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Multiple myeloma dr bikal
Multiple myeloma is a neoplastic proliferation of plasma cells that produce monoclonal immunoglobulins. It commonly presents with anemia, bone pain, elevated creatinine, and fatigue. Diagnosis requires clonal bone marrow plasma cells ≥10% plus biomarkers of end organ damage like hypercalcemia, renal insufficiency, or bone lesions. Treatment involves managing complications, chemotherapy like bortezomib/lenalidomide with dexamethasone, and sometimes stem cell transplant. Prognosis depends on staging systems like ISS which incorporate serum albumin and beta-2 microglobulin levels.
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Multiple myeloma dr bikal
- 1. MULTIPLE MYELOMA DR.BIKAL LAMICHHANE 1STYEAR IM RESIDENT
- 2. INTRODUCTION • Neoplastic proliferationof plasma cells derived from a single clone • Myeloma cells produce monoclonal immunoglobulins - produce symptoms
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- 5. EPIDEMIOLOGY • Occurs inall races and all geographic locations • Blacks> whites • Lowest in asia and developing countries • M>F • Obese • Older adults-Median age=69 yearRS
- 6. ETIOLOGY • No singlecommon 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
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- 9. CLINICAL PRESENTATION Common featuresUncommon features Anemia Hyperviscosity syndrome Bone pain Paresthesias Elevated creatinine Hepatomegaly - splenomegaly Fatigue/generalized weakness Spinal cord compression from an extramedullary plasmacytoma - Medical emergency Hypercalcemia Lymphadenopathy Weight loss Pleural effusion Infection
- 10. 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
- 13. CLINICAL PRESENTATION • Elevatedcreatinine • 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
- 14. • 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
- 15. 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
- 16. CLINICAL PRESENTATION • Hyperviscositysyndrome( 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
- 17. CLINICAL PRESENTATION • Hepatomegaly-4 percent cases • Splenomegaly -1 percent cases. • Spinal cord compression from an extramedullary plasmacytoma/#( 5%) - Medical emergency • Lymphadenopathy -1 percent • Pleural effusion(rare)
- 18. PATHOLOGIC FEATURES • SecretoryMyeloma • 97 % secrete Monoclonal (M) protein • IgG – 52 percent • IgA – 21 percent • Kappa or lambda light chain only (Bence Jones) – 16 percent • IgD – 2 percent • Biclonal – 2 percent • IgM – 0.5 percent • Negative – 6.5 percent
- 19. PATHOLOGIC FEATURES • Oligo-secretorymyeloma • 5 to 10 % of MM patients at diagnosis • Absence of measurable disease in serum or urine by the following parameters • Serum M protein <1 g/dL, and • Urine M protein <200 mg/24 hours • Monitoring using FLC
- 20. PATHOLOGIC FEATURES • LightChain 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)
- 21. PATHOLOGIC FEATURES • Non-secretorymyeloma • 3% of all cases • Serum, urine immunofixation - normal • 60 % - monoclonal FLC +ve • Nonmeasurable, FLC only myeloma • 40% - normal serum FLC ratio • 85 % = M-protein that can be detected in the cytoplasm of the neoplastic plasma cells • 15 % = True non-producer myeloma
- 24. 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
- 25. • SPEP/UPEP • Serum& urine Immunofixation • Free light chain assay
- 28. FREE LIGHT CHAINASSAY Indicated where serum and M protein are either -Undetectable i.e Non secretory Myeloma -Decreased -FLC ASSAY MEASURES: -Free kappa light chain:- 0.33 t0 1.94 mg/dl --Free lambda light chain :- 0.57 to 2.63mg/dl -Free light cahin ratio is assesed:- -Kappa/ lambda = 0.26 to 1.65 -< 0.26 = monoclonal lambda free light chain disease -> 1.65 = monoclonal kappa free light chain disease
- 29. INVESTIGATIONS • Urinalysis • Protein-near all light chains initially-Bence Jones proteinuria • After glomerular involvement • non selective proteinuria • Albumin • Casts • KFTs • Elevated urea / creatinine • Serum calcium- raised • Serum uric acid- raised
- 30. • Anion gapdecreased- M component and calcium ---unmeasured cations. • Serum ALP – Normal(absent osteoblastic activity) • Serum protein – elevated • Albumin- decreased • Globulins- elevated • Serum Beta -2 microglobulin- Higher= poorer prognosis
- 31. INVESTIGATIONS • Bone marrowexamination • Percent monoclonal plasma cells = >10 % • Morphology • Oval with abundant basophilic cytoplasm • Nucleus is round and eccentrically located • Perinuclear halo • "clock-face" or "spoke wheel" chromatin without nucleoli • Cytoplasmic immunoglobulin inclusions -Mott cells, Morula cells, Russell bodies, Flame cells
- 32. INVESTIGATIONS • Bone marrowexamination • Immunophenotype – Flow cytometry or immunohistochemistry • The normal kappa/lambda ratio in the bone marrow is 2:1. A ratio of more than 4:1 or less than 1:2 is considered to meet the definition of kappa or lambda monoclonality, respectively. • CD79a, VS38c, CD138, and CD38 +ve • CD19 -ve • Cytogenetics
- 34. Diagnostic criteria –InternationalMyeloma 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
- 35. Diagnostic criteria • Biomarkerassociated 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)
- 36. DIFFERENTIAL DIAGNOSIS Monoclonal gammopathyof undetermined significance Smoldering multiple myeloma Waldenström macroglobulinemia and IgM MM Solitary plasmacytoma AL amyloidosis POEMS syndrome Metastatic carcinoma
- 37. Monoclonal gammopathy ofundetermined significance • M protein <3 g/dL • Clonal bone marrow plasma cells <10 percent • Absence of lytic lesions, anemia, hypercalcemia, and renal insufficiency (end-organ damage) that can be attributed to the plasma cell proliferative disorder Risk of progression to MM of approximately 1 % per year Non-IgG subtype abnormal kappa/lambda free light chain ratio serum M protein >1.5 g/dL
- 38. Smoldering multiple myeloma •M-protein ≥3 g/dL or urinary monoclonal protein ≥500 mg per 24 hr and/or 10 to 60 percent bone marrow plasma cells • No end-organ damage Progression to MM risk bone marrow plasmacytosis >10% abnormal kappa/lambda free light chain ratio serum M protein >3 g/dL
- 39. Solitary plasmacytoma • Biopsy-provensolitary lesion of bone or soft tissue with evidence of clonal plasma cells • Normal bone marrow • Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) • Absence of end-organ damage Extramedullary plasmacytomas usually involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses without marrow plasmacytosis.
- 40. Waldenström macroglobulinemia andIgM multiple myeloma • Lymphoplasmacytic lymphoma (LPL) • Lymphoplasmacytic infiltration in bone marrow or lymphatic tissue and an IgM monoclonal gammopathy in the blood. • Features • Tumor infilration- Cytopenias, fever, night sweats, weight loss, LN, HSM • M-protein- Hyperviscosity, cryoglobulinemia, cold agglutinin, neuropathy, amyloidosis • CD56 -ve • CD19, and CD20 +ve
- 41. POEMS syndrome • POEMSsyndrome (osteosclerotic myeloma: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) • endocrinopathy (excluding diabetes mellitus or hypothyroidism)
- 42. AL amyloidosis • previouslyreferred to as primary amyloidosis • plasma cell proliferative disorder • <20 percent bone marrow plasma cells • no lytic bone lesions on imaging • modest amount of Bence Jones proteinuria • tissue deposits of amyloid fibrils or non-fibrillar material • nephrotic syndrome • heart failure • hepatomegaly, and other findings that are not seen in MM.
- 43. Metastatic carcinoma • Kidney,Breast, Non-small cell lung cancer etc • Lytic bone lesions • constitutional symptoms • a small M component • <10 percent clonal plasma cells in the bone marrow likely to have metastatic carcinoma with an unrelated MGUS rather than MM
- 44. DURIE SALMON STAGINGFOR MULTIPLE MYELOMA
- 45. STAGING International staging system (ISS) RevisedISS (R-ISS) = ISS + Stage I B2M <3.5 mg/L and serum albumin ≥3.5 g/dL normal LDH and no del(17p), t(4;14), or t(14;16) by FISH Stage II neither stage I nor stage III neither stage I nor stage III Stage III B2M ≥5.5 mg/L plus LDH above normal limits and/or detection of one of the following by FISH: del(17p), t(4;14), or t(14;16).
- 47. Treatment • 1. Supportivetreatment / management of complications • 2. Specific therapy
- 48. TREATMENT OF COMPLICATIONS HypercalcemiaAsymptomatic Anorexia, nausea, vomiting Polyuria, polydipsia Constipation Weakness, confusion, or stupor Renal insufficiency Hydration- isotonic saline@200-300mL/h Dexamethasone as part of myeloma therapy Bisphosphonate such as zoledronic acid (4 mg I/V) once a month initially Calcitonin (4 IU/kg q8h) Denosumab Hemodialysis Renal insufficiency Uremic features Avoidance of nephrotoxins HD
- 49. Infection Fever Influenza,pneumococcal vaccine IVIG Antibiotic prophylaxis (1st month of induction)- fluoroquinolone Rx according to agent Skeletal lytic lesions Bone pain Fractures Bisphosphonate Vertebroplasty/Kyphoplasty # = Conservative, Surgery Cord compression Features S/o myelopathy Dexamethasone Local Radiation Surgical decompression
- 50. + Pain Pain NSAID Opiods AnemiaFatigue Blood tranfusion Hyperviscosity syndrome oronasal bleeding, blurred vision, neurologic symptoms, confusion, and heart failure. Plasmapharesis Thrombosis As per DVT Rx Neuropathy Pain, tingling, numbness Stop bortezomib Pregabalin/Gabapentin/ Duloxetine
- 53. Refrences • Uptodate.com • Harrison20th edition • ICMR consensus document on multiple myeloma 2017
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- 57. 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
- 58. Effectiveness of variousregimens • 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.
- 59. • Daratumumab isa monoclonal antibody targeted against CD38 • Elotuzumab is a humanized monoclonal antibody targeted against SLAMF7, a glycoprotein expressed on MM and natural killer cells • Panobinostat — Panobinostat is a histone deacetylase (HDAC) inhibitor
- 60. • Bortezomib • Herpeszoster 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.