Multiple myeloma

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 5 th to 7 th 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: V ertebral collapse- cord compression, radicular pain, loss of bowel bladder control Susceptibility to bacterial infection : 2 nd 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: Systemic therapy to control myeloma 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 2/3 rd 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