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PLASMA CELL DYSCRASIAS

CLASSIFICATION. Monoclonal gammopathy of uncertain significance (MGUS) Idiopathic Associated with other diseases (autoimmune, infectious, non-heme cancer, etc) Plasma cell or lymphoid malignancy Waldenstrom's macroglobulinemia Other lymphoproliferative disorders Smoldering multiple myeloma

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PLASMA CELL DYSCRASIAS

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  1. CLASSIFICATION Monoclonal gammopathy of uncertain significance (MGUS) Idiopathic Associated with other diseases (autoimmune, infectious, non-heme cancer, etc) Plasma cell or lymphoid malignancy Waldenstrom's macroglobulinemia Other lymphoproliferative disorders Smoldering multiple myeloma Multiple myeloma PLASMA CELL DYSCRASIAS

  2. MOLECULAR PATHOGENESIS OF MYELOMA Lancet 2004;363:875

  3. Definition Increased numbers of abnormal or immature plasma cells in the bone marrow, or localized plasmacytoma Monoclonal protein in blood or urine Some patients are nonsecretors Lytic bone lesions Not all patients have lytic bone disease MULTIPLE MYELOMA

  4. EPIDEMIOLOGY Incidence in US approx 3 cases/100,000/yr 98% of cases > 40 yrs old Risk factors: genetic radiation exposure ? chemical exposure MULTIPLE MYELOMA

  5. MULTIPLE MYELOMA Serum and urine protein electrophoresis Monoclonal IgG Free light chain Serum Urine

  6. Multiple myeloma (IgG kappa) IgG 2080 Anemia, leukopenia Lytic bone lesions 10% marrow plasma cells

  7. Multiple myeloma (IgA) IgA 1010 (nl 70-140) IgG 165 (nl 695-2190) IgM 14 (nl 60-265) Anemia, thrombocytopenia 16% marrow plasma cells

  8. MGUS Ifix: monoclonal IgG kappa No proteinuria IgA 234 (50-540) IgG 1840 (600-1600) IgM 85 (40-250) Normal CBC

  9. Waldenstrom macroglobulinemia with hyperviscosity syndrome Anemia, fatigue, retinopathy, bleeding disorder IgA 125 (70-440) IgG 724 (695-2190) IgM 5130 (60-265) Serum viscosity 3.6 Marrow: <5% plasmacytoid B-lymphocytes

  10. Waldenstrom macroglobulinemia Mild fatigue IgM 8460, serum viscosity 2.7 Hgb 12, WBC 3700, platelets 143,000 Marrow: 50% plasmacytoid B-lymphocytes

  11. Kappa light chain myeloma with cardiac amyloidosis Serum (hypogammaglobulinemia) Urine (kappa light chain) Always check the urine!

  12. MULTIPLE MYELOMA – BONE MARROW ASPIRATE

  13. MYELOMA CYTOGENETICS t(4;14) del (13) Lancet 2004;363:875

  14. DIAGNOSIS Monoclonal paraprotein Intact immunoglobulin in serum (SPEP) Light chains in serum or urine (IEP) Marrow plasmacytosis (> 20% - may be patchy) Lytic bone lesions Plasmacytoma MULTIPLE MYELOMA

  15. CLINICAL MANIFESTATIONS Anemia progressing to pancytopenia Bone pain/destruction Hypercalcemia Humoral immune defect Local effects of plasmacytomas Systemic effects of paraprotein MULTIPLE MYELOMA

  16. COMPLICATIONS Hyperviscosity (IgM >> IgA > IgG) Renal dysfunction (light chains) Glomerular Tubular Neuropathy Other organ damage (rare) Cryoglobulinemia (types I and II) Amyloidosis MONOCLONAL GAMMOPATHY

  17. MULTIPLE MYELOMA Cast nephropathy

  18. Brit J Haematol 2004; 124:565 CRYOGLOBULINEMIA IN IgM GAMMOPATHY

  19. Mayo Clin Proc 2003;78:21 MULTIPLE MYELOMA Demographics

  20. MULTIPLE MYELOMA Presenting features (1027 pts) Mayo Clin Proc 2003;78:21 Bone pain 58% Fatigue 32% Weight loss 24% Paresthesias 5% Fever 0.7% ECOG PS >2 10%

  21. MULTIPLE MYELOMA Preexisting conditions and risk factors Mayo Clin Proc 2003;78:21 Cancer in 1st degree relative 42% Myeloma in 1st degree relative 2% Hx of plasma cell proliferative disorder 34%

  22. Mayo Clin Proc 2003;78:21 MULTIPLE MYELOMA Pre-existing plasma cell disorders

  23. MULTIPLE MYELOMA Physical findings Mayo Clin Proc 2003;78:21 Palpable liver 4% Palpable spleen 1% Lymphadenopathy 1%

  24. MULTIPLE MYELOMA Hematologic findings at presentation Mayo Clin Proc 2003;78:21 Hgb < 12 73% Hgb < 8 7% ESR > 20 84% ESR > 100 33% WBC < 4000 20% WBC < 2000 1% Plts < 100K 5% Plts > 500K 2%

  25. Mayo Clin Proc 2003;78:21 MULTIPLE MYELOMA Laboratory findings

  26. MULTIPLE MYELOMA Serum and urine proteins Mayo Clin Proc 2003;78:21 Monoclonal band on SPEP in 82% 3% non-secretory at presentation

  27. MULTIPLE MYELOMA Types of monoclonal proteins Mayo Clin Proc 2003;78:21

  28. MULTIPLE MYELOMA Radiographic findings at presentation Mayo Clin Proc 2003;78:21

  29. MULTIPLE MYELOMA Survival Mayo Clin Proc 2003;78:21

  30. MULTIPLE MYELOMA Prognostic factors Mayo Clin Proc 2003;78:21 * * * * * * Most important factors in multivariate analysis

  31. *Adapted from Greipp et al, Blood 2003;102:190a

  32. Adverse cytogenetics in myeloma del13 or del13q t(4;14 del17p

  33. INDICATIONS FOR TREATMENT Symptomatic disease Bone destruction Anemia Organ dysfunction Hypercalcemia Increasing paraprotein or ß2-microglobulin level MULTIPLE MYELOMA

  34. Calcium increased Renal dysfunction Anemia Bone lesions Treatment mnemonic

  35. MULTIPLE MYELOMA TREATMENT • Initial treatment: • Thalidomide or lenalidomide + dexamethasone • Bortezomib + dexamethasone • Bortezomib + lenalidomide + dexamethasone • Melphalan + prednisone + lenalidomide/thalidomide • Autologous SCT prolongs survival • Refractory disease: • High dose cyclophosphamide • Platinum-based regimen • Bisphosphonates as adjunctive Rx • Allogeneic transplant role?

  36. Overall and progression-free survival in multiple myeloma: standard chemotherapy vs high-dose chemotherapy with stem cell rescue NEJM 2003;348:1875

  37. Blood 2010;116:679-686

  38. N Engl J Med 1996;334:488-93

  39. Lancet 2004;363:875

  40. How do thalidomide & related drugs work? Science 2014;343:256

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