MANAGEMENT OF MULTIPLE MYELOMA

Dr Saqib Ahmad Shah PG

DEPARTMENT OF RADIATION ONCOLOGY SKIMS

MODERATOR:- DR NAZIR AHMAD KHAN

ADDT PROF SKIMS

PLASMA CELL

DISORDER

BENING LIKE MGUS,CASTLE

MANS DISESASE,ALPHA CHAIN DISEASE

MULTIPLE MYELOMA

AND ITS VARIANTS

PLASMOCYTOMA

MEDULLARY AND EXTRA MEDULLARY

AGGRESSIVE

PLASMA CELL LEVKEMIA

INDOLENT egwaldernstorm

macroglobinemia

1.Plasma cell proliferation.2.Monoclonal protein secretion3.immunodefficiency(paraprotenemia)

Sarah Newbury, the first reported patient with multiple myeloma.

A) Bone destruction in the sternum. (B) The patient with fractured femurs and right humerus. (C) Bone destrucion involving femur(reported by Dr William Macintyre in london 1845).Autopsy by dr John Dalrymple.)IN 1873 Rutizksy coined the term multiple myeloma.

Epidemology

The American Cancer Society has estimated 26,850 new cancer cases ofMM in the United States in 2014, with an estimated 11,240 deathsrepresenting 1% of all malignancies in whites and 2% in Afaricanamericans.

Among hematological malignancies it constitutes 10% (2nd in number) inUSA

The mean age of affected individuals is 62 years for men (75% >70 years of age)and 61 years for women (79% >70 years of age).

The 5-year survival rate reported in the SEER database has increased from25% in 1975 to 34% in 2003 due to newer and more effective treatmentoptions available.( survilance epidemology and end results programme).

MALES more common than females(1.6:1)

India..0.5 % of all malignancies.

KASHMIR:-76/3940(0.02%) in 2014.

ETIOLOGY

• Radiation

• Occupational (Ni,agricultural chemicals,benzene,petroleum,silicon )

• Mineral oil used as laxative

• Heriditary and genetic.

• HLA-cw2 over expression

• Race (2:1)• Repeated infections(however no evident cause

associated).

• MGUS(premalignant condition).

B cell differentiation

PathophysiologyIndolent phase

(MGUS , smoldering myeloma, myeloma IA )1-3 yr or longer

Overt phase Increase in M pr

Appearance of end organ damage6 m0- 1 yr

Plateau phase

Aggressive terminal phase

Dependent on BM stroma

Treat effectively

Temporarily can be controlled by chemo

Responses short lived, survival poor

Multiple Myeloma - Cytogenetics

Deletion 17p and Abnormalities associated with

chromosome 13 carry a particularly unfavorable

prognosis & respond poorly to therapy

radiation exposureChr. Osteomyelitis, HHV8

Bone marrow micro environment

Clinical features

Expansion of neoplastic cells

Secretory proteins

Host response

Multiple myeloma

Marrow infiltration

Release of cytokines

Bone destruction Bone pain

Hypercalcemia

IL-6

Il 1 β

Anemia

Monoclonal protein Immune deficiency

Renal failure hyperviscosity Amylodosis Infection

Neurological symptoms

coagulopathy

EMD

Serum Protein Electrophoresis

Serum Protein Electrophoresis :

• Serum is placed on special paper treated with agarose gel and exposed to an electric current. This separates the serum protein components into five classifications by size and electrical charge : serum albumin, alpha-1 globulins, alpha-2 globulins, beta globulins, and gamma globulins.

• Immunoglobulins ( IgG, IgM, IgA) usually migrate to gamma region but may sometimes extend to beta region.

• SPEP should always be performed in combination with serum immunofixation in order to determine clonality

SPEP

SPEP showing Monoclonal Gammopathy

• Shows a tall “narrow” band in gamma region – “M-Spike”

• Also, note reduction in the normal polyclonal gamma band

SPEP SPEP showing Polyclonal Gammopathy

• Shows a broad based peak in gamma region .

• Seen in chronic infections, inflammation, connective tissue disease, lymphoproliferative disease.

Immunofixation

• More sensitive than SPEP

• Immunofixation is performed when SPEP shows a sharp “peak” or a plasma cell disorder is suspected despite a normal SPEP

• Immunofixation always done to confirm the presence of M-Protein and to determine the type (IgM or IgG etc and the light chain

restriction : k or λ)Unlike SPEP, immunofixation does not give an estimate of the size of the M protein (ie, its serum concentration), and thus should be done in conjunction with electrophoresis.

Bone marrow exaination

Skeltal surveySkull – punched out lesions

The bone lesions - proliferation of tumor cells, activation of osteoclasts and suppression of osteoblasts

The bone lesions are lytic in nature and are rarely associated with osteoblastic new bone formation.

radioisotopic bone scanning is less useful in diagnosis than is plain radiography.

MM & Skeletal Complications

~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey

• Vertebrae: 65%

• Ribs: 45%

• Skull: 40%

• Shoulders: 40%

• Pelvis: 30%

• Long bones: 25%

Dimopoulos M, et al. Leukemia. 2009:1-12.

.

MRI offers a sensitive means to document extent of bone marrow infiltration and cord or root compression in patients with pain syndromes.

PET SCAN

STAGING

Prognostic factors

: MONOCLONAL GAMMOPATHIES

Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder i.e;Undetermined Significance

Monoclonal Gammopathy of UndeterminedSignificance ( MGUS)

• Incidence of MGUS increases with age :• 1% of adults in US

• 3% of adults over age 70 years

• 11% of adults over age 80 years

• 14% of adults over age 90 years

• Significance : Can progress to monoclonal Disease

IgG or IgA MGUS IgM MGUS

Monoclonal Gammopathy of UndeterminedSignificance ( MGUS)

• Predictors of Progression : • Size of the M-protein at the time of recognition of MGUS -

most important predictor of progression

• IgM & IgA monoclonal proteins have a greater risk of progression than an IgG M-protein.

• Risk of progression does not go away with time!

• Risk of progression 1% per year • CUMULATIVE RISK

• 10% at 10 years, 25% at 25 years from diagnosis

• So, Management :

MGUS - Progression

• Both criteria should be met :• Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10

percent

• No end organ damage related to plasma cell dyscrasia (see CRAB)

• Management : • Does not require any intervention

• Close surveillanace is necessary to ensure stability of the disease ( SPEP, CBC, Creatinine and calcium every 3 to 4 month and Skeletal Survey annually to pick up asymptomatic bone lesions)

Smoldering Myeloma

• Rare variant : About 1% of Myelomas

• May present with Bone lesions ( most common presenting symptom bone pain)

• No serum or urine monoclonal protein ( diagnosis can be missed if one is not aware of this entity, NSMM).

• Renal failure and hypercalcemia are generally lacking

• Anemia may be present

• Bone marrow biopsy must be performed in suspected cases: Immunostaining for a monoclonal protein on bone marrow sections may establish the diagnosis, Clonal plasma cell population in marrow.

• Must rule out IgD and IgE myeloma

Non-Secretory Myeloma

Solitary Plasmacytoma

Localized plasma cell tumor• Absence of a plasma cell infiltrate in random marrow biopsies• No evidence of other bone lesions by radiographic examination• Absence of renal failure, hypercalcemia or anemia

• Plasma cell tumors that arise outside the bone marrow and no features of Multiple Myeloma

• Most Common Primary Sites - Head and Neck region: Upper air passages and oropharynx (May involve draining lymph nodes.

• Less Common Sites – Lymph nodes (primary), salivary glands, spleen, liver, etc.

• 25% have small monoclonal spike

• Rare dissemination, rarer evolution to myeloma

• Management :• If completely resected during biopsy, no further

therapy

• If incompletely resected, radiation therapy locally

Extramedullary Plasmacytoma

All three criteria must be met

• Presence of a serum or urinary monoclonal protein

• Presence of 10 percent or more clonal plasma cells in the bone marrow or a plasmacytoma

• Presence of end organ damage felt related to the plasma cell dyscrasia, such as: CRAB : Hypercalcemia (calcium > 11.5gm%), Renal Insufficiency, Anemia (hgb < 10gm%) or Lytic bone lesions

Multiple Myeloma

Multiple Myeloma

Spinal Cord Compression : oncological Emergency

Spinal cord compression occurs in 5 % of patients with multiple myeloma ( plasmacytoma or pathological fracture related)

Managed with urgent:1. Corticosteroids2.Neurosurgical intervention (laminectomy or anterior decompression in pathological #) + radiation therapy to preserve neurological function3. Radiation therapy alone ( plasmacytoma)

*Thal/dex or dex are additional options especially if immediate response is needed.

Clearly not transplantation candidate based on age, performance

score, and comorbidity

BD/MPT, MPB, Len/dexor clinical trial*

Potential transplantation candidate

Nonalkylator-based induction x 2 cycles

(BD/BDD/BTD/LD/BCD)

Stem cell harvest

Initial Approach to Treatment of MM

Novel Frontline Options

Immunomodulatory drugs (IMiDs)

• Thalidomide

• Lenalidomide

Proteasome inhibitors

• Bortezomib

• Carfilzomib

Thalidomide: Proposed Mechanism of Action

Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085.

Lenalidomide

Immunomodulatory derivative of thalidomide

More potent than thalidomide in preclinical models

• Dose-dependent decrease in TNF-α and interleukin-6

• Directly induces apoptosis, G1 growth arrest

• Enhances activity of dexamethasone

More favorable toxicity profile than thalidomide

Difficult to use in renal insufficiency ( dose adjust)

Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950.

Bortezomib:A Reversible Proteasome Inhibitor

Chymo-tryptic

Site

Post-Glutamyl

Site

TrypticSite

b1 b2

b3

b4

b5

b6

b7

Cross section of b ring

Bortezomib

Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338.

H N B

N H

O

O

OHN

N

OH

Interferes with intracellular pathway that degrades proteins regulating cell cycle, apoptosis,angiogenesis

Transplant candidates

Induction chemotherapy

Stem cell transplant

Maintenance

Induction cemotherapy

Who is not a candidate for transplant ?• Age >65 yrs

• Myeloma related organ or tissue impairment (end organ damage) ( ROTI)

Hb 2 g /dl below the lower limit of normal

or, <10 g /dl

s. Ca - 25 mmol/l above the upper limit of

normal or, >75 mmol/ l

bone lesions- lytic lesions or osteoporosis with compression fractures

s creat - >173 µmol/ l

symptomatic hyperviscosity, amyloidosis, reccurent bac infections

(>2 episodes in 12 months)

Hence majority of patients are not

candidates

Non transplant candidates

Rationale of SCT

Myeloablation with stem cell support

• 1.TBI (12 Gy in 8 #) and cyclophosphamide

• 2. TBI (8 Gy ) +high dose melphalan +/- Cyclo

• 3. high dose melphalan alone (140-200 mg/m2)

• High dose carboplatin /etopside /cyclo.

Total body irradiation Goal – as palliation in radiation sensitive disease to eradiacte

residual cancer Used along with stem cell support Technique –1. using large field size to encompass entire body – stationary beam

Extended SSD – 200-600cmStandard SSD

LINAC

2. use less than whole body FS -

Moving beam / couch

Rigorous dosimetry Use of compensators at head neck region Dose variation acceptible- 10 % of prescribed dose Supine postion , at extended SSD, using AP/PA – most

desirable Back up must be available

Presciption – midpoint at level of umbilicus

Dose / fractionation 8- 10 Gy/ SF at dose rate 12-15 Gy @ 1-5 -2 Gy / # twice or thrice daily

Complications Pneumonitisfractionated regimes tolerated better

Role of maintenance therapy?

Why the question?

• Despite ↑remission rates, -no clear plateau in the survival curves following conventional or HDT.

• Although the proportion of patients achieving CR has increased, all patients eventually relapse.

• Various maintenance therapies have been evaluated in MM in an effort to sustain remission.

Maintenance therapy Depends on type , length of induction therapy If steroids used- depends on type, dose,

scheduleNo standard therapy to prolong TTP. modest increase in only EFS not OSAgents tried– low dose (50 mg )alt day prednisolone

Berenson et al. Blood 2002;99:3163.

Lenalidomide(25 mg)

Br J Haematol 2013;112:1020-34

thalidomide 200 mg OD Attal et al. Blood 2006;108:3289.

Role of radiation

Mainstay of treatment prior to availability of chemotherapy

Present day roleDefinitive solitary bone / extradural plasmacytoma Dose – 40-50 Gy @ 2 Gy / #Palliative impending bone fracture- vertebra, humerus,

femur, pelvis spinal cord compression For irradiation hemipelvis, monitor hemogram

Portal

8 cm wide

Centered on spine

Extends one to two vertebral bodies above and below

• Dose- 30 Gy/ 10 #,/20 Gy/ 5 #,(30 Gy dose better than 20gy )Radies D et al:J cli oncology:2005

• Energy- 1.25 Mv/

• Prone• Supine- treat through table, after raising table ht to max• Cervical spine- direct posterior field.

Thoracic spine- single post field.• Lumbar spine/pelvis- AP – PA field / single post field

• Fractures of long bone - fixation - post op RT

• Symptomatic vertebral compression fractures-vertebroplasty/ kyphoplasty - post op RT

• 50 % of nonambulatory cases regain ambulation after RT• 67 % cases improve sphincter function• 89 % - relief of back pain .• Median duration of response 12 months

LECOVET ET AL:BR J HEMATOLOGY:1997

• For analgesia, however, avoid NSAID• use lumbar corsets, braces for stabilising spine

Bisphosphonates• Bisphosphonates are structural analogues of pyrophosphates that bind to

hydroxyapatite crystals in bone & inhibit osteoclast induced bone resorption

drug IV/oral dose

pamindronate Iv 60 – 90 mg

4wkly

zoledronate iv 4 mg 4 wkly

clodronate PO 1600 mg / d

ibandronate PO 50 mg/d

Oral formulations less tolerated because of GI toxicity

Overall bisphosphonates results in 44 % relief in bone pain, 28 - 56 % decrease in bony complications , including hypercalcemia, decrease need for EBRT.

Relatively safe & inexpensive, at least 1 yr therapy reqd for any significant response

Zoledronic acid more effective than pamidronate

Combining CCT well tolerated & also improves PFS

• However , these agents can cause

• Renal dysfunction –

Pamindronate – glomerular lesion , with proteinuria (nephrotic levels )

zolendronic acid – tubular dysfunction

• Ostenecrosis of jaw – before starting – all patients should have dental examination

• Monitor s. calcium- if s. calcium reduced oral calcium 1000 mg daily and Vitamin D (800 IU ) can be given

• Ensure adequate hydration – 2-3 l of liquids to promote excretion of light chains, Ca , UA

Special clinical problems and other supportive measures

Hypercalcemia Nausea, fatigue, confusion,polyuria, constipation

Best approach-admit, check RFT,SE,Alb, Ca

IV fluids, dexam,bisphosphonate

Renal failure Hydrate, treat hypercalcemia, reduce s .UA,consider hemodialysis if reasonableevidence of good prognosis and have not failed initial therapy

Infections Foremost cause of death

Prophylactic use of IVIg, antibiotics not required

Hyper viscosity Bleeding, retinopathy,malaise,stroke,coma

Serum M protein > 3-4 g/dl

plasmapheresis

Anemia Normocytic, normochromic

Erythropoetin-improves Hb by >2 g/dl

• ULTRA HIGH RISK MM.• 25 % of MM patients are now are classfied in to UHRM.

• They include the following

• ISS 3 with clinical presentation as EMD OR Plasma cell leukemia

• LDH high,FISH shows 17q deletion with PCLI >1%.

• SURVIVAL <2YRS

• POMALIDOMIDE(3rd generation im is used /currently recommended)

Future therapies

• t(4,14) >>>> FGGR3 gene>>>>>dovatinib

• t(11,14)>>>cyclin d>>>>>>seleciclib,dinaciclib

• Braf mutation>>>>>>tipifaranib

THANKU