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. 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