1. Myeloma Basics Rodger Tiedemann M.D., Ph.D., F.R.A.C.P., F.R.C.P.A. Assist. Professor of Medicine, University of Toronto Senior Scientist & Staff Physician, Ontario Cancer Institute Princess Margaret Hospital

3. Overview

4. Pre-B cell Naive B cell Interfollicular area Immature B-cell Progenitor B-cell What are plasma cells? Follicular area FDC Lymph Node Germinal Centre B-cell development

5. Ag Pre-B cell Naive B cell Follicular B blast Centroblast Centrocyte Marginal Zone Memory B-cells Plasma cell Extrafollicular B-Immunoblast Interfollicular area Immature B-cell Progenitor B-cell What are plasma cells? Follicular area FDC Ag Lymph Node Germinal Centre SHM + class switching Germs IgM IgG IgA B-cell affinity maturation

6. What are antibodies? light chain – κ, λ heavy chain – G, A, M, E, D

7. What is an M-protein? SPEP Polyclonal smear M-spike Normal antibody repertoire Myeloma antibodies

8. Understanding your Bloodwork Donna Reece 9:30-10:15

9. Stepwise progression MGUS Smoldering MM Smoldering MM Active MM Active MM Extra medullary Extra medullary Clonal cells PC > 10% End organ damage BM independent

10. InternationaI Working Group (IWG) diagnostic criteria MM An M-protein (in serum or urine) + Marrow plasmacytosis or soft tissue plasmacytoma (clonal) + End-organ damage: ‘CRAB’ MM An M-protein (in serum or urine) + Marrow plasmacytosis or soft tissue plasmacytoma (clonal) + End-organ damage: ‘CRAB’ SMM Serum M-protein ≥3.0 g/dL and / or Marrow plasma cells ≥10% (clonal) + No related organ or tissue impairment SMM Serum M-protein ≥3.0 g/dL and / or Marrow plasma cells ≥10% (clonal) + No related organ or tissue impairment MGUS Serum M-protein <3.0 g/dL + Marrow plasma cells <10% + No related organ damage No other B cell NHL or amyloidosis MGUS Serum M-protein <3.0 g/dL + Marrow plasma cells <10% + No related organ damage No other B cell NHL or amyloidosis

11. MGUS =Monoclonal gammopathy of undetermined significance prevalence increases with age: 3.2% at >50yo 5.3% at >70yo 7.5% at >85yo on average, 1% risk per year of progression to Multiple Myeloma or lymphoma (7x risk ‘normal’ population) virtually all MM patients probably had MGUS before MM

12. MM Features Calcium elevation Renal disease Anemia Bone disease M-protein (often >30g/l in serum) IgG > IgA > IgD or Light chain only Clonal plasma cells (often >10% in BM) Smith. Br J Haematol. 2005;132:410.

13. What causes plasma cells to become malignant?

14. Chromosomal changes in MM Hypodiploid < 45 Hyperdiploid >46/47 Near tetradiploid >75 Pseudodiploid 44/45 – 46/47

15. Leif Bergsagel Marta Chesi 5+ recurrent chromosome translocations (breakages) in MM

16. 9 Types of Myeloma IgH translocationHyperdiploid

17. Pre-B cell Naive B cell Mantle zone Follicular B blast Centroblast Centrocyte Marginal Zone Memory B-cells Extrafollicular B-Immunoblast Interfollicular area Immature B-cell Progenitor B-cell What causes Multiple Myeloma? Follicular area FDC Ag Lymph Node Germinal Centre SHM + class switching IgM IgG IgA MGUS Multiple Myeloma

18. Increased risk of MM in individuals exposed to: A-bomb Radiation (e.g. radiologists & nuclear power plant workers Pesticides? (evidence not compelling) Benzene? (evidence not compelling) Risk modified by gender & race What sparks the first mutation(s) that lead to MM? ??? “break”

19. Erroneous DNA repair? attempted repair“break” insult

20. Prognosis in MM?

21. International Staging System (ISS) 1Serum ß2 microglobulin <3.5 mg/dL + Serum albumin ≥ 3.5 g/dL 2 Not 1 or 3* 3 Serum ß2 microglobulin >5.5 mg/dL

22. International Staging System vs OS

23. R. Fonseca et al. Blood 2003 Chromosomal abnormalities (by FISH) t(4;14) t(14;16)  13 -17p13.1

24. Shaughnessy, J. D. et al. Blood 2007;109:2276-2284 Gene expression-defined high-risk signature

25. What medicines are available?

26. Alkylating agents Dr “Danny” Bergsagel melphalancyclophosphamideprednisonedexamethason e Glucocorticosteroids 19581967

27. Previous standard of care: circa 1999 < 70y (Vincristine) (Adriamycin) Dexamethasone > 70y ? inductionconsolidationmaintenance Repeat? Melphalan Prednisone Melphalan 200mg/m 2 with autologous SCT ?steroid ?interferon

28. IMiDs: Thalidomide, Lenalidomide and Pomalidomide Lenalidomide 15-25 mg/d Myelosuppression Skin rash DVT Structurally similar, but functionally different, both qualitatively and quantitatively Thalidomide 100-200 mg/d Neuropathy Constipation Sedation DVT Pomalidomide 1-4 mg/d N O O N H O O NH 2

29. MOA of IMiDS Teo SK, AAPS Journal. 2005; 07(01):

30. Carfilzomib Irreversible Proteasome (Thr) Bortezomib Slowly reversible (Thr or Ser protease) Proteasome Inhibitors

31. Proteasome inhibition X proteasome Myeloma cell trash Proteasome inhibited (e.g. with Velcade) Trash++

32. How can these drugs be best used?

33. Many patients do well with Revlimid induction & transplant E4A03: Overall Survival after 4x Rev/Dex + Auto SCT P=NS Rd RD 92% 3-year OS rate HDM+Transplant following 4 cycles of RD vs. Rd Transplant N = 90 (median age: 57 years) Median F/U: 36 months Rajkumar et al, 2008.

34. Lenalidomide (Revlimid) does not overcome classical high-risk 0.2.4.6.8 1 PFS 01020304050 time (months) Standard Risk High Risk P < 0.001 median 18.5 months median 36.5 months Rev/Dex

35. Bortezomib improves outcome (OS) in high-risk MM, including t(4;14). Low risk MM, no t(4;14) or -17p High risk MM, t(4;14) Bortezomib added to TT3 but absent from TT2 Pineda-Roman et al., Br J Haematol. 2008 Mar;140(6):625-34 OS TT3 TT2 TT2 + Thal TT3 TT2 TT2 + Thal

36. MM response rates: new drugs and combinations % of patients responding Old regimensNew regimens

37. Current Approaches for the Newly Diagnosed Patient Dr Keith Stewart 1:00-1:45 Dr Donna Reece 1:00-1:45 What to do at Relapse