1. PLASMA CELL DYSCRASIAS 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 CLASSIFICATION

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

3. MULTIPLE MYELOMA 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 Definition

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

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

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

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

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

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

17. MULTIPLE MYELOMA Cast nephropathy

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

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

20. MULTIPLE MYELOMA Presenting features (1027 pts) Mayo Clin Proc 2003;78:21 Bone pain58% Fatigue32% Weight loss24% Paresthesias5% Fever0.7% ECOG PS >210%

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

23. MULTIPLE MYELOMA Physical findings Mayo Clin Proc 2003;78:21 Palpable liver4% Palpable spleen1% Lymphadenopathy1%

24. MULTIPLE MYELOMA Hematologic findings at presentation Mayo Clin Proc 2003;78:21 Hgb < 1273% Hgb < 87% ESR > 2084% ESR > 10033% WBC < 400020% WBC < 20001% Plts < 100K5% Plts > 500K2%

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

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

34. Treatment mnemonic Calcium increased Renal dysfunction Anemia Bone lesions

35. MULTIPLE MYELOMA 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? TREATMENT

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