Multiple Myeloma and Amyloidosis

2. Objectives To introduce the terminology used in describing the plasma cells neoplasm. To explain the physiology of the normal cells & the pathological effects of their neoplastic growth. To describe the classification of plasma cells neoplasm. To discuss the relationship with amyloidosis and its pathology.

3. Plasma cells Terminally differentiated B- Lymphocytes that are capable of producing immunoglobulins. Paraprotein : Structurally identical & homologous ig.of the same clone i.e monoclonal. Lymphoplasmacytic Neoplasm : Neoplasm of the plasma cells producing excess paraprotein.

4. Classification of plasma cell neoplasms Monoclonal gammopathy of undetermined significance. Multiple myeloma. Macroglobulinemia.

5. 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

6. 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

7. Macroglobulinemia Tumour of lymphoplasmacytoid cells producing Monoclonal ig most commonly ( Igm ) Types : - Essential macroglobulinemia. - waldenstrom macroglobulinemia. Clinical Features : Weight loss, fatigue. Bleeding usually epistaxis. Bone marrow infiltration by the lymphoplasmcytic cells “less mature than plasma cells” presenting as anemia thrombocytopenia or leucopenia.

8. 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

9. 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

10. 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

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

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

13. 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

14. 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

15. 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

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

17. 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 years conventional chemotherapy non-myeloablative therapy with allogeneic transplantation („mini”)

18. 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

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

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

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

22. 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 inflammation

23. Amyloidosis Primary amyloidosis : Deposition of light chain of Ig as in multiple myeloma sites : Tongue, GIT, Heart, Connective tissue. Secondary Amyloidosis : Deposition of amyloid -A- substance Sites : Spleen, Liver, Kidney Familial Amyloidosis: Due to genetic mutation Causing deposition of unmetalised prealbumin.