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

Multiple myeloma

Multiple Myeloma

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 plasmocytosis > 10 % hyperproteinemia hypercalcemia proteinuria

Multiple myeloma INITIAL DIAGNOSTIC WORKUP 2011

Diagnostic Criteria for Multiple Myeloma (old) 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

Multiple Myeloma

Diagnostic Criteria for Multiple Myeloma (present) Plasmocytosis >= 10% and/or plazmocytoma infiltration M protein Myeloma related damage (CRAB)

Diagnostic Criteria for Multiple Myeloma (present) C (Calcium) (> 2,75 mmol/l) R (Renal Insufficiency) creatinine concentration >173 mmol/l (1,96 mg/dl) A (Anemia) Hg <10 g/dl B (Bone lesions)

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

Smouldering 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

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

ISS (International Staging System for multiple myeloma) Stage MOS (months) I β2 microglobulin < 3,5 mg/l and albumins > 3,5 g/dl 62 II No criteria for I and III 44 III β2 mikroglobulin >5,5 mg/l 29

MM treatment Thalidomide TNF-α inhibitor b-FGF and VEGF2 inhibitor (antiangiogenic factor) Apoptosis promotion ( NF-κB ) Induktion of Th1 activity with production of IFN-γ i IL-2)

MM treatment MP („gold standard” ) Melfalan 9 mg/m2 po 1-4 day every 6 weeks Prednison 60 mg/m2 po 1-4 day every 6 weeks Up to 9 cycles OR (CR+PR+MR) 47% OS 32 months Infections (3 i 4 NCI grade) 18%

MM treatment Bortesomib Reversible proteasoms’ inhibitor NFκB inhibitor (promotes apoptosis) registered for 2nd and 3rd line

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.

Treatment of Multiple Myeloma New methods Non-myeloablative therapy and allogeneic transplantation Tandem transplants Bortesomib (proteasome inhibitor) Lenalidomide Arsenic trioxide Statins

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

2011

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