Multiple Myeloma

1. Multiple Myeloma • Definition: B-cell malignancy characterised by abnormal proliferation of plasma cells able to produce a monoclonal immunoglobulin (M protein) • Incidence: 3 - 9 cases per 100000 population / year more frequent in elderly modest male predominance

2. Multiple myeloma

3. Multiple Myeloma • Clinical forms: multiple myeloma solitary plasmacytoma plasma cell leukemia • M protein: - is seen in 99% of cases in serum and/or urine IgG > 50%, IgA 20-25%, IgE i IgD 1-3% light chain 20% - 1% of cases are nonsecretory

4. Multiple Myeloma Clinical manifestations are related to malignant behavior of plasma cells and abnormalities produced by M protein • plasma cell proliferation: multiple osteolytic bone lesions hypercalcemia bone marrow suppression ( pancytopenia ) • monoclonal M protein decreased level of normal immunoglobulins hyperviscosity

5. Multiple Myeloma

6. Multiple Myeloma Clinical symptoms: • bone pains, pathologic fractures • weakness and fatigue • serious infection • renal failure • bleeding diathesis

7. Multiple Myeloma Laboratory tests: • ESR > 100 • anaemia, thrombocytopenia • rouleaux in peripheral blood smears • marrow plasmacytosis > 10 -15% • hyperproteinemia • hypercalcemia • proteinuria • azotemia

8. Diagnostic Criteria for Multiple Myeloma Major criteria I. Plasmacytoma on tissue biopsy II. Bone marrow plasma cell > 30% III. Monoclonal M spike on electrophoresis IgG > 3,5g/dl, IgA > 2g/dl, light chain > 1g/dl in 24h urine sample Minor criteria a. Bone marrow plasma cells 10-30% b. M spike but less than above c. Lytic bone lesions d. Normal IgM < 50mg, IgA < 100mg, IgG < 600mg/dl

9. Multiple Myeloma

10. Diagnostic Criteria for Multiple Myeloma Diagnosis: • I + b, I + c, I + d • II + b, II + c, II + d • III + a, III + c, I II + d • a + b + c, a +b + d

11. Staging of Multiple Myeloma Clinical staging (Salmon-Durie) • is based on level of haemoglobin, serum calcium, immunoglobulins and presence or not of lytic bone lesions • correlates with myeloma burden and prognosis I. Low tumor mass II. Intermediate tumor mass III. High tumor mass • subclassification A - creatinine < 2mg/dl B - creatinine > 2mg/dl

12. Multiple myeloma • MGUS – monoclonal gammapathy of undetermined significance • Smoldering multiple myeloma • Symptomatic multiple myeloma

13. Monoclonal gammopathy of undetermined significance ( MGUS) • M protein present, stable • levels of M protein: IgG < 3,0g IgA < 2g LC<1g/day • normal immunoglobulins - normal levels • marrow plasmacytosis < 10% • complete blood count - normal • no lytic bone lesions • no signs of disease

14. Smoldering multiple myeloma • M protein present, stable • levels of M protein: IgG  3,0g IgA  2g LC1g/day • normal immunoglobulins - normal levels • marrow plasmacytosis 10% • complete blood count - normal • no lytic bone lesions • no signs of disease

15. Diagnostic Criteria for Multiple Myeloma • Plasma cell ≥ 10% in the bone marrow or tissue biopsy • Monoclonal protein  3g/dl in the serum or urine (>1g/dl) • Presence of end-organ damage • Hypercalcemia • Ca > 2,75 mmol/l • Renal insufficiency • Creatinine > 173 mmol/l • Anemia • Hb < 10g/dl • Bone lesions • Lytic lesions or osteopenia with compression fractures • Other • Symptomatic hyperviscosity, amyloidosis, recurrent bacterial infection (> 2 episodes in 12 months)

16. Multiple Myeloma Poor prognosis factors • beta-2 microglobulin > 3,5 mg/l • albumin > 3,5 g/dl • cytogenetical abnormalities: 13q del; t(4,14)

17. Treatment of Multiple Myeloma • Conventional chemotherapy • High dose therapy and autologous hematopoietic stem cell transplantation • Reduced intensity conditioning with allogeneic stem cell transplantation

18. Treatment of Multiple Myeloma • Patients < 65 - 70 years • high-dose therapy with autologous stem cell transplantation • allogeneic stem cell transplantation (conventional and „mini”) • Patients > 65 - 70 years • conventional chemotherapy

19. Treatment of Multiple Myeloma • Conventional Treatment • Talidomide + Dexamethasone • VAD (Vincristin, Adriamycin, Dexamethasone) • Melphlan + Prednisone • M2 (Vincristine, Melphalan, Cyclophosphamid, BCNU, Prednisone) • D (Dexamethasone) • Response rate 50-60% patients • Long term survival 5-10% patients

20. Treatment of Multiple Myeloma • Autologous transplantation (tandem) • patients < 65-70 years • treatment related mortality < 5 -10% • response rate 80% • long term survival 20-40% • Conventional allogeneic transplantation • patients < 45-50 years with HLA-identical donor • treatment related mortality 40-50% • long term survival 20-30%

21. Treatment of Multiple Myeloma Event-free and overall survival times of 515 patients receiving autotransplants and a median follow-up of at least 5 years.

22. Treatment of Multiple Myeloma • Novel method • Non-myeloablative therapy and allogeneic transplantation • Tandem transplants • Bortesomib (proteasome inhibitor) • Lenalidomid • Arsenic trioxide • Statins

23. Treatment of Multiple Myeloma • Supportive treatment • biphosphonates, calcitonin • recombinant erythropoietin • immunoglobulins • plasma exchange • radiation therapy

24. Disorder Associated with Monoclonal Protein • Neoplastic cell proliferation • multiple myeloma • solitary plasmacytoma • Waldenstrom macroglobulinemia • heavy chain disease • primary amyloidosis • Undetermined significance • monoclonal gammopathy of undetermined significance (MGUS) • Transient M protein • viral infection • post-valve replacement • Malignacy • bowel cancer, breast cancer • Immune dysregulation • AIDS, old age • Chronic inflamation

25. Monoclonal gammopathy of undetermined significance ( MGUS) • M protein • 3% of people > 70 years • 15% of people > 90 years • MGUS is diagnosed in 67% of patients with an M protein • 10% of patients with MGUS develop multiple myeloma