Tuesday Case Conference

1. Tuesday Case Conference

2. Multiple Myeloma Multiple Myeloma Myeloma related renal failure Treatment

3. Myeloma A clonal disorder of plasma cells Affects 1 in 300,000 1% of all new malignancies (16,000 per year) 10% of all new hematologic malignancies 2% of all cancer deaths (11,3000 per year) Median age of onset: 66 Most common hematologic malignancy in African Americans

4. Development of Myeloma Cells Transformation of a normal B cell into a malignant plasma cell Environmental/occupational exposures have been implicated Cytokines IL-6, RANK, TNF VEGF

5. Multiple Myeloma - diagnosis Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma) A monoclonal protein (paraprotein) in either serum or urine Evidence of end-organ damage

6. Structure of immunoglobulin Nelson DL, Cox MM. Lehninger principles of biochemistry, 4th ed. WH Freeman pub. New York 2005.

7. Serum Protein Electrophoresis Astion ML, Rank J, Wener MH, Torvik P, Schneider JB, Killingworth LM. Electrophoresis-tutor: an image-based personal computer program that teaches clinical interpretation of protein electrophoresis patterns of serum, urine and CSF. Clin chem. 1995 Sep;41(9):1328-32

8. Immunofixation Electrophoresis (IFE) Astion ML, Rank J, Wener MH, Torvik P, Schneider JB, Killingsworth LM. Electrophoresis-tutor: an image based personal computer program that teaches clinical interpretation of protein electrophoresis patterns of serum, urine, and CSF. Clin Chem. 1995 Sep;41(9):1328-32.

9. Frequency of isotypes of heavy and light chains produced bynon–immunoglobulin (Ig) M myelomas

10. Staging and Prognostic Factors

11. Epidemiology 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 < 1.5 compared to 50% in pts with a Cr > 2.3 5, 10, and 20 year survivals 31, 10, and 4% respectively Prognosis is especially poor in pts who require dialysis

12. Types of renal involvement in dysproteinemias

13. Pathogenesis of the different types of renal lesions in dysproteinemias

14. Myeloma Kidney Most common Dx by demonstration of tubular casts in the distal nephron

15. 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) • Concurrent volume depletion • Prognosis Rayner HC, Haynes AP, Thompson JR, Russell N, Fletcher J: Perspectives in multiple myeloma: Survival, prognostic factors and disease complications in a single center between 1975 and 1988. Q J Med 79: 517–525, 1991

16. Light Chain Deposition Disease Most commonly presents with both renal insufficiency and nephrotic syndrome Usually due to kappa immunoglobulin fragments which deposit in kidneys (basement membrane)

17. Amyloidosis Usually due to lambda light chains (AL) Light chains are taken up and partially metabolized by macrophages and then secreted – then precipitate to form fibrils that are Congo red positive, b-pleated Like LCDD, due to tubular injury and also presents as nephrotic syndrome

18. Hypercalcemia Hypercalcemia occurs in multiple myeloma due to bone resorption from lytic lesions Serum calcium > 11.0 mg/dL occurs in 15% of pts with multiple myeloma Hypercalcemia commonly contributes to renal failure by renal vasoconstriction, leading to intratubular calcium deposition

19. Renal Tubular Dysfunction – Acquired Fanconi syndrome On occasion, light chains cause tubular dysfunction without renal insufficiency Most commonly occurs with kappa light chains This presents as Fanconi syndrome – proximal renal tubular acidosis with wasting of potassium, phosphate, uric acid, and bicarbonate

20. Renal Insufficieny Fang LS. Light-chain nephropathy. Kidney Int. 1985 Mar;27(3):582-592.

21. Presentation and outcome in myeloma-associated renal disease Multiple Myeloma_Korbet_JASN_2006

22. Plasmapheresis in MM Theoretical benefit in removing the toxic circulating light chains to spare renal function Would seem to be most effective when circulating light chains in serum are present (i.e. significant M-spike on SPEP) Limited data to support efficacy Treatment of choice if hyperviscosity symptoms are present

23. Plasmapheresis in MM

24. Plasmapheresis studies Johnson et al., Arch Intern Med. 1990

25. Plasmapheresis studies Zuchelli et al., Kidney Int 1988

26. Plasmapheresis studies –Limitations Few prospective trials done Available trials have small numbers of patients enrolled A larger prospective, randomized trial would be beneficial in establishing the clinical utility of plasmapheresis in preventing ESRD in MM

27. Multiple Myeloma - treatment

29. Novel Therapies Velcade (bortezomib) Proteasome inhibitor Induces apoptosis via caspase-8, 9 Anti-myeloma effects by blocking NF-kB Revamid IMiD Induce G1 growth arrest

32. Revlimid (lenalidomide) First of new class of drugs called IMiDs

33. Alkylating agents, Bortemozid, corticosteroids inhibit cell growth and induce apoptosis Bortemozid inhibits NF-kB Thalidomide and Bortemozid inhibit interaction between myeloma cells & stromal cells as well as cytokine production (TNF-alpha, IL-6) Thalidomide inhibits angiogenesis and enhances CD8+ and NK cell functions

34. Incidence of renal involvement in dysproteinemias

35. 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

36. Treatment of renal failure in MM Hydration with IV fluids Treatment of hypercalcemia Loop diuretics Caution with bisphosphonates Treatment of myeloma Pulse steroids +/- thalidomide VAD chemotherapy Possible role for plasmapheresis Dialysis, as necessary

37. Multiple Myeloma - treatment Arsenic trioxide Thalidomide +/- Melphalan Cyclosporin A nonimmunosuppresive analogs Anti-IL-6 and anti-IL-6R antibodies Bortezomid (Velcade) Proteasome inhibitor Bone marrow transplantation