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

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

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

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

Multiple Myeloma Laboratory tests: ESR > 100 anaemia, thrombocytopenia rouleaux in peripheral blood smears marrow plasmacytosis > % hyperproteinemia hypercalcemia proteinuria azotemia

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

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

Staging of Multiple Myeloma Clinical staging 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

Multiple Myeloma Poor prognosis factors cytogenetical abnormalities of 11 and 13 chromosomes beta-2 microglobulines > 2,5 ug/ml

Treatment of Multiple Myeloma Patients < years – high-dose therapy with autologous stem cell transplantation – allogeneic stem cell transplantation ( conventional and mini) Patients > 65 years –conventional chemotherapy –non-myeloablative therapy with allogeneic transplantation (mini)

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

Treatment of Multiple Myeloma Autologous transplantation –patients < years –treatment related mortality 10-20% –response rate 80% –long term survival 40-50% Conventional allogeneic transplantation –patients < years with HLA-identical donor –treatment related mortality 40-50% –long term survival 20-30%

Treatment of Multiple Myeloma New method –non-myeloablative therapy and allogeneic transplantation –thalidomid

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

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

Monoclonal gammopathy of undetermined significance ( MGUS) M protein presence, stable levels of M protein: IgG < 3,5g IgA < 2g LC<1g/day normal immunoglobulins - normal levels marrow plasmacytosis < 5% complete blood count - normal no lytic bone lesions no signs of disease

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