Waldenström’s macroglobulinemia : Similar but Different to Myeloma?

1. Waldenström’smacroglobulinemia:Similar but Different to Myeloma? Steve Treon MD, MA, PhD Dana Farber Cancer Institute Harvard Medical School Boston, Massachusetts, United States

2. Second Intl Workshop on Waldenstrom’sMacroglobulinemia Closing Ceremony at the Acropolis, Athens, Greece 2002

3. Clinicopathologic Definition of WM Pathologic diagnosis of lymphoplasmacytic lymphoma using REAL/WHO criteria. Presence of a monoclonal IgM protein,irrespective of serum level. IWWM2, ATHENS 2002 Owen RG, et al. Semin Oncol. 2003;30(2):110-115.

4. Lack of relationship between serum IgM levels and BM involvement in WM. IgM (mg/dL) BM Involvement (%)

5. Lymphoplasmacytic Lymphoma • Cells: lymphocytes, lymphoplasmacytoid cells, plasma cells • excess mast cells in association with lymphoid • aggregates • BM: interstitial pattern with diffuse or nodular infiltrates • excess mast cells in association with lymphoid • aggregates • LN/SP: diffuse pattern ** BM BM LN

6. Immunophenotypic expression of WM • almost always expressed: sIgM, CD19, • CD20, CD22, CD79 • usually expressed: CD25, CD27, FMC7, • BCL-2, CD52 • variable expression: CD5, CD10, CD23 • small population: CD138 (plasma cells) San Miguel et al, Semin Oncol 2003; Hunter et al, Clin Lymphoma 2005

7. Cytogenetics in WM • del 6q21-25 are commonly observed (30-50%) in WM; • Present in familial and sporadic WM cases; • Absent in IgM MGUS; • IgH (Chr.14) translocations are absent and help distinguish WM from IgM MM. FISH for 6q21 Schop, Blood 2002; Avet Loiseau , Semin Oncol 2003; Treon, Ann Oncol 2006; Ocio BJH 2007.

8. Microenvironmental Support in WM by CD40L expressing mast cells. • H • I WM-1 WM-2 • J Tournilhac et al, Ann Oncol 2006 • Tryptase CD40 Ligand

9. sCD27 in WM-Mast Cell Interactions Y MMP-8 SGN-70 Soluble CD27 CD70 Alemtuzumab CD27 Y Alemtuzumab Y CD52 APRIL TACI, BCMA CD52 X C-kit CD40L CD40 Imatinib mesylate Lymphoplasmacytic cells Mast cells Tournilhac et al, Ann Oncol 2006; Ho et al, Blood 2008

10. Clinicopathologic Manifestations of WM HCT, PLT, WBC Hyperviscosity Syndrome: Epistaxis, HA, Impaired vision >4.0 CP Adenopathy, splenomegaly ≤15% IgM Neuropathy (22%) Cryoglobulinemia (10%) Cold Agglutinemia (5%) Fatigue, Constitutional Sxs Cytokinemia? Treon SP et al. Cancer Treat Res. 2008;142:211-242.

11. Funduscopic exam of a WM patient with hyperviscosity syndrome From Dr. Marvin Stone

12. Cryoglobulinemia in a patient with Waldenstrom’smacroglobulinemia Pre-Pheresis Post-Pheresis

13. IgM Related Neuropathies in WM • Observed in about 22% of WM patients • Most commonly is demyelinating and related to IgM neuropathic antibody. • Usually sensory and related to antibodies targeting: • Myelin Associated Glycoprotein (MAG) • Ganglioside M1 (GM1) • Sulfatide Courtesy Todd Levine, MD MAG antibody staining

14. Genetic Predisposition

15. Familial disease predisposition in WM • N=1076 consecutive patients with clinicopathological diagnosis of WM • 26.1% of WM patients have a first or second degree relative with a B-cell LPD. Distribution of B-cell LPD in relatives of 281 Familial WM patients. Treon et al, ICML 2011.

16. Familial Associations in other B-cell LPD • Prospective study of 1,948 pts with B-cell LPD • First/Second Degree Relatives • CLL (17.5%) • NHL (12.6%) • Hodgkin’s (11.9%) Brown et al, BJH 2008 DFCI

17. Relative Risk of other B-cell LPD in patients with CLL, MM, and WM Swedish Registry Data Kristinsson, Int J Cancer 2009; Blood 2009; Goldin, Haematologica 2009.

18. GWAS: Copy Number Polymorphisms in GSTM1 and GSTT1 in WM Patients Varies by Family History * P <0.01 vs. Mixed B-Cell History Hunter et al, ASH 2009

19. Impact of familial status in rituximab-naïve patients receiving a rituximab containing regimen. Response to Therapy p=0.029 p=0.032 P<0.001 Treon et al, ASH 2011

20. Familial Disease Is Associated with shorter PFS and Time to Next Therapy 100 100 PFS TTNT 90 90 80 80 70 70 60 60 50 50 Percent without progression Percent without progression 40 40 30 30 20 20 10 10 No familial disease Familial disease No familial disease Familial disease 0 0 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100 Months Months p=0.015 p=0.024 Treon et al, ASH 2011

21. Familial Disease Status in WM is an Independent Prognostic for PFS

22. Does the type treatment impact response for familial patients? N=36 p=0.05 p=0.0006 Treon et al, ASH 2011

23. Impact of Bortezomib-based therapy on PFS in Familial and Sporadic WM Patients. Familial WM Sporadic WM p=0.08 p=0.68 Treon et al, ASH 2011

24. Consensus Panel Recommendations for Initiation of Therapy in WM • Hb ≤10 g/dL on basis of disease • PLT <100,000 mm3 on basis of disease • Symptomatic hyperviscosity (>4.0 cp) • Moderate to severe peripheral neuropathy • Symptomatic cryoglobulinemia, cold agglutinemia, amyloidosis, or symptomatic autoimmune-related events on the basis of disease Kyle RA, et al. Semin Oncol. 2003;30(2):116-120.

25. Natural Killer Cell CD20- Directed Rituximab Monoclonal Antibody Fc receptor Fc Fab CD20 WM cell

26. Serum IgM Levels Following Rituximab in Patients With WM 14,000 WM 1 P 12,000 WM 2 WM 3 10,000 WM 4 P P WM 5 P WM 6 8000 P P WM 7 Serum IgM (mg/dL) WM 8 6000 WM 9 WM 10 4000 WM 11 P 2000 0 0 2 4 6 8 10 12 14 Wks P denotes patient-required plasmapheresis for hyperviscosity. Treon SP, et al. Ann Oncol. 2004;15(10):1481-1483.

27. +monocytes +rituximab +anti-IL6 beads +monocytes + rituximab IVIg Rituximab +monocytes FcγRIIA Monocytes IL-6 IgM (ng/ml) IL-6R IgM WM-LPC Bystander Release of IL-6 by Monocytes May Account for the Rituximab IgM Flare

28. Primary Therapy of WM with Rituximab-Based Options

29. Disease Transformation and MDS/AML Following Nucleoside Analogues in WM 1. Leleu X, et al.J Clin Oncol. 2009;27(2):250-255. 2. Tamburini J, et al. Leukemia. 2005;19(10):1831-1834. 3. Leblond V, et al. J Clin Oncol. 1998;16:2060-2064. 4. Rakkhit R, et al. Blood. 2008;112: Abstract 3065.

30. Lenalidomide-Induced Anemia in WM Decreased Hct observed in 10/12 pts following first week of lenalidomide monotherapy Median Hct decrease: 3.9% (31.9% to 28.0%; P = .003) No evidence for hemolysis; concurrent thrombocytopenia observed in 1 pt 4 patients hospitalized for anemia related complications (Afib, syncope, CHF) Pretherapy Posttherapy 38 36 34 32 30 Hematocrit (%) 28 26 24 22 20 1 2 3 4 5 6 7 8 9 10 11 12 Afib, atrial fibrillation, CHF, congestive heart failure, Hct, hematocrit. Treon SP, et al. Clin Cancer Res 2008 Patient

31. Phase I Study of Pomalidomide, Dexamethasone, and Rituximab (PDR) in WM • Aggravated Anemia less pronounced • IgM Flare potentiated • CR in Dose Level -1

32. Proteasome Inhibitors

33. Bortezomib Combination Therapy in WM • Primary Bortezomib (1.3 mg/m2/biwkly)/Dexamethasone/Rituximab ORR 95%; CR 22%; TTP >4 yrs; 30% Grade 3 PN Bortezomib (1.6 mg/m2/wk)/Rituximab ORR 92%; CR 8%; 80% 1 Y PFS; No Grade 3 PN • Salvage Bortezomib (1.6 mg/m2/wk)/Rituximab ORR 81%; CR 5%; TTP 12 months; 5% Grade 3 PN. Bortezomib (randomized wkly vs biwkly)/Rituximab ORR 80%; CR 0%; TTP ?; 0% Grade 3 PN. vs. 10-12% in MM! Treon SP, et al. J ClinOncol. 2009;27(23):3830-383. Ghobrial IM, et al. Blood. 2010;116: Abstract 832. Ghobrial IM, et al. J ClinOncol. 2010; 28(8):1422-1428. Agathocleous A, et al. Blood. 2007;110: Abstract 2559.

34. Bortezomib-Based Rituximab Therapy Twice A Week Once A Week CR/VGPR Neuropathy PFS (?) Time to Response Rituximab IgM Flare

35. Primary Therapy of WM with Carfilzomib, Rituximab, Dex (CARD) Induction Cycle 1 q21 days Days 1,2,8,9 Carfilzomib 20 mg/m2 IV; Dexamethasone 20 mg IV. Days 2,9 Rituximab 375 mg/m2 Induction Cycle 2-6 q21 days Days 1,2,8,9 Carfilzomib 36 mg/m2 IV; Dexamethasone 20 mg IV. Days 2,9 Rituximab 375 mg/m2 2 months Maintenance Cycles 1-8 q 2 months Days 1,2 Carfilzomib 36 mg/m2 IV; Dexamethasone 20 mg IV. Days 2 Rituximab 375 mg/m2

37. Bendamustine in WM ClH2C Bendamustine Carboxylic acid N N ClH2C COOH N Benzimidazole ring Nitrogen mustard NH2 CH3 N Cl N Cyclophosphamide N N Cl O O HOCH2 N P O Cl Cladribine N H OH

38. 0 1 22 43 64 85 106 0 1 29 57 85 113 141 CHOP day 1 22 43 64 85 106 B = Bendamustine 90 mg/m2 day 1+2 29+30 57+58 85+86 113+114 141+142 R = Rituximab Rituximab 375 mg/m2 day 0 29 57 85 113 141 375 mg/m2 day 0 22 43 64 85 106 Bendamustine plus Rituximab (B-R) B B-R B-R B-R B-R B-R R Tag Randomization CHOP plus Rituximab (CHOP-R) CHOP CHOP-R CHOP-R CHOP-R CHOP-R CHOP-R R Tag Rummel MJ, et al. Blood. 2008;112: Abstract 2596.

39. Waldenström Patient Characteristics: B-R vs CHOP-R 20th Aug 2008 Bendamustine-RCHOP-R40 evaluable pts.(n = 23) (n = 17) Age (median) 65 yrs 64 yrs Stage IV 100 % 100 % Beta-2 Microglobulin 3,2 3,4 IgM (median, mg/dl) 2.790 1.690 Range IgM (mg/dl) 11.220 - 1.100 8.510 - 900 Hb (median, g/dl) 10,2 9,9 Toxicity treatment associated Neuropathy (patients) 1 3 Rummel M, et al. Presented at: Third International Pt Physic Summit on WM; May 1-3, 2009; Boston, Massachusetts, United States.

40. PFS: Benda-R vs CHOP-R in Frontline WM 1.0 0.9 Bendamustine-R 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 CHOP-R 0.1 0.0 0 12 24 36 48 60 72 months Rummel M, et al. Presented at: Third International Pt Physic Summit on WM; May 1-3, 2009; Boston, Massachusetts, United States.

41. Bendamustine in Relapsed/Refractory WM P<.0001 P = .0002 • ORR 83% • PFS 13.2 mos. Treon S, et al. Clin Lymphoma Myeloma Leuk. 2011;11(1):133-135.

42. PFS is impacted by Depth of Response in WM Pts Treated With Rituximab-Based Therapy. 1.00 1.00 CR CR/VGPR 0.75 0.75 VGPR PR Without progression (%) Without progression (%) 0.50 0.50 MR/PR MR 0.25 0.25 NR P = 0.04 P < .0001 0.00 0.00 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100 Time from treatment initiation (months) Time from treatment initiation (months) N=159 Treon S, et al. Br J Haematol. 2011 May 12 [Epub ahead of print].

43. VAL/VAL 10-12% VAL/PHE 35-40% PHE/PHE 40-50% Treon S, et al. Clin Lymph Myeloma. 2010;10(5):347-352.

44. FcγRIIIA-158 Polymorphisms Predict Response in WM P-values vs VGPR/CR P = .04 P = .03 P = .02 Treon S, et al. Br J Haematol. 2011 May 12 [Epub ahead of print].

45. Modified elbow • hinge • Apoptosis induction • Glycoengineered Fc • domain • Enhanced ADCC • effect GA101: Novel Humanized CD20 MAB Mossner E, et al. Blood. 2010;115(22):4393-4402.

46. GA101 Rituximab % Total Cytotoxicity Log Ab concentration (ug/ml) GA101 % Total Cytotoxicity Rituximab Log Ab concentration (ug/ml) ADCC Against WM Cells for GA101 is Greater Among Autologous NK Cells Genotyped for FCGRIIIA-158 F/F V/V WM patient FcγRIIIA-158 V/V F/F WM patient FcγRIIIA-158 F/F Yang G, et al. J Clin Oncol. 2010;28(15S): Abstract 8112.

47. GA101 Demonstrates Greater Direct Killing vs Rituximab in BCWM.1 WM Cells Untreated 17.1% 23.6% Rituximab 20.2% 31.4% GA101 77.6% 45.6%

48. To Maintain or Not to Maintain?

49. PFS in rituximab naïve WM patients who were observed or given maintenance rituximab therapy. 100 75 With Maintenance Alive or without progfression (%) 50 No Maintenance 25 Untreated, Observation Untreated, Maintenance Prev Treated, Observation Prev Treated, Maintenance 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Time from treatment initiation (months) N=248 Treon S, et al. Br J Haematol. 2011 May 25 [Epub ahead of print].

50. Infectious Events in WM Patients Who Underwent Observation or Maintenance Rituximab Therapy P = .0064 P = .718 Treon S, et al. Br J Haematol. 2011 May 25 [Epub ahead of print].