1. Plasma cell Disorders S. Sami Kartı, MD, Prof.

2. Plasma cells  Terminally differentiated cells of B- lymphocyte lineage  Produce antibodies  Normal plasma cells are incapable of dividing

3. Classification of plasma cell disease  Multiple myeloma  Variants  Non-secretory myeloma  Indolant myeloma  Smoldering myeloma  Plasma cell leukemia

4. Classification of plasma cell diseases  Plasmocytoma  Solitary plasmocytoma  Multiple plasmocytoma  Primary amyloidosis  POEMS Syndrome  Waldenström’s Macroglobulinemia  Heavy Chain Diseases

5. Multiple Myeloma

6. Definition  B-cell malignancy characterised by abnormal proliferation of plasma cells able to produce a monoclonal immunoglobulin (M protein)

7. Incidence  3-9 cases per 100,000 population/y  more frequent in elderly  modest male predominance

8. Clinical forms of MM  Multiple myeloma  Non-secretory myeloma  Smoldering myeloma  Plasma cell leukemia

9. M-protein (paraprotein)  Seen in 99% of cases in serum and/or urine IgG > 50% IgA 20-25% IgE and IgD 1-3% light chain 20%  1% of cases are nonsecretory

10.  Clinical manifestations are related to malignant behavior of plasma cells  and abnormalities produced by M protein

11.  plasma cell proliferation  multiple osteolytic bone lesions  Hypercalcemia  bone marrow suppression ( pancytopenia )  monoclonal M protein  decreased level of normal immunoglobulins  hyperviscosity

12. Symptoms  Bone pains  Weakness and fatigue  Weight loss

13. Laboratory  ESR > 100  anaemia, thrombocytopenia  rouleaux in peripheral blood smears  marrow plasmacytosis  hyperproteinemia  hypercalcemia  proteinuria  azotemia

14. Causes of renal failure in MM  Hyperviscosity  Hypercalcemia  Hyperuricemia  Light chain deposition  Analgesic nephropathy

15. Evaluation for a suspected MM  Serum and urine protein electrophoresis  Serum and urine immunofixation and immunglobulin quantitation  Radiographic skeletal survey  Bone marrow examination

16. Protein electrophoresis in a MM patient

17. Rouloux formation in peripheral smear

18. Lytic lesions in cranial x-ray

19. Bone marrow aspiration and biyopsy in a MM patient

20. Bone marrow aspiration of a MM patient

21. Immunohistochemistry in MM

23. 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 urin 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 Minimum of 1 major and 1 minor or 3 minor criteria including A and B

24. 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

25. Poor prognosis factors  Cytogenetical abnormalities of 11 and 13 chromosomes  Beta-2 microglobulin > 2,5 ug/ml

26. Treatment  Patients <65-70 years Velcade + Deksametazon Thalidomid VAD (Vincristin, Adriamycin, Dexamethasone) high-dose therapy with autologous stem cell transplantation allogeneic stem cell transplantation ( conventional and „mini”)  Patients >65 years conventional chemotherapy

27. Treatment  Conventional chemotherapy Velcade + dekasametazon Talidomid VAD (Vincristin, Adriamycin, Dexamethasone) Melphlan + Prednisone M2 ( Vincristine, Melphalan, Cyclophosphamid, BCNU, Prednisone)  Response rate 50-60% patients  Long term survival 5-10% patients

28. Treatment  Autologous transplantation patients < 65-70 years treatment related mortality 10-20% response rate 80% long term survival 40-50%

29. Treatment non-myeloablative therapy and allogeneic transplantation

30. Treatment  Supportive treatment biphosphonates, calcitonin recombinant erythropoietin immunoglobulins plasma exchange radiation therapy

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

32. Monoclonal gammopathy of undetermined significance ( MGUS)  M protein 3% of people > 70 years 15% of people > 90 years 10% of patients with MGUS develop multiple myeloma

33. Diagnostic criteria for smoldering myeloma  Same as MGUS except: Serum M-component at myeloma levels Marrow plasmocytosis 10-30%

34. Plasma cell leukemia

35.  >2x10 9 plasma cells in peripheral blood  Younger age  Higher incidence of organomegaly and lymphadenopathy  More extensive bone marrow infiltration  Poor response to chemotherapy

36. Non-secretory myeloma  1% of multiple myeloma  No serum or urine monoclonal protein  Must rule out IgD and IgE myeloma

37. Waldenström’s Macroglobulinemia  Monoclonal protein is IgM  No lytic lesions  Hyperviscosity (headache, tinnitus, dizziness, somnelence, etc)  Bone marrow aspiration reveals lymphoplasmocytic cells

38. Bone marrow aspiration and biopsy in WM

39. Solitary plasmacytoma  Localized plasma cell tumor  Absence of plasma cell infiltrate in bone marrow biyopsy  No evidence of other lytic lesions on radiographic examination  Absence of renal failure, anemia or hypercalcemia

40. Osteosclerotic Myeloma (POEMS Syndrome)  Polyneuropathy  Organomegaly (hepatomegaly, LAP)  Endocrinopathy (hypogonadism, hypoyhtroidism)  Monoclonal gammopathy  Skin changes (hyperpigmentation)