Multiple myeloma is a malignant proliferation of plasma cells that commonly affects bone. It causes bone pain, fractures, renal failure, anemia, and susceptibility to infection. The cause is unknown but genetic factors may be involved. Myeloma cells interact with bone marrow to increase osteoclast activity, causing lytic bone lesions. Diagnosis requires bone marrow plasmocytosis, serum/urine monoclonal protein, and end-organ damage. Risk is stratified using beta-2 microglobulin and FISH. Treatment involves induction, consolidation, and maintenance therapies such as bortezomib, lenalidomide, and dexamethasone combinations. Supportive care focuses on complications like hypercalcemia, fractures, and anemia

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