MULTIPLE MYELOMA

PRESENTED BY: DR.RAMESH KUMAR

GUIDE:- DR. O.P. MEENA SIR
 DEFINITION

• Multiple myeloma represents a malignant proliferation

of plasma cells derived from a single clone. The
tumor, its products, and the host response to it result
in a number of organ dysfunctions and symptoms,
including bone pain or fracture, renal failure,
susceptibility to infection, anemia, hypercalcemia,
and occasionally clotting abnormalities, neurologic
symptoms, and manifestations of hyperviscosity.
Gammopathy
• Gammopathy refers to over-production of one or
more classes of immunoglobulin.
• It may be polyclonal or monoclonal.

Monoclonal Gammopathy
• This term refers to the presence of a monoclonal
immunoglobulin band in the serum.
• Monoclonal immunoglobulin band = M-protein or
paraprotein.
• Paraproteins are abnormal immunoglobulin produced by
atypical plasma cell.
• Monoclonal gammopathies/Paraproteinemia may occur in
association with normal or reduced levels of the other
immunoglobulins.
Polyclonal Gammopathy

• A gammopathy in which there is heterogeneous increase in

immunoglobulins involving more than one cell line.

• Normally serum immunoglobulin are polyclonal and

represent the combined output from millions of different
plasma cells.
EPIDEMIOLOGY

• Annual incidence of MM is 4 per 1,00,000.

• Blacks have nearly twice the incidence of whites.

• Myeloma accounts for 1% of all malignancies in whites and 2% in

blacks.

• 13% of all hematologic cancers in whites and 33% in blacks.

• The incidence of myeloma is highest in African Americans
and Pacific islanders; intermediate in Europeans and North
American whites; and lowest in developing countries
including Asia.

• Myeloma increases in incidence with age. The median age

at diagnosis is 70 years; it is uncommon under age 40.

• Male > females

ETIOLOGY

• No single common molecular pathogenetic pathway has yet

emerged.

• Radiation.

• Farmers, wood workers, leather workers, and those

exposed to petroleum products.

• Hyperdiploidy, 13q14 deletions, translocations

t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16), 1q
amplification or 1p deletion, and 17p13 deletions.

• N-ras, K-ras, and B-raf mutations are most common.

CLINICAL PRESENTATION
CLINICAL PRESENTATION
• Anemia
• normocytic, normochromic,
• Bone marrow replacement,
• Kidney damage,
• Dilution in the case of a large M-protein,

• Bone pain- OAF(Osteoclast activating factor)

• Fractures,
• Vertebral collapse- spinal cord compression,
• Bone pains induced by movement,
• No night pain,
• Lytic lesions – no osteoblastic activity.
CLINICAL PRESENTATION
• Elevated creatinine
• Light chain cast nephropathy (also called myeloma
kidney)
• Hypercalcemia
• Amyloid
• Hyperuricemia
• Recurrent UTI
• NSAIDS/bisphosphonates
• Myeloma cell infiltration in kidney
• Earliest manifestation of tubular damage-
FANCONI SYNDROME
• AKI- if dehydration
• Fatigue/generalized weakness,

• Hypercalcemia,
• Due to osteolytic lesions,
• lethargy, weakness, depression, and confusion.

• Weight loss,

• Clotting abnormalities
• failure of antibody-coated platelets to function properly,
• Interaction of the M component with clotting factors I, II, V,
VII, or VIII;
• Antibody to clotting factors; or
• amyloid damage of endothelium.
CLINICAL PRESENTATION
• Infection

• Impaired lymphocyte function,

• Suppression of normal plasma cell function,
• Hypogammaglobulinemia,
• Streptococcus pneumoniae and gram-negative organisms
are the most frequent pathogens,
• Most common infections are pneumonias and
pyelonephritis,
• Streptococcus pneumoniae, Staphylococcus aureus, and
Klebsiella pneumoniae in the lungs,
• Escherichia coli and other gram-negative organisms in
the urinary tract.
CLINICAL PRESENTATION
• Hyperviscosity syndrome( normal relative serum viscosity is 1.8)
• IgM > IgA/IgG (IgG3 max),
• Encephalopathy,
• Headache , visual disturbances, ataxia, vertigo, retinopathy,
• Shortness of breath,
• Chest pain,
• Vaso-occlusion, exacerbation or precipitation of heart failure,
• Raynaud’s phenomenon and impaired circulation,
• if the M component forms cryoglobulins.

• Paresthesias
• Thoracic or lumbosacral Radiculopathy- M/C neurologic complication of MM,
• Infiltration of peripheral nerves by amyloid,
• carpal tunnel syndrome,
• sensorimotor mono- and polyneuropathies (S>M),
• More with IgM isotypes.
PATHOLOGIC FEATURES

• Light Chain Myeloma

• 16%
• Kappa > Lambda
• Lambda light chains are more common in IgD myeloma
and myeloma associated with amyloidosis
• Higher chance of Renal failure( Lambda> kappa)
INVESTIGATIONS

• Haemogram- Anemia, Leukopenia, Thrombocytopenia,

Raised ESR(often>100).
• values correlate neither with tumor burden nor with
treatment response. Hence its importance is uncertain.

• Peripheral smear
• Rouleaux formation,
• Pancytopenia,
• Monoclonal plasma cells can be seen.
• > 2000/mm3 S/O Plasma cell leukemia.
• SPEP/UPEP
• Serum & urine Immunofixation
• Free light chain assay
Diagnostic criteria –International Myeloma Working Group
Criteria

• Clonal bone marrow plasma cells ≥10 percent OR biopsy-proven

plasmacytoma

PLUS one of the following

• Anemia – Hemoglobin <10 g/dL OR >2 g/dL below normal(lower

limit)
• Hypercalcemia – Serum calcium >11 mg/dL
• Renal insufficiency – eCrCl <40 mL/min or serum creatinine >2
mg/dL
• Bone lesions – One or more osteolytic lesions ≥5 mm

CRAB/MDE
Diagnostic criteria

• Biomarker associated with near inevitable progression to

end-organ damage
• ≥60 % clonal plasma cells in the bone marrow
• Involved/uninvolved FLC ratio > 100
• MRI with more than one focal lesion (involving bone or
bone marrow)
DIFFERENTIAL DIAGNOSIS

• Monoclonal gammopathy of undetermined significance,

• Smoldering multiple myeloma,
• Waldenström macroglobulinemia and IgM MM,
• Solitary plasmacytoma,
• AL amyloidosis,
• POEMS syndrome,
• Metastatic carcinoma.
INTERNATIONAL MYELOMA WORKING GROUP (IMWG)
CRITERIA FOR THE DIAGNOSIS OF MULTIPLE MYELOMA

• The revised IMWG criteria allow, in addition to the

classic CRAB features, three “myeloma defining events”
(MDEs).

• The presence of at least one of these markers is

considered sufficient for a diagnosis of multiple
myeloma, regardless of the presence or absence of
symptoms or CRAB features.
POEMS syndrome

• POEMS syndrome (osteosclerotic myeloma: Polyneuropathy,

Organomegaly, Endocrinopathy, Monoclonal protein, Skin
changes)

• endocrinopathy (excluding diabetes mellitus or

hypothyroidism)
FISH
Skeletal Survey

• Essential not only for the diagnosis of MM but also pre-empting

potential complication.
• Lateral skull
• Frontal chest radiograph
• Cervical-thoracolumbar spine
• Shoulders
• Pelvis
• Femur
Multiple myeloma
Multiple
myeloma

WITH GENERALISED OSTEOPAENIA

Metastasis
• Lytic metastases,
– Kidney
– Lung
– Thyroid
– Breast
• Sclerotic metastases,
– Brain, Bronchus, Breast, Bladder, Bowel, Lymphoma
&Prostate,
• Mixed lytic sclerotic metastases,
– Breast carcinoma
– Lung carcinoma
– Carcinoma of the cervix
– Testicular tumors
– Prostate carcinoma,
• Metastases may be diffuse, focal or expansile.
MANAGEMENT

• 1. Supportive treatment / management of

complications.
• 2. Management of complication.
• 3. Specific therapy.
Treatment algorithm for multiple myeloma. C, cyclophosphamide; D, dexamethasone; M, melphalan; P,
prednisone; R, lenalidomide; RVD-lite, weekly regimen; V, bortezomib. Alternate regimen-combinations
including daratumumab; elotuzumab; panobinostat; carfilzomib; ixazomib, pomalidomide or agents;
ASCT, autologous stem cell transplantation; HDT, high-dose therapy; MDE, myeloma defining events.
• Bortezomib
• Herpes zoster prophylaxis
• Neuropathy can be decreased both by its subcutaneous administration and
administration on a weekly schedule.

• Lenalidomide
• Prophylaxis for deep-vein thrombosis (DVT) with either aspirin or if
patients are at a greater risk of DVT, warfarin or low-molecular-weight heparin.
Effectiveness of various regimens

• Thalidomide + dexamethasone- 66%

• Lenalidomide/Bortezomib + Dexamethasone- >80%

• Lenalidomide + Bortezomib + Dexamethasone - 100%

response rate and 30% complete response (CR) rate

• Bortezomib + thalidomide + dexamethasone or bortezomib +

cyclophosphamide + dexamethasone)- >90% response rate.
EVALUATING RESPONSE TO TREATMENT

• Should be evaluated before each treatment cycle to

determine how their disease is responding to therapy and to
assess for potential treatment-related and disease-related
complications.
• Measurement of M protein in serum and urine
• FLC assay

• Patients without measureable M-protein or abnormal FLC

• periodic bone marrow aspirates and biopsies
• Whole body PET/CT
18F-FDG PET/CT : also a
valuable tool to
evaluate response in
patients with oligo- or
non-secretory myeloma.

PET/CT showing
multiple
fluorodeoxyglucose
(FDG)-avid lesions in
skeleton (left panel)
with their resolution on
achieving complete
response (CR) (right
panel)
Resource poor setting

• Unavailability of HCT, Bortezomib, Lenalidomide etc

• Standard risk
• Melphalan + Prednisolone +/- Thalidomide
• Bortezomib + Cyclophosphamide + Dexamethasone

• High Risk
• Melphalan + Prednisolone + Thalidomide

• If HCT is available
• Induction with Thalidomide + Dexamethasone
• Avoid Melphalan
RELAPSED DISEASE
• Almost all patients with MM who survive initial treatment will eventually relapse

• Relapsed or refractory MM is usually identified on routine surveillance

• Therapy for relapsed disease is indicated if there is a clinical relapse or a rapid rise in paraproteins

• Options:-
• HCT
• a rechallenge of the previous chemotherapy regimen
• a trial of a new regimen

• Multiple regimens
• Daratumumab, lenalidomide, dexamethasone (DRd)
• Elotuzumab, lenalidomide, dexamethasone(Erd)
• Daratumumab, bortezomib, dexamethasone (DVd)
• Bortezomib, lenalidomide, dexamethasone (VRd)
• Bortezomib, cyclophosphamide, dexamethasone (VCD)
• Ixazomib, lenalidomide, dexamethasone (IRd)
• Panobinostat, bortezomib, dexamethasone
TREATMENT: Symptomtic myeloma(standard Risk)

• Determine HCT eligibility

• All patients need to be assessed to determine eligibility for
autologous hematopoietic cell transplantation (HCT)
• Age >70 years, significant cardiopulmonary problems, or other
comorbid illnesses

• Induction therapy
• Patients eligible for HCT = Induction therapy - HCT -
Maintenance
• Patients ineligible for HCT = Induction - Maintenance chemo
HCT eligible
• Induction regimens

• Lenalidomide plus dexamethasone (Rd),

• Bortezomib, lenalidomide, dexamethasone
(VRd)- SUPERIOR,
• Bortezomib, cyclophosphamide,
dexamethasone (VCd),
• Bortezomib, melphalan, prednisone (VMP)
three to four months prior to stem cell collection.
HCT eligible

• Following induction therapy and stem cell collection

• Early transplant strategy – Proceed with autologous
HCT (single or double) directly after recovery from stem cell
collection
• Delayed transplant strategy – Continued therapy,
usually with the same regimen used for induction, reserving
autologous HCT until first relapse
• Allogeneic HCT

• early or delayed autologous HCT > either chemotherapy

alone or allogeneic HCT
Refrences
• Uptodate.com
• Harrison 20th edition
• ICMR consensus document on multiple myeloma
2017
THANK YOU