2. Multiple Myeloma Alan Johns, M.D. Kristine Krafts, M.D.

3. Richard – A Case Study

4. Richard S. 51 year old male presented 8/95 with vague epigastric distress and weight loss of 5 lbs. 51 year old male presented 8/95 with vague epigastric distress and weight loss of 5 lbs. Denies fevers, chills or back pain Denies fevers, chills or back pain PMH – neg. PMH – neg. Meds – none Meds – none Smoking, alcohol – none Smoking, alcohol – none Works as a carpenter Works as a carpenter

5. Physical Exam: BP= 134/84, Pulse = 70 Physical Exam: BP= 134/84, Pulse = 70 Temp = 98.4 degrees Temp = 98.4 degrees HEENT – neg Neck – no lymphadenophy Lungs – clear, Heart – no gallop or murmur Abdomen – nontender, no organomegaly Rectal – normal, stool hemoccult negative Extremities – no edema or deformities, no tenderness

6. Initial Lab: Hemoglobin = 6.7 Hemoglobin = 6.7 WBC = 8,300 WBC = 8,300 Plts. = 166,000 Plts. = 166,000 MCV = 94.5 (82-99) MCV = 94.5 (82-99) RDW = 13.0 (11.0-15.0) RDW = 13.0 (11.0-15.0) Reticulocyte Count = 0.9% (0.4-1.8) Reticulocyte Count = 0.9% (0.4-1.8) Hemoccult (stool) – negative for blood Hemoccult (stool) – negative for blood

7. Other Lab: Creatinine = 4.5 (0.8-1.3) Creatinine = 4.5 (0.8-1.3) UA – trace protein, no rbc’s or wbc’s UA – trace protein, no rbc’s or wbc’s

8. Problem List: 1) Severe anemia 1) Severe anemia 2) Acute renal failure with proteinurea 2) Acute renal failure with proteinurea 3) Epigastric distress 3) Epigastric distress 4) Weight loss 4) Weight loss

9. Bone Marrow

13. Diagnosis – Multiple Myeloma Diagnosis – Multiple Myeloma

14. Multiple Myeloma monoclonal plasma cell proliferation monoclonal gammopathy decreased normal immunoglobulins osteolytic lesions Things You Must Know

15. M-spike Type of IgG IgG in 60% of cases IgA in 20% of cases IgD or IgE in rare cases Never IgM Bence-Jones protein in urine Decreased normal Ig Laboratory Findings

16. Normal serum protein electrophoresis

17. Serum protein electrophoresis showing monoclonal band (M protein)

18. Blood: anemia, rouleaux Marrow: plasma cells, amyloid Morphology

19. Multiple Myeloma

21. Myeloma, mature type

22. Myeloma, intermediate type

23. Myeloma, plasmablastic type

24. Flame cells

25. Russell bodies

26. Dutcher body and Mott cell

27. Rouleaux

28. Amyloid

29. Solitary plasmacytoma Plasma cell leukemia Waldenström macroglobulinemia Lymphoplasmacytoid lymphoma IgM Hyperviscosity syndrome MGUS (Monoclonal gammopathy of undetermined significance) Small M spike with no myeloma symptoms Occasionally transforms into myeloma OTHER PLASMA CELL TUMORS

30. Richard Serum protein electrophoresis: Serum protein electrophoresis: Serum immunoelectrophoresis Serum immunoelectrophoresis Urine immunoelectrophoresis Urine immunoelectrophoresis

34. Biology of Normal Plasma Cells Plasmablasts in lymph nodes (IgM) Activated B cells in bone marrow (IgG, IgA) Differentiate into plasma cells (small in number, well-differentiated, characteristic phenotype, die by apoptosis)

35. Biology of Malignant Plasma Cells Plasmablasts in lymph nodes Plasmablasts in lymph nodes Plasmablasts in bone marrow (IgG, IgA) Plasmablasts in bone marrow (IgG, IgA) Plasmablasts do not differentiate into plasma cells, continue to proliferate and accumulate in marrow, produce large amounts of immunoglobulins, normal death of cells doesn’t occur, crowds out other cells – rbc precursors. Suppress antibody synthesis by normal plasma cells. Plasmablasts do not differentiate into plasma cells, continue to proliferate and accumulate in marrow, produce large amounts of immunoglobulins, normal death of cells doesn’t occur, crowds out other cells – rbc precursors. Suppress antibody synthesis by normal plasma cells.

37. Interleukin – 6 Essential for survival and growth of myeloma cells Essential for survival and growth of myeloma cells Growth factor for myeloma cells Growth factor for myeloma cells Also promotes survival of myeloma cells by preventing spontaneous apoptosis. Also promotes survival of myeloma cells by preventing spontaneous apoptosis. Increased levels in myeloma patients Increased levels in myeloma patients

38. Clinical Features 80% of patients present with bone pain 80% of patients present with bone pain (low back, pelvis, or ribs). Pain is associated with multiple lytic bone lesions. (low back, pelvis, or ribs). Pain is associated with multiple lytic bone lesions. Bruising or bleeding from decreased platelets Bruising or bleeding from decreased platelets Infections from decreased levels of normal immunoglobulins Infections from decreased levels of normal immunoglobulins

41. Clinical Features – con’t Hypercalcemia from bone destruction Hypercalcemia from bone destruction 50% of patients present with renal failure 50% of patients present with renal failure Hyperviscosity syndrome – caused by large amounts of circulating immunoglobulins causing purpura, confusion, decreased vision Hyperviscosity syndrome – caused by large amounts of circulating immunoglobulins causing purpura, confusion, decreased vision Major causes of death – infection, renal failure Major causes of death – infection, renal failure Classic triad – anemia, bone pain, renal failure Classic triad – anemia, bone pain, renal failure Average age of diagnosis – 69 years Average age of diagnosis – 69 years

42. Criteria for Diagnosis 1) Bone marrow with >20% plasma cells OR 2) Plasmacytoma plus one of the following: monoclonal protein in serum > 3 g/dl monoclonal protein in urine lytic lesions 3) Usual clinical features of myeloma 4) Exclude connective tissue diseases, chronic infections, carcinoma, lymphoma, leukemia

44. Therapy Conventional Dose Chemotherapy Conventional Dose Chemotherapy Classic combination – melphalan and Classic combination – melphalan and prednisone (1962) prednisone (1962) Complete Remission - < 5% Complete Remission - < 5% Median Survival – 3 years Median Survival – 3 years

45. Conventional Chemo-con’t VAD – vincristine, doxyrubicin and dexamethasone dexamethasone VAMP – vincristine, doxyrubicin and methyprednisolone methyprednisolone Did not prolong survival more than other regimens Excessive morbidity and mortality from prolonged myelosupression

46. Autologous Peripheral Blood Stem Cell Transplant - PBSC Hematopoietic stem cells from peripheral blood Hematopoietic stem cells from peripheral blood Growth factors are given after transplantation Growth factors are given after transplantation Safe – 1-2% death rate from the transplant Safe – 1-2% death rate from the transplant Problem – contamination of the autologous graft by myeloma cells Problem – contamination of the autologous graft by myeloma cells

47. High-Dose Therapy with Stem-cell Transplant (1992) Melphalan in high doses can induce complete remissions in 20-30%. Death from treatment alone is 10-30%. Stem-cell transplant after high dose Melphalan (with or without radiation) can produce a 30-50% complete remission in newly diagnosed patients. Problems – only 58% of patients over 60 could tolerate.

48. Single vs. double autologous stem-cell transplantation (2003)

49. New Agents Thalidomide Thalidomide First used with advanced and refractory myeloma (2001) First used with advanced and refractory myeloma (2001) Now used for newly diagnosed disease in combination with high-dose melphalan and double stem-cell transplant (2005) Now used for newly diagnosed disease in combination with high-dose melphalan and double stem-cell transplant (2005)

50. Copyright ©2004 American Society of Hematology. Copyright restrictions may apply. Barlogie, B. et al. Blood 2004;103:20-32 Figure 3. Thalidomide in advanced and refractory myeloma

51. Bortezomib (Velcade) Bortezomib (Velcade) Proteasome inhibitor Proteasome inhibitor

52. Copyright ©2004 American Society of Hematology. Copyright restrictions may apply. Barlogie, B. et al. Blood 2004;103:20-32 Figure 6. PS 341 (Velcade) plus thalidomide for posttransplantation relapse in 46 patients

53. New Supportive Therapies Biphosphonates – inhibit bone resorption, treats bone lesions and hypercalcemia. Biphosphonates – inhibit bone resorption, treats bone lesions and hypercalcemia. Erythropoietin – helps anemia and decreases need for transfusions. Erythropoietin – helps anemia and decreases need for transfusions.

54. Future Approaches Interleukin-2, Interleukin-4, Interferon gamma- pilot studies show no benefit. Interleukin-2, Interleukin-4, Interferon gamma- pilot studies show no benefit. Anti-interleukin-6 Anti-interleukin-6 Initial studies produced some effect but no lasting benefit. Initial studies produced some effect but no lasting benefit. Further trials underway Further trials underway

55. Future approaches – con’t Immunotherapy Immunotherapy Monoclonal immunoglobulins in an individual patient may have a tumor- specific antigen. Monoclonal immunoglobulins in an individual patient may have a tumor- specific antigen. T-cells seem to recognize the idiotypes of the patients myeloma protein. T-cells seem to recognize the idiotypes of the patients myeloma protein. IgG from patient transferred to a bone marrow donor then patient received transplant. Two years later patient has remained well with minimal M component. IgG from patient transferred to a bone marrow donor then patient received transplant. Two years later patient has remained well with minimal M component.

56. Prognosis 15 % die within 3 months of diagnosis 15 % die within 3 months of diagnosis Subsequent death rate 15% per year Subsequent death rate 15% per year Causes of death- marrow replacement with pancytopenia (16%), renal failure (10%), sepsis (14%), acute leukemia (5%), other chronic illnesses unrelated to myeloma (23%) Causes of death- marrow replacement with pancytopenia (16%), renal failure (10%), sepsis (14%), acute leukemia (5%), other chronic illnesses unrelated to myeloma (23%)

57. Richards’ Treatment 8/95 Melphalan and Prednisone cycles started. M = 6.6 g% 8/95 Melphalan and Prednisone cycles started. M = 6.6 g% 9/95 M = 3.96 Creatinine = 1.2 9/95 M = 3.96 Creatinine = 1.2 4/96 M = 1.95 4/96 M = 1.95 5/96 M = 2.4 Bone Marrow 7% plasma cells 5/96 M = 2.4 Bone Marrow 7% plasma cells 8/96 M = 1.85 8/96 M = 1.85

58. Richards’ Treatment Cont’ 2/97 M = 2.5 2/97 M = 2.5 4/97 M = 4.05 Bone Marrow shows 44% plasma cells 4/97 M = 4.05 Bone Marrow shows 44% plasma cells 5/97 VAD started 5/97 VAD started 7/97 M = 3.8 7/97 M = 3.8 8/97 Bone lesions noted pelvis and femur 8/97 Bone lesions noted pelvis and femur 1/98 M = 3.9 Bone marrow shows 20% plasma cells 1/98 M = 3.9 Bone marrow shows 20% plasma cells

59. Richards’ Treatment Cont’ 4/98 M = 5.2 4/98 M = 5.2 Allogenic bone marrow transplant after Cytoxan and whole body radiation at Mayo Clinic (brother was donor) Allogenic bone marrow transplant after Cytoxan and whole body radiation at Mayo Clinic (brother was donor) Post-transplant renal failure and pulmonary hemorrhage. Post-transplant renal failure and pulmonary hemorrhage. Died 6/6/98 Died 6/6/98