Multiple Myeloma and Amyloidosis

1. 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.