1. Multiple Myeloma By Dr Sameh Shamaa

2. Multiple Myeloma Epidemiology: 1% Of all malignant diseases. Annual incidence: 3-4/100 000. Age: - Median age: 65y. - The diagnosis of MM in a patient < 30y should only be made after careful evaluation of all data.

4. OPG/OCIF OC precursor OAF receptor (RANK) OSTEOCLAST ACTIVATION Osteoclast RANKL/OAF Osteoblast/ stromal cell /tumour cells/ myeloma Teitelbaum Science 2000

5. MULTIPLE MYELOMA: Clinical Picture

6. Bone Marrow Failure: * Anemia:usually normocytic normochromic :due to marrow infiltration and plasma volume expansion. * Neutropenia is frequent(++ susceptibility to infection). * Thrombocytopenia is rare.

7. Bone Disease: Skeletal lytic lesions,with or without osteoperosis,wedging or collapse of vertebral bodies or pathological fractures. Renal Failure: In 20-40% of cases,due to: -BJP,and/0r hypercalcemia (in 95% of cases). -Other causes: hyperuricemia,hypeviscosity,sepsis& nephrotoxic drugs.

8. Hypercalcemia: Secondary to osteolysis----->polyurea,and polydypsia may lead to severe dehydration Hyperviscosity : usually associated with IgM M-protein---- ocular,hemostatic,and neurological disturbances. Coagulopathy: either: -Hemorrhage: due to interference with action of clotting factors and platelets. -Thrombosis: due to acquired protein C deficiency.

9. Immune Paresis: -In 70% of patients with IgG MM, 40% of IgA MM and 20% of acses with BJP MM but cell mediated immunity is intact. So----- incresed risk of bacterial sepsis. Amyloidosis: In less than 5% of MM cases: more common with BJP and IgA MM-- deposition of amyloid material-- congesive heart failure, Carpal tunnel syndrome, macroglossia, gastrointestinal disturbances and europathies., renal amyloidosis.

10. MULTIPLE MYELOMA Lab investigation : ESR: very high. Serum protein electrophoresis: M-band. Immunofixation or immunoelectrophoresis: are confirmatory studies to define M-protein heavy and light chain classes.

11. MULTIPLE MYELOMA Lab investigation : Serum Ca: often. Serum creatinine: often. Anaemia (not obligatory): (rouleaux formation of RBCs). In uninvolved immunoglobulins. +BJP in 24 hr urine collection (monoclonal light chains).

12. MULTIPLE MYELOMA BM PICTURE: (Aspirate & Trephine Biopsy) >10 % myeloma cells.. More basophilic cytoplasm. Increased mitotic figures or multiple nuclei. Coarse chromatin. Plasma cell nests.

13. Immunophenotyping: CD 38 +ve. CD 19, 20, 22 -ve. Intracytoplasmic Ig +ve. sIg -ve. MULTIPLE MYELOMA

14. RADIODIAGNOSIS: Radiological survey of the entire skeleton: is mandatory. MRI: is superior to CT for screening the vertebral column for osteolytic lesions. Bone scan: is not indicated (cold lesions). REMEMBER!! Iodine-containing contrast media may cause acute renal failure in case of paraproteinaemia.

15. MM: SWOG Criteria for Diagnosis: (At least 1 major + 1 minor or 3 minors) Major Criteria: (1) Plasmacytoma on tissue biopsy (2) Marrow plasmacytosis > 30 %. (3) Monoclonal protein: Ig G > 3.5 g / dl. Ig A > 2 g / dl. BJP > 1 g / 24 hr. Minor Criteria: (1) Marrow plasmacytosis 10-29 %. (2) Monoclonal protein present but less than the above levels (3) Lytic bone lesions (4) Decrease in uninvolved Ig: Ig M < 50 mg / dl. Ig A < 100 mg / dl. Ig G < 600 mg / dl.

16. Prognostic Factors (1) Staging (2) -2 microglobulin most significant) (3) CRP (reflect IL-6 activity) (4) PCLI (5) Cytogenetics (6) LDH MULTIPLE MYELOMA

17. MM: Prognostic Factors M.S. (mo) Both 2M or CRP Both < 6 > 6 2M & CRP 54 27 6 Level (mg/l) Risk Group Low-risk Intermediate High-risk

18. MM: Prognostic Factors Cytogenetics : Cytogenetics abnormalities occur in 80-90% of patients. FISH is the best technique to discover them. Del 13 (partial or complete) & t involving 11q are associated with poor prognosis in ABMT patients only. Hypodiploidy is associated with drug resistance. Any abnormal karyotype leads to inferior outcome with standard therapy.

19. MM Treatment Options Chemotherapy High dose-therapy with transplant Radiation Maintenance therapy (e.g. alpha interferon, prednisone) Supportive care for –Anaemia –Pain –Bone disease (Bisphosphonates) –Hypercalcemia –Antibiotics –Emergency care (e.g. dialysis, plasmapheresis, surgery) Management of drug-resistant or refractory disease New and emerging treatments

20. Treatment of MM Use of Bisphosphonate in MM: Mechanism of action: 1.Decrease IL-6 release 2.Direct effect on Myeloma (may slow tumor growth) 3.Effect of angiogenesis

21. Treatment of MM Radiotherapy: Indications: Big osteolytic lesions. Significant osteolytic lesions in weight-bearing bone (for fear of pathological fracture). Cord compression. Extramedullary plasmacytoma.

24. Survival of Multiple Myeloma patients No treatment: 3-6 months Conventional chemotherapy: 3 years Chemotherapy + IFN-α: 3 years ± 6 months Auto transplant: 5 years 25% dies within 1st year 25% survival 8 years No cure by conventional chemotherapy