Multiple Myeloma

MYELOMA Definition: abnormal proliferation and accummulation of plasma cells producing one type of paraproteins . Clinical course has typical picture

myeloma activity laboratory, X-ray symptoms

anemia fatigue, weakness, etc.

Bone marrow infiltration neutropenia risk of infection

thrombocytopenia bleeding

X-ray: osteolysis pain + neurol. symptoms

osteolsis osteoporosis pathol. fractures

hypercalcemia nausea, thirst, coma

Paraprotein production paraproteinemia sy. of hyperviskosity

paraproteinuria „myeloma kidney“

Multiple myeloma incidence and mortality

• Prevalence (1 year)– world: 32,947 (♂); 27,925 (♀)– Europe: 13,089 (♂); 12,512 (♀)– USA: 7,671 (♂); 5,868 (♀)

• Incidence (age-standardized rates)– world: 1.7/100,000 (♂); 1.2/100,000 (♀)– Europe:

• north, south, west: 3.5–4/100,000 (♂); 2.5–2.9/100,000 (♀)• central and east: 1.6/100,000 (♂); 1.3/100,000 (♀)

– USA: 4.8/100,000 (♂); 2.9/100,000 (♀)

• Mortality (age-standardized rates)– world: 1.2/100,000 (♂); 0.9/100,000 (♀)– Europe

• north, south, west: 2.0–2.6/100,000 (♂); 1.6–1.9/100,000 (♀)• central and east: 1.0/100,000 (♂); 0.8/100,000 (♀)

– USA: 2.9/100,000 (♂); 2.1/100,000 (♀)

International Agency for Research on Cancer (IARC) GLOBOCAN 2002 data.Available at: www-dep.iarc.fr/

Multiple myeloma: epidemiology

• Approximately 1% of all cancers– second most prevalent haematological cancer

• Median age at diagnosis: 71 years– 74 years (community population)

– 62 years (hospital population)

– 2% of cases < 45 years

• Risk factors– age

– male gender

– African descent

– occupational exposure to herbicides, insecticides, petroleum products, heavy metals, plastics, asbestos

– exposure to radiation

Kyle RA, et al. J Clin Oncol. 1994;12:1577-83.

Pathogenesis

MM plasma cells

Bone marrow pathophysiology

Normal bone• Balanced osteoblast and

osteoclast function• Osteoclasts express

RANK• Osteoblasts or other cell

types express and secrete RANKL

• Bone marrow stromal cells secrete osteoprotegerin (OPG) as a decoy receptor

MM• Increased osteoclast

activity • MM cells interact with

bone marrow stromal cells, immune cells

• Upregulation of RANKL• Downregulation of OPG

Diagnosis

Monoclonal gammopathy of undetermined significance (MGUS)

• Serum M protein < 30 g/l• Bone marrow plasma cells < 10% and low level

of plasma cell infiltration in trephine biopsy (if done)

• No evidence of other B-cell proliferative disorders

• No ROTI• 1% per year progress to MM

International Myeloma Working Group. Br J Haematol. 2003;121:749-57.

ROTI = related organ or tissue impairment.

Related organ or tissueimpairment (CRAB)

• Calcium levels – serum calcium > 0.25 mmol/l above upper limit of normal or

> 2.75 mmol/l• Renal insufficiency

– creatinine > 170 mmol/l• Anaemia

– haemoglobin 2.0 g/dl below lower limit of normal or < 10 g/dl• Bone lesions

– lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify)

• Other– symptomatic hyperviscosity, amyloidosis, recurrent infections

(> 2 episodes in 12 months)

CRAB (calcium, renal insufficiency, anaemia, or bone lesions)

International Myeloma Working Group. Br J Haematol. 2003;121:749-57.

Asymptomatic myeloma (smouldering myeloma)

• Serum M protein ≥ 30 g/l

and/or

• Bone marrow plasma cells ≥ 10%

• No related organ or tissue impairment

International Myeloma Working Group. Br J Haematol. 2003;121:749-57.

Symptomatic MM

• M protein in serum and/or urine*• Bone marrow (clonal) plasma cells or

plasmacytoma• ROTI (related Organ orTissue Involvement)

CRAB

* No specific level required for diagnosis. Can have no detectable serum or urine M protein with ROTI.

Serum free-light-chain ratio as independent risk factor for progression in MGUS

Reproduced with permission from Rajkumar SV, et al. Blood. 2005;106:812-17.©Am Soc Hematol.

All 3 factors abnormal (abnormal FLC ratio, non-IgG MGUS, and serum M protein ≥ 15 g/l) Any 2 factors abnormalAny 1 factor abnormalSerum M-spike < 15 g/l, IgG subtype, and normal FLC ratio

Time (years)

Pat

ien

ts (

%)

60

40

20

0

0 5 10 15 20 25 30

Presenting features of MM

Data from Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.

97%

66%

58%

19%

13%

11%

4%

4%

3%

73%

0 10 20 30 40 50 60 70 80 90 100

S/U M protein

Anaemia

Lytic bone lesions

Bone pain

Renal insufficiency

Hypercalcaemia

Minor or no abnormalities

Hepatomegaly

Amyloidosis

Non-secretory (no S/U M protein)

Patients (%)

Types of serum monoclonal proteinsin 1,027 patients with MM

Type of monoclonal protein

IgG IgG IgA IgA IgM IgM IgD IgD Free Free Biclonal Negative only only

Pat

ien

ts (

%)

Data from Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.

Diagnosis and investigation

• History and physical examination• Blood and urine

– full blood count– serum or plasma electrolytes, urea, creatinine, calcium, albumin, uric acid– electrophoresis of serum and concentrated urine, immunofixation– quantification of non-isotypic serum immunoglobulins– quantification of serum paraprotein– quantification of urinary light chains– creatinine clearance, measured or calculated 2-microglobulin, C-related protein, LDH– plasma viscosity– (serum erythropoietin)– (vitamin B12/folate)

• Skeletal survey– X-rays of spine, pelvis, skull, humeri, femora– MRI for investigation for suspected spinal cord compression– CT OR today: PET/CT for extramedullary disease

• Bone marrow aspirate ± trephine biopsy– cytogenetics, FISH, immunophenotyping, (clonality studies)

X-ray images of MM bone lesions

Myeloma lesion in right femurPlasmacytoma causing deformity of L4 vertebral body

MRI of MM bone lesions

T1-weighted MRI reveals myelomatous involvement within

the glenoid and coracoid process

In this T2-weighted, fat-suppressed image,

the myeloma lesionis hyperintense

Staging

Durie-Salmon staging system for MM

Stage Criteria Myeloma cell mass ( 1012 cells/m2)

I All of the following:Haemoglobin > 10 g/dlSerum calcium < 2.6 mmol/l (normal) Normal bone or solitary plasmacytoma on X-rayLow M-component production rate:

IgG < 50 g/l; IgA < 30 g/lBence Jones protein < 4 g/24 hours

< 0.6 (low)

II Not fitting stage I or III 0.6–1.2 (intermediate)

III One or more of the following:Haemoglobin < 8.5 g/dlSerum calcium > 3.0 mmol/lAdvanced lytic bone lesions on X-rayHigh M-component production rate: IgG > 70 g/l; IgA > 50 g/l Bence Jones protein > 12 g/24 hours

> 1.2 (high)

Adapted from Durie BG, Salmon SE. Cancer. 1975;36:842-54.

Subclassification CriteriaA Normal renal function (serum creatinine < 170 mol/l)B Abnormal renal function (serum creatinine 170 mol/l)

International Staging System for MM

Reproduced with permission from Greipp PR, et al. J Clin Oncol. 2005;23:3412-20.©Am Soc Clin Oncol.

Stage CriteriaMedian survival,

months

I Serum 2-microglobulin < 3.5 mg/l

Serum albumin ≥ 35 g/l62

II Serum 2-microglobulin < 3.5 mg/l

Serum albumin < 35 g/l

OR

Serum 2-microglobulin 3.5 to < 5.5 mg/l*

44

III Serum 2-microglobulin ≥ 5.5 mg/l 29* Irrespective of serum albumin level.

ISS: survival

Reproduced with permission from Greipp PR, et al. J Clin Oncol. 2005;23:3412-20.©Am Soc Clin Oncol.

Pat

ien

ts s

urv

ivin

g (

%)

Time after initial chemotherapy (months)

216192168144120967248240

40

20

0

60

80

100Median (range),

monthsDeaths/N

Stage I 606/1,111 62 (58–65)

Stage II 1,054/1,505 44 (42–45)

Stage III 968/1,305 29 (26–32)

ISS: cytogenetic data

Data from Greipp PR, et al. J Clin Oncol. 2005;23:3412-20.

0

10

20

30

40

50

60

Any clonal CA Complexkaryotype

t(11;14) t(4;14) del(13) byFISH

Pa

tie

nts

(%

)

Stage I

Stage II

Stage III

n = 390

• No strong correlation of cytogenetic data with ISS stage• t(4;14) occurred at lower incidence in stage I than in

stage II or III patients (p = 0.035)

Treatment schemes

Treatment initiation

• Immediate treatment for symptomatic MM• Patients without clinical symptoms, but with

radiological evidence of bone disease should commence treatment immediately

• Monitor patients with MGUS and asymptomatic myeloma until there are signs of progression

Smith A, et al. Br J Haematol. 2005;132:410-51.

Treatment considerations

• Attaining early CR important for stable disease control and for survival

• Stem-cell-supported high-dose therapy – high CR rate– standard treatment for eligible patients

• Classic chemotherapies– patients ineligible for high-dose therapy

• Newer biological therapies– improving CR rate (especially with combinations)– newly diagnosed, relapsed/refractory, transplant induction

Smith A, et al. Br J Haematol. 2005;132:410-51.

Updated October 2009.Updated October 2009.

Initial chemotherapy

High-dose chemotherapy planned

High-dose chemotherapy not planned

Dexamethasone-based induction therapy

combinations with novel agents are superior to classic “VAD” regimens

Melphalan, prednisolone (MP)

Melphalan, prednisolone, thalidomide (MPT)

Melphalan, prednisolone, bortezomib (MPV)

Harousseau JL. Ann Oncol. 2009;20 Suppl 4:97-9.

Updated October 2009.Updated October 2009.

Patient with perspective to undergo high dose therapy & ASCT (PBSCT)

• ASCT = autologous (hematopoietic) stem cell transplantation• Standard consolidation treatment in MM after the induction therapy

• Suitable patients: up to 65 years in general, biologically fit up to 70 years

• Allogeneic transplantation: not satisfiable reesults

Updated October 2009.Updated October 2009.

MM: induction treatment, 1. line in pts suitable for ASCT (PBSCT)

• CTD: cyclophosphamide (C) + thalidomide + dexamehtasone OR• CVD: C + bortezomib (Velcade) + dexamethasone

Mobilization & harvest of auto PBSC (Peripheral Blood StemCcells)

High dose Melphalan (200mg/m2) i.v. + ASCT(APBSCT)

24–75% CR and a median survival of 4–5 years asfirst-line therapy

Updated October 2009.Updated October 2009.

Principles of autologous hematopoietic stem cell transplantation

HSC harvest Myeloablative therapy

HSC reinfusion - transplantation

Bone marrow PBSC (mobilization)

freezing

Thaw of the HSCT

In vitro purging??

OS according to presence or absenceof VGPR at first ASCT

Reproduced with permission from Attal M, et al. N Engl J Med. 2003;349:2495-502. ©2003, MA Med Soc.

Very good partial response after first transplant

0

25

50

75

100

220 44 66 88

Months after first transplant

Ove

rall

surv

ival

(%

)

Double-transplantgroup (n = 46)

Single-transplantgroup (n = 81)

Double-transplantgroup (n = 128)

Single-transplantgroup (n = 84)

0 22 44 66 880

25

50

75

100

Ove

rall

surv

ival

(%

)

Months after first transplant

Absence of very good partialresponse after first transplant

p < 0.001

Supportive therapies

• Bone disease– analgesics for bone pain (avoid NSAIDs)– palliation of bone pain with radiation (8 Gy) – vertebroplasty or kyphoplasty for persistent pain– bisphosphonates

• Anaemia: transfusions or RBC growth factors– consider trial of erythropoietin in patients with symptomatic anaemia– hold or reduce erythropoietin dose when Hb > 12.0 g/dl

• Hypercalcaemia– rehydration, bisphosphonates

• Renal dysfunction or hyperviscosity– rehydration, treatment of infection, plasmaphoresis

• Infections: antibiotics, flu vaccination

Smith A, et al. Br J Haematol. 2005;132:410-51.

Bisphosphonates

• Randomized placebo-controlled studies have showna significant clinical benefit in MM

• Recommended for all symptomatic MM patients requiring chemotherapy, whether or not bone lesions are evident

• Oral clodronate (1600 mg/day), i.v. pamidronate (90 mg every 4 weeks) and i.v. zoledronate (4 mg every 4 weeks) are effective

• Treatment continued ≥ 2 years– long-term therapy reduces skeletal events and improves

quality of life

• Monitor renal function– caution in patients with moderate to severe renal dysfunction– no zoledronate if creatinine > 265 mmol/l

Djulbegovic B, et al. Cochrane Database Syst Rev. 2002;3:CD003188.Smith A, et al. Br J Haematol. 2005;132:410-51.

Management of relapsed/refractory disease

Regimens similar to those used initially can induce a second remission

Regimens currently used: – lenalidomide combinations– thalidomide combinations– bortezomib combinations

Harousseau JL. Ann Oncol. 2009;20 suppl 4:97-9.