Multiple myeloma

1. MULTIPLE MYELOMA
DR BIPUL BORTHAKUR
PROF & HEAD
DEPT OF ORTHOPAEDICS
SILCHAR MEDICAL COLLEGE

2. DEFINITION:
• Multiple myeloma represents a malignant
proliferation of plasma cells derived from a
single clone.
• Most common primary malignancy of bone.
• Malignant B cell lymphoproliferative disorder
of the marrow with plasma cell
predominating,.
• Males> females
• Common in 5th to 7th decade

3. DEFINITION:
• The tumor, its products and the host response to it results in number of
dysfunctions and symptoms:
• Bone pain or fracture
• Renal failure
• Susceptibility to infection
• Anemia
• Hypercalcemia
• Occasional clotting abnormalities, neurological symptoms and
manifestations of hyperviscosity

4. ETIOLOGY:
• The cause of myeloma is not known.
• More common seen in farmers, wood workers, leather workers, and those
exposed to petroleum products.
• Chromosomal alterations in MM:
• Hyperdiploidy
• 13q14 deletions
• Translocations t(11;14) t(4;14) t(14;16)
• N-ras, K-ras, and B-raf mutations are common (occurring in >40%
patients)

5. PATHOGENESIS AND CLINICAL MANIFESTATIONS:
• MM cells bind to bone marrow stromal cells (BMSCs) and extracellular
matrix (ECM) via cell surface adhesion molecules
triggers
• MM cell growth, survival, drug resistance, and migration in bone marrow.
• These effects are due to:
• Direct MM cell-BMSC binding via adhesion molecules (Adhesion
mediated signaling)
• Induction of various cytokines ( Cytokine mediated signaling)

6. PATHOGENESIS AND CLINICAL
MANIFESTATIONS:

7. PATHOGENESIS AND CLINICAL MANIFESTATIONS:
• Most common symptom : bone pain (70% patients)
• Persistent localised pain usually signifies a pathological fracture.
• Bone lesions are lytic in nature and are caused by:
• Proliferation of tumor cells
• Activation of osteoclast
• Suppression of osteoblasts

8. PATHOGENESIS AND CLINICAL MANIFESTATIONS:
• Increased osteoclastic activity is mediated by osteoclast activating factor
(OAFs)
• OAFs is produced by myeloma cells which is mediated by:
• IL-1
• Lymphotoxin
• VEGF
• Receptor activator of NF-k B ligand
• Macrophage inhibitory factor (MIF)-1 alpha
• Tumor necrosis factor(TNF)
• This bony lysis leads to hypercalcemia.

9. Typical “Punched out” lesion of skull Multiple small lytic foci throughout
the pelvic bone

10. PET-CT showing multiple FDG avid lesions in skeleton

11. PATHOGENESIS AND CLINICAL MANIFESTATIONS:
• Vertebral collapse- cord compression, radicular pain, loss of bowel
bladder control
• Susceptibility to bacterial infection : 2nd Most common clinical
problem
• Most common infection-pneumonias and pyelonephritis
• > 75% patients will have a serious infection at some time in their
course

12. PATHOGENESIS AND CLINICAL MANIFESTATIONS:
• Reason for susceptibility to infection:
• Diffuse hypogammaglobulinemia: both decreased
production and increased destruction of antibodies
• Decreased Th1 response, increased Th17 cells
producing proinflammatory cytokines and aberrant T
rec cell function
• Complement function abnormality

13. PATHOGENESIS AND CLINICAL MANIFESTATIONS:
• Renal failure in >25% patients
• Most common cause of renal failure : hypercalcemia
• other causes: glomerular amyloid deposition, hyperuricemia, recurrent
infection, use of NSAIDs, iodinated contrast dye for imaging, bisphosphonate
use
• Tubular damage associated with excretion of light chain is almost always
present.
• Proteinuria is observed if glomerulus involved

14. PATHOGENESIS AND CLINICAL MANIFESTATIONS:
• Normocytic normochromic anemia- 80% patients
• Granulocytopenia and thrombocytopenia are rarely seen
• Clotting abnormalities- due to failure of antibody coated platelets to function
properly
• Deep vein thrombosis- observed with use of thalidomide
• Hyperviscosity syndrome- may lead to headache, shortness of breath, heart
failure, visual disturbances, ataxia, vertigo, retinopathy.
• Hypercalcemia- lethargy, weakness, depression, confusion

15. DIAGNOSIS AND STAGING:
• The diagnosis of myeloma requires:
• marrow plasmocytosis (>10%)
• A serum and/or urine M component
• At least one of the following myeloma defining event-

16. DIAGNOSIS AND STAGING:
• The most important differential diagnosis in patients with myeloma are:
• MGUS ( Monoclonal gammapathy of undetermined significance)
• Smoldering multiple myeloma ( Asymptomatic myeloma)

17. DIAGNOSIS AND STAGING:
• Standard investigative workup in Multiple Myeloma:
• Investigations to evaluate for clonal plasma cells:
• Bone marrow aspirate and biopsy
• Histology
• Clonality by kappa/lambda immunostaining by flow
cytometry or immunohistochemistry

18. DIAGNOSIS AND STAGING:

19. DIAGNOSIS AND STAGING:
• Investigation to evaluate clonal paraprotein:
• Serum protein electrophoresis and immunofixation
• Quantitative serum immunoglobin levels (IgG, IgA and IgM)
• 24 hour urine protein electrophoresis and immunofixation
• Serum free light chain and ratio
• Immunofixation for IgD or IgE in select cases

20. DIAGNOSIS AND STAGING:
• Investigation to evaluate End-Organ damage:
• Hemogram for anemia, leukopenia, thrombocytopenia
• ESR- Raised (often >100)
• Chemistry panel for renal function and calcium
• Skeletal survey to evaluate bone lesions
• PET/CT or MRI

21. DIAGNOSIS AND STAGING:
• Investigation for Risk Stratification:
• Beta 2 microglobulin and serum albumin for ISS stage
• Fluorescent in situ hybridization for hyperdiploidy, del 17p,
t(4;14), t(14;16), amp1q34, and del 13
• LDH
• Specialized investigation in selected cases:
• Abdominal fat pad for amyloid
• Serum viscosity

22. DIAGNOSIS AND STAGING:
• Clinical examination:
• Careful physical examination for tender bone and masses
• Chest and bone x-rays- lytic lesion or diffuse osteopenia

23. PROGNOSIS:
• Serum beta-2 microglobulin is single most powerful predictor of
survival.
• Three stage international staging system (ISS):

24. TREATMENT:
• Patients with symptomatic and/or progressive myeloma require
therapeutic intervention.
• Such therapy has two purpose:
1. Systemic therapy to control myeloma
2. Supportive care to control symptoms of the disease, its
complications, and adverse effects of therapy

25. TREATMENT:
• Therapy includes an initial induction regimen followed by consolidation and
maintenance therapy.
• For newly diagnosed MM patients-
• Thalidomide + dexamethasone – response in 2/3rd of cases
• Lenalidomide + dexamethasone- response in >80% cases
• Bortezomib + dexamethasone- response in >80% cases
• Lenalidomide + bortezomib + dexamethasone- 100% response rate
• Bortezomib + thalidomide + dexamethasone- >90% response
• Bortezomib + cyclophosphamide + dexamethasone- >90% response

26. TREATMENT:
• Patients who are transplant candidates- alkylating agents
(melphalan) should be avoided (damage stem cells)
• High dose therapy (HDT) and maintenance are standard practice
in majority of eligible patients.
• Two successive HDTs (tandem transplantation) are more effective
than single HDT.
• Maintenance therapy prolongs remissions following standard dose
regimens as well as HDT.

27. TREATMENT:
• 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 options are:
• HDT
• A rechallenge of previous chemotherapy regimen
• A trial of a new regimen

28. TREATMENT:

29. TREATMENT:
Treatment algorithm for Multiple Myeloma

30. TREATMENT:
• The median overall survival of patients with myeloma is 8+ years, with
younger patients surviving >10 years.
• SUPPORTIVE CARE:
• Hypercalcemia: respond to bisphosphonates, glucocorticoids, hydration,
calcitonin.
• Kyphoplasty and vertebroplasty in painful collapsed vertebra
• Hyperviscosity syndrome- treatment of choice is plasmapheresis

31. TREATMENT:
• In patients in whom neurologic deficit is increasing- surgical
decompression may be necessary.
• Anemia: respond to erythropoietin along with hematinic (iron,
folate, cobalamin)

32. THANK YOU