU/kg three t imes week ly or 40,000 IU week ly) . Two p lacebo-contro l led t r ia ls in myeloma

pat ients demonstrate s ign i f icant ly improved hemoglobin levels and a reduced number of red

ce l l t ransfus ions in pat ients rece iv ing erythropoiet in (1038,1039). An inappropria te ly low

endogenous erythropoiet in concentrat ion is the most important fac tor predic t ing response

(1040)

Secondary Myelodysplasia and Acute Leukemia The most ominous cause of anemia in the sett ing of previous ly t reated mult ip le myeloma is

a secondary myelodysplast ic syndrome or acute leukemia. Kyle e t a l . (578) were among the

f i rst to recognize that cyto toxic agents can induce myelodysplasia and acute myelo id

leukemia (578,579,580,581) . The r isk o f a secondary myelodysplast ic syndrome or acute

leukemia is ~3% at 5 years and 10% at 8 to 9 years (1041,1042), wi th est imates as high as

25% at 10 years (1043), wi th mul t ip le o ther est imates somewhere in between (373,582,583).

Some authors have suggested that h igher cumulat ive doses of melphalan are impl icated as

a r isk for acute leukemia (1041). Others have shown no d i f ference in inc idence based on

the number o f courses of chemotherapy or the cumulat ive melphalan dose between pat ients

who d id and d id not develop acute leukemia (1042). In the F inn ish s tudy, the mean number

o f chemotherapy cyc les was 19.7 and 18.5 in pat ients wi th and wi thout secondary leukemia;

mean cumulat ive melphalan doses were 1,440 and 1,400 mg, respect ive ly (1042). Al though

cyc lophosphamide has been shown to be leukemogenic, data suggest that i t is less so than

melphalan (1041,1044,1045). Af ter secondary leukemia is d iagnosed, median surviva l tends

to be short—about 2 months (1042).

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The occurrence of concurrent acute leukemia in mult ip le myeloma suggests that there may

be a proc l iv i ty for acute leukemia to develop in pat ients wi th myeloma (1046,1047). After

s tem ce l l t ransplantat ion for myeloma, the r isk o f myelodysplast ic syndrome appears to be

re lated to pr ior chemotherapy ra ther than to the t ransplant i tsel f , a t least in one

re t rospect ive ser ies (1048).

Cryoglobulinemia

Approximate ly 5% of myeloma gammaglobul ins exhib i t revers ib le prec ip i ta t ion in the cold ,

so-ca l led cryoglobul ins , forming ei ther a f loccu lent precip i ta te or a ge l- l ike coagulum when

the serum is cooled (1049).

Hyperviscosity Plasmapheres is rel ieves the symptoms of hyperviscos i ty, but the benef i t o f th is t reatment in

the absence of concurrent chemotherapy is short- l ived (1050).

Renal Failure Normal c reat inine va lues are present in ~50% of mult ip le myeloma pat ients a t d iagnos is

(130,131,132,133,167,168,169,170) , and on ly 15 to 25% have a creat inine va lue >2 mg/d l

(132,173) . Pat ients in whom the renal fai lure is reversed have bet ter overa l l surviva l than

those wi thout improvement (171,174) . Factors that increase renal tubular cast format ion

include dehydrat ion, infec t ion, and hyperca lcemia. Mainta in ing a 24-hour f lu id in take of a t

least 3 L can improve renal funct ion (171) .

Because l ight chains wi th the lowest isoe lect r ic poin ts tend to be more nephrotoxic in

an imal models, avoidance of a low or ac idic ur inary pH is recommended. Ora l or

in t ravenous b icarbonate is useful in the sett ing of acute renal fa i lure (1051). The MRC 3rd

Myelomatos is Tr ia l randomized mult ip le myeloma pat ients wi th s ign i f icant renal fa i lure to

ora l sodium b icarbonate to neutra l ize ur ine pH (or not ), wi th a t rend toward bet ter surviva l

in the b icarbonate recipients (171) .

The use of p lasmapheres is in the sett ing of renal fa i lure remains controvers ial . There are

three randomized t r ia ls addressing this quest ion, wi th conf l ic t ing resul ts. One smal l

randomized s tudy of pat ients wi th ac t ive myeloma and progress ive renal fa i lure suggested

benef i t in a subset of pat ients (1052). Twenty-one pat ients were randomized to receive

e i ther forced d iures is and chemotherapy (10 pat ients) or forced diuresis , chemotherapy, and

p lasmapheres is (11 pat ients) . There was a t rend toward bet ter outcome in the

p lasmapheres is group, but the di f ference was not s tat is t ical ly s ign i f icant. I t is unclear

whether the lack of s ign i f icance is due to the smal l sample s ize or to an equiva lence of the

two therapeut ic st ra tegies. The s tudy d id demonstrate that the severi ty o f myeloma cast

format ion corre la ted di rec t ly wi th lack of improvement , regard less of t reatment st ra tegy.

Another randomized s tudy in myeloma pat ients wi th severe renal compromise compared

p lasma exchange (and hemodialys is when needed) wi th per i toneal d ia lysis (1053). Al l

pat ients rece ived chemotherapy and cor t icosteroids . Of the 29 pat ients in the s tudy, 24

received d ia lysis and 5 maintained serum creat in ine concentrat ions of >5 mg/dl wi thout

d ialys is . Th i rteen of the 15 pat ients in the p lasmapheres is (hemodia lysis group recovered

renal funct ion, reaching serum creat in ine va lues of ≤2.5 mg/d l in most cases, whereas on ly

2 pat ients in the per i toneal d ia lysis group had enough improvement to s top dialys is . The 1-

year surviva l ra tes were 66 and 28%, respect ive ly (p < .01) . The study's design was f lawed

in that one group received per i toneal d ia lysis and the other hemodialys is; the quest ion

about the ro le o f p lasmapheresis is not adequately sett led.

The largest and most recent tr ia l was a negat ive s tudy (1054). One hundred and four

pat ients wi th newly d iagnosed myeloma and a creat in ine of 2.3 mg/d l were randomized to

convent ional chemotherapy wi th or wi thout 5 to 7 sessions of plasma exchange over 10

days. The primary outcome was a composi te measure of death, dialys is dependence, or

g lomeru lar f i l t ra t ion ra te of <30 ml /min/1.73 m 2 . At 6 months the endpoint was reached in

58% of the p lasma exchange group and 69% of the contro l group. At 6 months, 7 of the 39

contro l pat ients (18%) and 5 of 58 p lasma exchange pat ients (9%) were on dialys is . At 6

months, 33% of each group had d ied. Cri t ic isms of this s tudy included the pat ient se lec t ion,

includ ing the absence of renal biopsy, the use of re lat ive ly inef fec t ive convent ional

chemotherapy, and smal l sample s ize. Pat ients were el ig ible i f the serum creat inine leve l

was at least 2 .3 mg/d l wi th an increase >0.6 mg/dl in the preceding 2 weeks despi te

correct ion of hypercalcemia, hypovolemia, and metabol ic acidos is . Th is impl ies that

inst i tu t ion of p lasma exchange was delayed and that there could have been other under ly ing

patho log ic renal lesions other than cast nephropathy, which would not be respons ive to

p lasma exchange. More than twice as many pat ients on the p lasma exchange group had

melphalan and prednisone as in the control group, which could have confounded the resul ts

because both overa l l response rates are lower and t ime to response is longer wi th

melphalan and prednisone than wi th VAD.

Infection Management In fec t ions are a major cause of morb id i ty in myeloma pat ients (1055,1056). Pneumonias and

ur inary t rac t in fect ions caused by Streptococcus pneumoniae, Haemophi lus in f luenzae, and

Escher ichia col i are most f requent (183,1057,1058,1059). The suscept ib i l i ty to in fec t ion

var ies wi th the phase of i l lness (182,1060). In one prospect ive s tudy, the overa l l ser ious

in fec t ion ra te was 0.92 in fec t ion per pat ient -year and was four t imes h igher dur ing per iods

of ac t ive d isease (1.90) than in p la teau-phase myeloma (0.49) (181). In a re t rospect ive

s tudy evaluat ing the sequential incidence of in fec t ion, the f i rs t 2 months of in i t ia l

chemotherapy emerged as a par t icular ly h igh-r isk per iod, wi th near ly ha l f o f the pat ients

exper ienc ing at least one cl in ica l ly s igni f icant in fec t ion (182) . In fec t ions la te in the course

of mul t ip le myeloma may be an inevi table resu l t of long-s tanding immunosuppress ion and

overwhelming tumor burden. Prevent ion of in fec t ion is a cr i t ica l goal for improving survival .

Prevent ion of in fect ions by use of vacc ines is an at t rac t ive st ra tegy. Unfortunate ly,

responses to vacc ines are poor among myeloma pat ients (191,1061,1062,1063). Pat ients

wi th myeloma were invest igated to assess whether immunologic r isk fac tors pred isposing to

ser ious in fec t ion could be ident i f ied (181) . Spec i f ic ant ibody t i ters to pneumococcal

capsular polysaccharides and te tanus and d iphther ia toxo ids were s igni f icant ly reduced

compared wi th the contro l populat ion. Low ant ipneumococcal and ant i -Escher ichia col i t i ters

corre lated wi th r isk o f ser ious in fec t ion. In addi t ion, among 41 immunized pat ients ,

responses to pneumococcus vacc ine and te tanus and d iphther ia toxo ids were poor. IgG

subc lass leve ls were s ign i f icant ly reduced, and a poor IgG response to pneumococcus

vaccine immunizat ion was associa ted wi th an increased r isk o f sept icemia. The predominant

s i te o f in fec t ion was the respi ratory t rac t. Decreased concentrat ions of the uninvolved

immunoglobul ins were s ign i f icant ly associa ted wi th a t least one serious infec t ion (181) .

The two most common prevent ion s t ra teg ies consis t of prophylaxis wi th ant ib io t ics (1064) or

in t ravenous immunoglobul in ( IVIg) (1064). A randomized, p lacebo-control led t r ia l o f

t r imethoprim-sul famethoxazole (TMP-SMX) demonstrated a s igni f icant decrease in severe

in fec t ions among newly d iagnosed myeloma pat ients randomized to TMP-SMX compared

wi th controls (1065). F i f ty-seven pat ients about to begin chemotherapy for mul t ip le myeloma

were randomly ass igned to prophylaxis for 2 months or to no prophylaxis (contro l) .

Ant ibio t ic prophylaxis cons is ted of TMP-SMX (160/800 mg ora l ly every 12 hours)

adminis tered for the f i rst 2 months of in i t ia l chemotherapy. Bacter ia l in fect ion occurred in

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11 contro l pat ients but in on ly 2 pat ients ass igned to rece ive TMP-SMX (p = .004) . Eight

severe infec t ions occurred in contro ls , compared wi th one in a TMP-SMX pat ient (p = .010).

Severe in fec t ions inc luded 5 cases of pneumonia (3 wi th seps is) , 2 ur inary t rac t infec t ions

wi th compl icat ing pneumonia or sepsis, 1 d ivert icu l i t is wi th per forat ion, and 1

s taphylococcal sca lded sk in syndrome. The rate of bacter ial in fec t ion was 2.43 per pat ient -

year for contro ls and 0.29 per pat ient -year for the TMP-SMX group (p = .001) . Toxic i ty (sk in

rash in 6 pat ients, nausea in 1 pat ient ) was not l i fe- threaten ing but requi red d iscont inuat ion

of TMP-SMX in 25% of pat ients . A randomized, double-bl ind p lacebo-contro l led t r ia l

demonstrated that IVIg s igni f icant ly reduced the number o f in fect ions in high-r isk pat ients

wi th p lateau-phase mult ip le myeloma (1064). Eighty- two such pat ients rece ived ei ther IVIg

(0 .4 g/kg per month) or an equal vo lume of p lacebo for 1 year . There were no episodes of

sept icemia or pneumonia in pat ients rece iv ing IVIg, compared wi th 10 in placebo pat ients (p

= .002) . There were 38 ser ious in fect ions in 470 pat ient -months for the p lacebo group,

compared wi th 19 in 449 pat ient -months for the IVIg group (p = .019). A poor ant ibody

response to pneumococcal vaccinat ion ( less than twofo ld increase) ident i f ied pat ients who

had maximum benef i t f rom IVIg. However, IVIg is expens ive and inconvenient and can be

associated wi th toxic i ty. Therefore, use of this agent is recommended only for pat ients wi th

a s igni f icant h is tory o f severe in fec t ions.

Differential Diagnosis The d iagnosis o f mul t ip le myeloma is made f rom a constel la t ion of f indings, inc lud ing

anemia, monoclonal prote ins , bone lesions, renal compl icat ions, hypercalcemia, and bone

marrow p lasmacytos is . Of ten the d iagnosis is stra ight forward, but other d isease ent i t ies

associated wi th hypergammaglobul inemia or monoc lonal bone marrow p lasma ce l ls must

a lso be cons idered. These inc lude react ive p lasmacytosis, MGUS, pr imary systemic

amyloidos is , W aldenström macroglobul inemia, l ight -chain deposi t ion d isease, acqui red

Fanconi syndrome, so l i tary p lasmacytoma, os teosclerot ic myeloma or POEMS syndrome,

and PCL.

Reactive Plasmacytosis and Polyclonal

Hypergammaglobulinemia React ive plasmacytosis and polyc lonal hypergammaglobul inemia must be d ist inguished f rom

a c lonal process. Pat ients wi th l iver d isease, chronic infec t ions including human

immunodef ic iency v i rus, connect ive t issue d iseases, o ther lymphopro l i ferat ive disorders ,

and carc inoma can have increased bone marrow p lasmacytos is (polyc lonal ) and

hypergammaglobul inemia (polyc lonal ) (24,119) . These condit ions should not be confused

wi th mul t ip le myeloma or MGUS, which are c lonal processes.

MGUS Two percent o f pat ients >50 years o ld have MGUS, which is a benign counterpar t or

precursor les ion of mul t ip le myeloma (108). I t is character ized by an M prote in in the serum

or ur ine, wi thout evidence of mul t ip le myeloma or other ser ious gammopathy-re lated

d isorder . MGUS pat ients do not have bone marrow suppression, ly t ic bone les ions,

hyperca lcemia, renal fa i lure, or suscept ib i l i ty to in fec t ion. Standard c l in ica l features do not

accurate ly predict which pat ients wi l l remain s tab le , and mul t ip le myeloma develops in ~1%

per year (108) . The cl in ica l d is t inc t ion between MGUS and asymptomatic mul t ip le myeloma

is derived f rom an arbi t rary def in i t ion (Table 99.2) , al though the under ly ing biologic

condi t ions may prove to be di f ferent .

The greatest chal lenges in di f ferent ia t ing MGUS f rom myeloma occur in pat ients who have

MGUS and (a) seni le osteoporos is , (b) renal insuf f ic iency f rom another cause, or (c )

hyperca lcemia due to hyperparathyro id ism. Approximate ly 50% of women >60 years have

osteoporos is , and a fract ion of these have vertebra l compress ion f ractures. CT scan of the

sp ine may help dist inguish between seni le os teoporos is and myelomatous bone d isease.

Simi lar ly, renal insuf f ic iency due to long-s tanding d iabetes, hyper tension, or nonsteroida l

drug use is not uncommon. In such cases, a pat ient may s t i l l have MGUS (or asymptomatic

myeloma, for that matter) and “end-organ damage.” The key is whether the damage is

a t t r ibutable to the p lasma prol i ferat ive d isorder or another cause. In some ins tances, renal

b iopsy may be requi red to c lar i fy this issue.

Primary Systemic Amyloidosis Primary systemic amylo idosis is a rare d isorder that is character ized by the depos i t ion of

amyloid f ibr i ls . These f ibr i ls are composed of immunoglobul in l ight -chain f ragments in a β -

p leated sheet conformation. I t should be suspected when a pat ient wi th a monoc lonal

protein in the serum or ur ine presents wi th nephrot ic - range prote inuria (pr imar i ly a lbumin)

wi th or wi thout renal insuf f ic iency, card iomyopathy, hepatomegaly, or per ipheral neuropathy.

Pat ients usual ly present wi th weight loss or fa t igue. Anemia is rare at presentat ion.

Symptoms rela ted to the af fec ted organ are a lso seen. A monoc lonal l ight chain is found in

the serum or ur ine in near ly 90% of pat ients wi th amylo idosis. Most o f the remaining

pat ients have monoclonal p lasma ce l ls detectable in the bone marrow; median percentage

of c lonal p lasma ce l ls in these pat ients is only 5%. A h is tologic d iagnosis is made by

demonstrat ing the amyloid f ibr i ls—green b i re f r ingence under polar ized l ight by us ing a

Congo red sta in , or 8- to 10-nm nonbranching f ibr i ls by elec t ron microscopy. The fat

aspi ra te is pos i t ive 70 to 80% of the t ime. The bone marrow demonstrates amylo id depos i ts

approximately hal f the t ime. Nearly 90% of pat ients wi th amylo id have a bone marrow or fa t

aspi ra te spec imen that is posi t ive for amylo id . In the remain ing 10%, a b iopsy spec imen of

the af fec ted organ is posi t ive.

Waldenström Macroglobulinemia

Waldenström macroglobul inemia should not be confused wi th IgM myeloma, which

compr ises on ly ~1% of myeloma cases (132) . Pat ients wi th Waldenström macroglobul inemia

may have anemia, hyperviscosi ty, B symptoms, bleeding, and neurologic symptoms.

Signi f icant lymphadenopathy or splenomegaly may a lso be present . Lyt ic bone disease is

markedly uncommon; i f i t is present , cons ider whether the pat ient has IgM myeloma. In

Waldenström macroglobul inemia, bone marrow biopsy typ ical ly reveals inf i l t ra t ion wi th

c lonal lymphoplasmacyt ic ce l ls (CD20-pos i t ive) . The natura l his tory and treatment opt ions

for Waldenström macroglobul inemia are d i f ferent f rom those of mul t ip le myeloma (1066).

Light-Chain Deposition Disease The nonamylo idogenic l ight -chain deposi t ion d iseases (LCDDs) are due to pathologic

protein depos i t ion in var ious t issues and organs. Unl ike the l ight -chain deposi ts observed in

pat ients wi th pr imary systemic amylo idos is , these in f i l t ra tes are not congophi l ic by l ight

microscopy, and by e lectron microscopy nonbranching f ibr i ls are not observed. Ins tead,

amorphous nodular depos i ts are seen.

LCDD may occur wi th or wi thout coexis t ing mul t ip le myeloma. Renal involvement is most

common, fo l lowed by card iac and hepat ic deposi ts . Cl in ica l ly, LCDD can be d i f ferent ia ted

f rom mul t ip le myeloma and primary systemic amylo idos is by the fo l lowing f indings. As in

pr imary systemic amyloidosis, ear ly in the d isease course the l ight -chain deposi ts have a

predi lec t ion for the renal g lomeru l i rather than the tubules. Th is resul ts in nonselect ive

proteinur ia , that is , a predominance of albuminuria , which is not

P.2420

usual in mul t ip le myeloma. I t is imposs ib le wi thout t issue b iopsy to dist inguish c l in ical ly the

cardiomyopathy and hepatopathy from primary systemic amyloidosis . In LCDD, the

under ly ing c lone is more commonly monoc lonal κ ra ther than λ .

The prognos is of pat ients who have this d isorder depends on whether there is under ly ing

mult ip le myeloma. In one re t rospect ive s tudy of 19 pat ients wi th LCDD, 5-year ac tuar ia l

pat ient surviva l and surviva l f ree of end-s tage renal d isease were 70 and 37%, respect ive ly

(1067).

Acquired Fanconi Syndrome Fanconi syndrome is a rare compl icat ion of p lasma cel l dyscrasias character ized by d i f fuse

fa i lure in reabsorpt ion at the level o f the proximal renal tubule and resul t ing in glycosuria ,

genera l ized aminoaciduria , and hypophosphatemia (179) . Fanconi f i rs t described the

syndrome in ch i ldren. Subsequent ly, acqui red forms were described in adul ts . Acqui red

Fanconi syndrome is usual ly assoc iated wi th MGUS. Overt hemato logic mal ignancies may

occur , such as mul t ip le myeloma, W aldenström macroglobul inemia, or other

lymphopro l i ferat ive d isorders. The prognos is is good in the absence of over t mal ignant

d isease. Cl in ica l manifestat ions include s lowly progressive renal fai lure and bone pain due

to os teomalacia . The d iagnos is of Fanconi syndrome can be made when a pat ient wi th a

monoclonal p lasma cel l d isorder presents wi th aminoac idur ia , phosphatur ia , and glycosuria .

Elect rolyte abnormal i t ies typ ica l ly inc lude hypokalemia, hypophosphatemia, and

hypouricemia. Bence Jones prote inur ia is usual ly present and is a lmost a lways of the κ type.

Rare pat ients have been repor ted wi th Fanconi syndrome associated wi th λ Bence Jones

proteinur ia .

Treatment cons is ts o f supplementat ion wi th phosphorus, ca lc ium, and vi tamin D.

Chemotherapy may benef i t pat ients wi th rapidly progressive renal fa i lure or symptomat ic

mal ignancy.

Solitary Plasmacytomas

Solitary Plasmacytoma of Bone (Intramedullary Plasmacytoma) Sol i tary plasmacytoma of bone is a rare form of plasma prol i ferat ive d isease. I ts t rue

incidence has not been descr ibed, but i t accounts for ~2 to 5% of mal ignant p lasma cel l

dyscrasias t reated at large referra l centers (223,1068,1069). In most ser ies , the def ini t ion

has requi red the fol lowing character is t ics : (a) histo log ic proof that the sol i tary lesion is a

p lasmacytoma; (b) no other bone lesions on metastat ic bone survey; (c ) <5% plasma cel ls

f rom a random bone marrow b iopsy s i te ; and (d) the absence of anemia, hypercalcemia, or

renal insuf f ic iency that had no at t r ibutab le cause. Some def in i t ions a l low for <10% bone

marrow p lasma ce l ls (718) , and others have rest r ic ted the quant i ty o f the serum or ur ine M

sp ike. Others have exc luded pat ients who developed d isseminated myeloma wi thin a year

a f ter d iagnosis o f the so l i tary plasmacytoma (1070). The In ternat ional Myeloma W ork ing

Group has adopted the above def in i t ion, but adds that i f MRI is done, i t should not

demonstrate any other areas of marrow invo lvement (220) .

There is a c lear male preponderance, and the median age is 55 years (718,1070,1071,1072).

Plasmacytomas most commonly ar ise f rom the axia l ske leton, par t icular ly the ver tebra l

bodies. Pain is the usual presentat ion. Spinal cord or nerve root compress ion may also be

present. I f the pat ient a lso has evidence of a periphera l neuropathy, and especia l ly i f the

bone lesion is sc lerot ic, one should cons ider the d iagnos is of POEMS. Monoclonal prote ins

are present in ~50% of pat ients (718,1070).

Careful s tag ing should be done in a l l pat ients , inc lud ing a complete b lood cel l count , protein

e lec t rophores is and immunofixat ion of the serum and ur ine, serum immunoglobul in f ree l ight

chains, a complete radiographic skele ta l survey, and random bone marrow aspi rat ion and

b iopsy. At a min imum, immunohis tochemica l s tains should be done on the bone marrow to

ident i fy a c lone apart f rom the so l i tary p lasmacytoma. MRI of the ent i re sp ine and pelv is

should also be done to determine whether the lesion is so l i tary. Us ing MRI, Moulopoulos et

a l . (157) found unexpected bone marrow involvement in 4 o f 12 pat ients wi th apparent ly

so l i tary p lasmacytomas of bone. FDG-PET may also provide useful in format ion.

From a h is tor ica l perspect ive, so l i tary plasmacytomas of bone were t reated surgica l ly wi th

or wi thout ad juvant rad iat ion (1073). Present-day, s ing le-modal i ty, def in i t ive rad ia t ion

therapy is the t reatment o f choice. Al though the opt imal dose has not been estab l ished by

randomized control led t r ia ls, 4 ,000 to 5 ,000 cGy encompassing a l l d isease wi th a marg in of

normal t issue is recommended by most exper ts on the basis o f re t rospect ive loca l re lapse

ra te data (718,719,720,1074). Th is pr inciple , however, has been chal lenged by recent data

that show no di f ference in local contro l as long as the therapeut ic dose is >3,000 cGy (721) .

Median 10-year d isease-f ree survival is ~25 to 40% (718,1075). Median t ime to fa i lure, that

is , local relapse, appearance of another p lasmacytoma, or d isseminated myeloma, is about

2 years (718,721,1075). Risk fac tors for evo lu t ion to myeloma include absence of a

monoclonal prote in at presentat ion (nonsecretory d isease), depress ion of immunoglobul in

va lues at presentat ion, pers is tence of the monoc lonal protein a f ter t reatment (1075),

abnormal immunoglobul in f ree l ight -chain ra t io at presentat ion (1076), tumor s ize of >5 cm,

and a nonver tebra l presentat ion (721).The persis tence of a monoc lonal protein a f ter

rad ia t ion therapy does not guarantee re lapse (223,718) , even af ter >10 years of fo l low-up

(1075). In rare ins tances, the maximum reduct ion of myeloma protein may take several

years af ter complet ion of the radia t ion therapy (223,718) . Median survival for a l l pat ients

present ing wi th so l i tary p lasmacytoma of bone—based on data f rom pat ients s taged before

rout ine use of MRI and bone marrow c lonal i ty s tud ies—was ~10 years

(718,721,1069,1075,1077). For those who progressed to myeloma, the median surviva l was

44 months after the s tar t o f chemotherapy (223). Adjuvant chemotherapy has not been

shown to produce a surviva l advantage and carr ies the r isk o f t reatment- re la ted

myelodysplast ic syndromes or acute leukemia; i t cannot be recommended.

W ith increasing ly sens i t ive d iagnost ic techniques, the incidence of so l i tary myeloma wi l l

decrease, but probably the relapse rate wi l l too.

Extramedullary Plasmacytoma Sol i tary ext ramedul lary plasmacytomas represent ~3% of a l l p lasma cel l neoplasms (1078).

They most commonly af fec t men in the ir ear ly 60s and occur in the upper respi ratory t rac t

(paranasal s inuses, nose, nasopharynx, and tons i ls ) . They a lso occur in lymph nodes, lung,

thyro id, gast ro in tes t inal t ract , l i ver , spleen, pancreas, tes tes, breast , or sk in (1079).

Amylo id invo lvement of the plasmacytoma occurs on occas ion. Al though ext ramedul lary

p lasmacytomas are not common in newly d iagnosed mult ip le myeloma, c lassic myeloma

must be exc luded by thorough staging. A monoc lonal protein in the serum and ur ine, ly t ic

bone lesions, anemia, renal insuff ic iency, and hyperca lcemia should be exc luded.

His to log ica l ly, an ext ramedul lary p lasmacytoma should be di f ferent ia ted f rom react ive

p lasmacytos is , p lasma ce l l granuloma, poorly di f ferent ia ted neoplasms, and immunoblast ic

lymphoma. Some ext ra-medul lary plasmacytomas may represent marginal zone B-ce l l

lymphomas that have undergone p lasmacyt ic di f ferent ia t ion (1080). Dimopoulos et a l .

(1078) compi led 128 ext ramedul lary p lasmacytoma pat ients f rom e ight publ ished ser ies

(1069,1079,1081,1082,1083,1084,1085,1086) and summarized thei r c l in ica l course. The

loca l fa i lure rate was 7%, mul t i focal ext ramedul lary re lapse occurred in 13%, and c lass ic

myeloma developed in 15%. Local radia t ion therapy is the t reatment o f choice, and ad juvant

chemotherapy is not recommended. The 10-year d isease- free surviva l is 70 to 80%. Ozsahin

et al . (1076) compi led 52 pat ients through a Rare Cancer Network study. There f ind ings

were s imi lar , wi th a 5-year progress ion rate of about 25% and a 5-year surviva l approaching

90%.

P.2421

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