1. Multiple Myeloma

2. Definition: Malignant proliferation of plasma cells derived from a single clone Etiology: radiation;mutations in oncogenes; familial causes;role of IL 6 Incidence/Prevalence: 14,400 cases in 1996; incidence 30/1,00,000 Incidence increases with age Males> females ; Blacks > Whites

3. Clinical Manifestations Common –bone pain and pathological fractures –anemia and bone marrow failure –infection due to immune-paresis and neutropenia –renal impairment Less common –acute hypercalcemia –symptomatic hyperviscosity –neuropathy –amyloidosis –coagulopathy

4. Clinical Manifestations Bone Pain: –70%,Precipitated by movement –Pathological fractures –Activation of Osteoclasts by OAF produced by myeloma cells Susceptibility to infections: –Diffuse hypogammaglob. If the M spike is excluded –Poor Antibody responses,Neutrophil dysfunction –Pneumococcus,S.aureus,GN aerobes- Pneumonia,Pyelonephrits

5. Clinical Manifestations Renal failure: 25% –Multiple contributory factors –Hypercalcemia,Hyperuricemia,recuurent Infections –Tubular damage produced by Light chains –type 2 proximal RTA,Non selective proteinuria Anemia: 80% –Normochromic/Normocytic –Myelophthisis;Inhibition by cytokines produced by plasma cells. –Leukopenia/thrombocytopenia only in advanced cases.

6. Bone Disease Lytic Lesions – 60% Osteoporosis, Fx, Compression Fx – 20% Myeloma Cells Produce Cytokines that: –Stimulate Osteoclastic Activity –Inhibit Osteoblastic Activity Can be Detected by Plain Xray

7. Lytic lesions(Punched out lesions) on X Ray.

8. Vertebral collapse secondary to osteoporosis/pathological fracture

10. Multiple myeloma: lesion in rib – Lab 11 Lesion Normal bone

11. Multiple myeloma: multiple lesions in skull – Lab 11

12. Renal Disease Serum Cr Elevated in 50% and >2 in 20% at Diagnosis Cast Nephropathy (Myeloma Kidney) –Large, Waxy Casts in Distal Tubules composed of Precipitated Light Chains Not detected on Dipstick –SSA Test – Positive detected as the degree of turbidity when SSA added to urine suggests presence of non- albumin proteins Hypercalcemia Amyloidosis

13. Case Report of Myeloma nephropathy Bone marrow biopsy: 70% cellularity, increased atypical plasma cells comprising 60% of cellularity, c/w multiple myeloma

14. Epidemiology of Myeloma nephropathy In two large multiple myeloma studies, 43% (of 998 pts) had a creatinine > 1.5 and 22% (of 423 pts) had a Cr > 2.0 The one-year survival was 80% in pts with Cr 2.3 Prognosis is especially poor in pts who require dialysis

15. Causes of renal failure in MM Cast nephropathy Light chain deposition disease Primary amyloidosis Hypercalcemia Renal tubular dysfunction Volume depletion IV contrast dye, nephrotoxic meds

16. Myeloma Kidney Two main pathogenetic mechanisms: –Intracellular cast formation –Direct tubular toxicity by light chains Contributing factors to presence of renal failure due to multiple myeloma: –High rate of light chain excretion (tumor load) –Biochemical characteristics of light chain –Concurrent volume depletion

17. Cast Nephropathy Most common pathological diagnosis on renal biopsy in multiple myeloma Due to light chains binding with Tamm-Horsfall mucoprotein, which is secreted by tubular cells in ascending loop of Henle, forming casts Multinucleated giant cells surround the casts Dehydration worsens cast nephropathy due to decreased flow in tubules, increased concentration of light chains

18. Cast Nephropathy

21. Minimal diagnostic criteria for myeloma >10% Plasma cells in bone marrow or plasmacytoma on biopsy Clinical features of myeloma Plus at least one of: – Serum M band (IgG >30 g/l; IgA >20 g/l) – Urine M band (Bence Jones proteinuria) – Osteolytic lesions on skeletal survey

22. Initial Work-up CBC w/diff – peripheral smear –Normocytic, Normochromic Anemia most common –Rouleaux Formation >50% of patients Chemistry (ca, alb, cr, LD, CRP, B2M) SPEP – Monoclonal Protein Serum Viscosity (if M-protein conc. Is high, >5g/dL) or sx of hyperviscosity are present UA and UPEP Metastatic bone Survey Bone Marrow Biopsy

23. Rouleaux formation

24. M protein Amount of the M protein -marker of tumor load Nature variable: –May be an intact molecule or a fragment –Extramedullary / Solitary plasmacytomas <1/3 have M spike –20% of Myelomas _ only Light Chains produced –Non Secretory Myelomas_rare –frequency of myelomas : Ig G> IgA > IgD

26. 1.Normal Plasma 2.Polyclonal Hyperglobulinemia 3.Monoclonal Spike4.Bence Jones proteins in urine

27. Plasmapheresis in MM

28. Diagnostic Criteria Presence of an M-Protein in serum and/or urine Presence of clonal bone marrow plasma cells or plasmacytoma Presence of Related Organ/Tissue involvement –Hypercalcemia, renal insufficiency, anemia, lytic bone lesions

29. Screening and Diagnosis Blood and urine tests X-rays Magnetic Resonance Imaging (MRI) Computerized Tomography (CT) Bone marrow examination

30. Normal Cell (5%)

31. Myeloma Cells (10%)

32. Plasma Cell

33. Bone Marrow Aspirate

34. Usually >10% plasma Cells, but can be from 5-100% –≥ 50% involvement – worse prognosis Immunoperoxidase staining detects either kappa or lambda light chains, NOT both (confirming proliferation is monoclonal) Immunophenotyping – Malignant Plasma Cells stain positive for CD38, CD56, and CD138

35. Bone Marrow Biopsy

36. Staging Stage 1 –Low amount of myeloma Stage 2 –Medium amount of myeloma Stage 3 –High amount of myeloma A –Normal kidney function B –Abnormal kidney function

37. International Staging System Stage I – B2M <3.5 mg/L and serum alb ≥ 3.5 g/dL Stage II – neither stage I nor Stage III Stage III – B2M ≥ 5.5 mg/L

38. Staging 1. Hb/Serum Ca/M component level/radiology –Stage I: Hb >10;Serum Ca < 12;Normal Bone survey;Low M component levels –Stage III: HB 12;Lytic lesions+;High M component levels –Stage II : Intermediate Divided into A or B depending on Serum Creatinine level than 2 mg/dl.

39. Staging 2 Serum b2 microglobulin levels. If < 0.004 g/L : Stage 1; Median survival 43 months If >0.004 g/L: Stage II; Median survival 12 months

40. Prognostic Factors Performance status 3 0r 4 Serum albumin < 3 g/dL Serum Cr ≥ 2.0 mg/dL Platelet Count <150,000 Age ≥ 70 years Beta-2-microglobulin >4 mg/L Serum Calcium ≥ 11 mg/dL Hemoglobin <10 g/dL

41. Treatment Options: –melphalan with or without prednisone –Infusional chemotherapy - vincristine and adriamycin infusion plus either dexamethasone all methylprednisolone –combination therapy - for example, adriamycin, carmustine, cyclophosphamide, and melphalan –weekly cyclophosphamide (“C weekly”)

42. Treatment Prompt reduction in bone pain,anemia,hypercalcemia. M component lags behind -4-6 weeks to fall 60% of patients will acieve a 75% reduction in tumor mass. Treat q 4-6 weeks for 1-2 years. Leads to a plateau phase- relapse within a year. Maintenance: alpha Interferon ???

43. Treatment Supportive therapy –analgesia –rehydration –treatment and any hypercalcemia –treatment of any renal impairment –treatment of any infection –local radiotherapy if required –chemotherapy –prevention of further bone damage

44. Treatment Melphalan and Prednisone (Oral) –Preferred Tx in pts NOT going for BMT –7 day course repeated q 6weeks (x 3) –Objective response in 50-60%, MS of 2-3 yrs Melphalan, prednisone, and Thalidomide –RR of 93% with 26% CR –When compared to above regimen, had better CR and RR; however, more toxicity Thalidomide with or w/o Dexamethasone –Preferred in Candidates for BMT –For pts with Relapsed or Resistent Disease VAD (Vincristine, Dex, and Adriamycin) Radiation – Reserved for pts with focal process that has not responded to chemo

45. Treatment Outcomes Cure – Not yet been Achieved Molecular Complete Response –No evidence of Disease Complete Response –No detectable M protein AND nml % of Plasma cells in Bone Marrow Progressive Disease –>25% increase in M Protein, new bony lesions, or a new plasmacytoma

46. MGUS: Monoclonal gammopathy of undetermined significance No explained symptoms suggestive of myeloma Serum M protein concentration < 30 g/l < 5 percent plasma cells in bone marrow Little or no M protein in urine No bone lesions No anemia, hypercalcemia, or renal impairment M protein concentration and other results stable on prolonged observation