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Multiple Myeloma

Multiple Myeloma. Multiple Myeloma. Definition: Malignant proliferation of plasma cells derived from a single clone Etiology: radiation;mutations in oncogenes; familial causes;role of IL 6 Incidence/Prevalence: 14,400 cases in 1996; incidence 30/1,00,000 Incidence increases with age

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Multiple Myeloma

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  1. Multiple Myeloma

  2. Multiple Myeloma • Definition: Malignant proliferation of plasma cells derived from a single clone • Etiology: radiation;mutations in oncogenes; familial causes;role of IL 6 • Incidence/Prevalence: 14,400 cases in 1996; incidence 30/1,00,000 • Incidence increases with age • Males> females ; Blacks > Whites

  3. Clinical Manifestations • Common • bone pain and pathological fractures • anemia and bone marrow failure • infection due to immune-paresis and neutropenia • renal impairment • Less common • acute hypercalcemia • symptomatic hyperviscosity • neuropathy • amyloidosis • coagulopathy

  4. Clinical Manifestations • Bone Pain: • 70%,Precipitated by movement • Pathological fractures • Activation of Osteoclasts by OAF produced by myeloma cells • Susceptibility to infections: • Diffuse hypogammaglob. If the M spike is excluded • Poor Antibody responses ,Neutrophil dysfunction • Pneumococcus,S.aureus,GN aerobes-Pneumonia,Pyelonephrits

  5. Clinical Manifestations • Renal failure: 25% • Multiple contributory factors • Hypercalcemia,Hyperuricemia,recuurent Infections • Tubular damage produced by Light chains • type 2 proximal RTA,Non selective proteinuria • Anemia: 80% • Normochromic/Normocytic • Myelophthisis;Inhibition by cytokines produced by plasma cells. • Leukopenia/thrombocytopenia only in advanced cases.

  6. Bone Disease • Lytic Lesions – 60% • Osteoporosis, Fx, Compression Fx – 20% • Myeloma Cells Produce Cytokines that: • Stimulate Osteoclastic Activity • Inhibit Osteoblastic Activity • Can be Detected by Plain Xray

  7. Lytic lesions(Punched out lesions) on X Ray.

  8. Vertebral collapse secondary to osteoporosis/pathological fracture

  9. Normal bone Lesion Multiple myeloma: lesion in rib – Lab 11

  10. Multiple myeloma: multiple lesions in skull – Lab 11

  11. Renal Disease • Serum Cr Elevated in 50% and >2 in 20% at Diagnosis • Cast Nephropathy (Myeloma Kidney) • Large, Waxy Casts in Distal Tubules composed of Precipitated Light Chains • Not detected on Dipstick • SSA Test – Positive detected as the degree of turbidity when SSA added to urine suggests presence of non-albumin proteins • Hypercalcemia • Amyloidosis

  12. Case Report of Myeloma nephropathy • Bone marrow biopsy: 70% cellularity, increased atypicalplasmacellscomprising60%ofcellularity, c/w multiple myeloma

  13. Epidemiology of Myeloma nephropathy • In two large multiple myeloma studies, 43% (of 998 pts) had a creatinine>1.5 and 22% (of 423 pts) had a Cr>2.0 • The one-year survival was 80% in pts with Cr < 1.5 compared to 50% in pts with a Cr > 2.3 • Prognosis is especially poor in pts who require dialysis

  14. Causes of renal failure in MM • Cast nephropathy • Light chain deposition disease • Primary amyloidosis • Hypercalcemia • Renal tubular dysfunction • Volume depletion • IV contrast dye, nephrotoxic meds

  15. Myeloma Kidney • Two main pathogenetic mechanisms: • Intracellular cast formation • Direct tubular toxicity by light chains • Contributing factors to presence of renal failure due to multiple myeloma: • High rate of light chain excretion (tumor load) • Biochemical characteristics of light chain • Concurrent volume depletion

  16. Cast Nephropathy • Most common pathological diagnosis on renal biopsy in multiple myeloma • Due to light chains binding with Tamm-Horsfall mucoprotein, which is secreted by tubular cells in ascending loop of Henle, forming casts • Multinucleated giant cells surround the casts • Dehydration worsens cast nephropathy due to decreased flow in tubules, increased concentration of light chains

  17. Cast Nephropathy

  18. Cast Nephropathy

  19. Cast Nephropathy

  20. Minimal diagnostic criteria for myeloma • >10% Plasma cells in bone marrow or plasmacytoma on biopsy • Clinical features of myeloma • Plus at least one of: • Serum M band (IgG >30 g/l; IgA >20 g/l) • Urine M band (Bence Jones proteinuria) • Osteolytic lesions on skeletal survey

  21. Initial Work-up • CBC w/diff – peripheral smear • Normocytic, Normochromic Anemia most common • Rouleaux Formation >50% of patients • Chemistry (ca, alb, cr, LD, CRP, B2M) • SPEP – Monoclonal Protein • Serum Viscosity (if M-protein conc. Is high, >5g/dL) or sx of hyperviscosity are present • UA and UPEP • Metastatic bone Survey • Bone Marrow Biopsy

  22. Rouleaux formation

  23. M protein • Amount of the M protein -marker of tumor load • Nature variable: • May be an intact molecule or a fragment • Extramedullary / Solitary plasmacytomas <1/3 have M spike • 20% of Myelomas _ only Light Chains produced • Non Secretory Myelomas_rare • frequency of myelomas : Ig G> IgA > IgD

  24. 1.Normal Plasma 2.Polyclonal Hyperglobulinemia 3.Monoclonal Spike4.Bence Jones proteins in urine

  25. Plasmapheresis in MM

  26. Diagnostic Criteria • Presence of an M-Protein in serum and/or urine • Presence of clonal bone marrow plasma cells or plasmacytoma • Presence of Related Organ/Tissue involvement • Hypercalcemia, renal insufficiency, anemia, lytic bone lesions

  27. Screening and Diagnosis • Blood and urine tests • X-rays • Magnetic Resonance Imaging (MRI) • Computerized Tomography (CT) • Bone marrow examination

  28. Normal Cell (5%)

  29. Myeloma Cells (10%)

  30. Plasma Cell

  31. Bone Marrow Aspirate

  32. Bone Marrow Aspirate • Usually >10% plasma Cells, but can be from 5-100% • ≥ 50% involvement – worse prognosis • Immunoperoxidase staining detects either kappa or lambda light chains, NOT both (confirming proliferation is monoclonal) • Immunophenotyping – Malignant Plasma Cells stain positive for CD38, CD56, and CD138

  33. Bone Marrow Biopsy

  34. Staging • Stage 1 • Low amount of myeloma • Stage 2 • Medium amount of myeloma • Stage 3 • High amount of myeloma • A • Normal kidney function • B • Abnormal kidney function

  35. International Staging System • Stage I – B2M <3.5 mg/L and serum alb ≥ 3.5 g/dL • Stage II – neither stage I nor Stage III • Stage III – B2M ≥ 5.5 mg/L

  36. Staging 1. • Hb/Serum Ca/M component level/radiology • Stage I: Hb >10;Serum Ca < 12;Normal Bone survey;Low M component levels • Stage III: HB < 8.5, Serum Ca >12;Lytic lesions+;High M component levels • Stage II : Intermediate • Divided into A or B depending on Serum Creatinine level < or > than 2 mg/dl.

  37. Staging 2 • Serum b2 microglobulin levels. • If < 0.004 g/L : Stage 1; Median survival 43 months • If >0.004 g/L: Stage II; Median survival 12 months

  38. Prognostic Factors • Performance status 3 0r 4 • Serum albumin < 3 g/dL • Serum Cr ≥ 2.0 mg/dL • Platelet Count <150,000 • Age ≥ 70 years • Beta-2-microglobulin >4 mg/L • Serum Calcium ≥ 11 mg/dL • Hemoglobin <10 g/dL

  39. Treatment • Options: • melphalan with or without prednisone • Infusional chemotherapy - vincristine and adriamycin infusion plus either dexamethasone all methylprednisolone • combination therapy - for example, adriamycin, carmustine, cyclophosphamide, and melphalan • weekly cyclophosphamide (“C weekly”)

  40. Treatment • Prompt reduction in bone pain,anemia,hypercalcemia. • M component lags behind -4-6 weeks to fall • 60% of patients will acieve a 75% reduction in tumor mass. • Treat q 4-6 weeks for 1-2 years. • Leads to a plateau phase- relapse within a year. • Maintenance: alpha Interferon ???

  41. Treatment • Supportive therapy • analgesia • rehydration • treatment and any hypercalcemia • treatment of any renal impairment • treatment of any infection • local radiotherapy if required • chemotherapy • prevention of further bone damage

  42. Treatment • Melphalan and Prednisone (Oral) • Preferred Tx in pts NOT going for BMT • 7 day course repeated q 6weeks (x 3) • Objective response in 50-60%, MS of 2-3 yrs • Melphalan, prednisone, and Thalidomide • RR of 93% with 26% CR • When compared to above regimen, had better CR and RR; however, more toxicity • Thalidomide with or w/o Dexamethasone • Preferred in Candidates for BMT • For pts with Relapsed or Resistent Disease • VAD (Vincristine, Dex, and Adriamycin) • Radiation – Reserved for pts with focal process that has not responded to chemo

  43. Treatment Outcomes • Cure – Not yet been Achieved • Molecular Complete Response • No evidence of Disease • Complete Response • No detectable M protein AND nml % of Plasma cells in Bone Marrow • Progressive Disease • >25% increase in M Protein, new bony lesions, or a new plasmacytoma

  44. MGUS: Monoclonal gammopathy of undetermined significance • No explained symptoms suggestive of myeloma • Serum M protein concentration < 30 g/l • < 5 percent plasma cells in bone marrow • Little or no M protein in urine • No bone lesions • No anemia, hypercalcemia, or renal impairment • M protein concentration and other results stable on prolonged observation

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