Advances in the Management of Relapsed/Refractory Multiple Myeloma

1. Advances in the Management of Relapsed/Refractory Multiple Myeloma Robert Z. Orlowski, Ph.D., M.D. Director, Myeloma Section Florence Maude Thomas Cancer Research Professor Departments of Lymphoma/Myeloma & Experimental Therapeutics Principal Investigator, MD Anderson SPORE in Multiple Myeloma Chair, Southwest Oncology Group Myeloma Committee

2. 2013 ASH Abstract 406Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma: Follow-up Analysis of the IFM 2005-02 Trial Michel Attal, ValérieLauwers-Cances, GéraldMarit, Denis Caillot, Thierry Facon, CyrilleHulin, Philippe Moreau, Claire Mathiot, Murielle Roussel, Catherine Payen, Pascale Olivier, and HervéAvet-Loiseau

3. Study Design

4. Analysis After Relapse PFS from Relapse • Primary analysis: len had better PFS, same OS • Current data suggest len may cause myeloma chemoresistance • BUT … Median2nd PFS Placebo 24 Months Lenalidomide 13 Months OS from Relapse Mediansurvival Placebo 48 Months Lenalidomide 29 Months

5. Choice of Second Line Therapy Matters 2nd line bortezomib-based 2nd line IMiD-based P<0.003 P=0.28 Placebo Placebo LEN LEN

6. Outline • Current standards of care and novel regimens that take advantage of them • Emerging agents showing activity in the relapsed and relapsed/refractory setting

7. Types of Relapse Alegre, A et al. Haematologica. 87:609, 2002.

8. Outcomes After Relapse From SCT Zamarin, D et al. Bone Marrow Transplant. 48:419, 2013.

9. APEX : Bortezomib vs. Dex 78% improvement in median time-to-progression 1.0 Median TTP All Pts Post-1st relapse 0.9 6.2 mos 7.0 mos Bortezomib 0.8 3.5 mos 5.6 mos Dexamethasone 0.7 0.6 Proportion of patients 0.5 0.4 P = .0001 0.3 Bortezomib 0.2 Dexamethasone 0.1 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 Time (days) Richardson, PG et al. N. Engl. J. Med. 352:2487, 2005.

10. SC vs. IV Bortezomib ± Dex Moreau, P et al. Lancet Oncol. 12:431, 2011.

11. TTP of SC vs. IV Vd 100 90 80 70 60 50 40 30 20 10 0 ORR identical after 4 cycles Patients without PD (%) IV : 9.4 months SC: 10.4 months (0.839 HR; P-value 0.38657) 0 50 100 150 200 250 300 350 400 450 500 550 600 Days from randomization No. patients at riskIVSC 74 60 56 50 36 24 16 10 7 5 4 3 1 148 126 109 93 72 51 32 18 13 8 5 2 1 Moreau, P et al. Lancet Oncol. 12:431, 2011.

12. 100 PLD + Bortezomib 9.3 months 80 60 Bortezomib 6.5 months Percent of Patients Progression-Free 40 Statistical analysis: HR (95% CI) 1.82 (1.41-2.35) p = 0.000004 20 0 0 100 200 300 400 500 Bortezomib/PLD vs. Bortezomib Orlowski, RZ et al. J. Clin. Oncol. 25:3892, 2007.

13. Len/Dex vs. Dex Weber, DM et al. N. Engl. J. Med. 357:2133, 2007.

14. Carfilzomib : Approved in July, 2012 • Results from PX-171-003-A1 study of carfilzomib in patients with relapsed and refractory myeloma • But, approved for patients who have had at least 2 prior lines of therapy Siegel, DS et al. Blood 120:2817, 2012.

15. Long-term Outcomes Siegel, DS et al. Blood 120:2817, 2012.

16. Toxicities • Most notable for the lower risk of peripheral neuropathy overall, and especially for the low rates of grade 3 or 4 events in this category Siegel, DS et al. Blood 120:2817, 2012.

17. Len/Carfilzomib/Dex Wang, M et al. Blood 122:3122, 2013.

18. Pomalidomide : Approved in February, 2013 • Approval based on the results of the MM-002 study • For patients with at least two prior lines of therapy

19. PomalidomideEfficacy Data Richardson, P et al. Blood preprint online, 2014.

20. Durability Data Richardson, P et al. Blood preprint online, 2014.

21. 2013 ASH Abstract 690Phase I/II Dose Expansion of a Multi-Center Trial of Carfilzomib and Pomalidomidewith Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple MyelomaJatin J. Shah, Edward A. Stadtmauer, RafatAbonour, Adam D. Cohen, William Bensinger, Cristina Gasparetto, Jonathan L. Kaufman, Suzanne Lentzsch, Dan T. Vogl, Robert Z. Orlowski, Erica L. Kim, Natalia Bialas, David D. Smith, and Brian GM Durie

22. Car/Pom/Dex • Cycle 1-6: 28 day cycle Carfilzomib Pomalidomide Dexamethasone

23. Response Data ORR = 70% CBR = 83%

24. Long Term Outcomes

25. 2013 ASH Abstract 689Pomalidomide +Low-dose Dexamethasone in Relapsed or Refractory Multiple Myeloma with Deletion 17p and/or Translocation t(4;14) Xavier Leleu, Lionel Karlin, Margaret Macro, CyrilleHulin, Laurent Garderet, Murielle Roussel, Bertrand Arnulf, Brigitte Pegourie, Brigitte Kolb, Anne-Marie Stoppa, Sabine Brechiniac, MauricetteMichallet, Gerald Marit, Claire Mathiot, Anne Banos, Laurence Lacotte, MouradTiab, Mamoun Dib, Jean-Gabriel Fuzibet, Marie-OdilePetillon, Philippe Rodon, Marc Wetterwald, Bruno Royer, Laurence Legros, LotfiBenboubker, Olivier Decaux, Denis Caillot, Martine Escoffre-Barbe, Jean Paul Fermand, Philippe Moreau, Michel Attal, HervéAvet-Loiseau, and Thierry Facon

26. del17p All t(4;14) Pomalidomide and Deletion 17p • Response rate with pom/dex comparable in patients ± del 17p • Pom may overcome this poor risk lesion Time to Progression del17p All t(4;14)

27. Pomalidomide/Bortezomib/Dex 3 + 3 Design (21-day cycles) Evaluation Every 21 Days (± 3 Days) Follow-Up for OS and SPM Until 5 Years Post-enrollment *For cycles 1-8, then D1, 8 for cycles 9+; †For cycles 1-8, then D1-2, 8-9 for cycles 9+; ‡10 mg for pts aged > 75 yrs Richardson, PG et al. ASH Abstract 727, 2012.

28. Response Summary • ORR (≥ PR): 73%; VGPR: 27%; SD: 27% • Median time to response: 1 cycle (range 1-2) • Most responses are ongoing Richardson, PG et al. ASH Abstract 727, 2012.

29. Len/Thal/Dex Clinical Benefit Ratio (≥ MR) of 64% Shah, JJ et al. ASH Abstract 75, 2012.

30. Outcomes in Len Refractory Disease Lenalidomide Refractory: Clinical Benefit Ratio (≥ MR) of 51% Lenalidomide Naïve: Overall Response (≥ PR) of 14/16 (88%) Shah, JJ et al. ASH Abstract 75, 2012.

31. Outline • Current standards of care and novel regimens that take advantage of them • Emerging agents showing activity in the relapsed and relapsed/refractory setting

32. Novel Agents : Elotuzumab + Len/Dex Richardson, PG et al. 2010 ASH Abstract 986.

33. Other Antibodies : Daratumumab Part 1 Open label, weekly i.v. infusion, 8 weeks Dose-escalation: 3+3 scheme* 0.005→0.05→0.1→0.5→1.0 →2.0→4.0→8.0→16.0 →24.0 mg/kg Dose-escalation cohorts Part 2 Open label, single arm, i.v. infusion weekly: 8 weeks every other week: 16 weeks every fourth week: up to 96 weeks 8 mg/kg, 16 patients Expansion cohort Plesner, T et al. ASH Abstract 73, 2012.

34. Paraprotein Responses < 1 mg/kg 2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg 24 mg/kg A A A B A B A C A B C A A A A A A A C A C A C C A A B A C A A A Plesner, T et al. ASH Abstract 73, 2012.

35. 2013 ASH Abstract 1986Preliminary Safety and Efficacy Data of Daratumumabin Combination with Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple MyelomaTorbenPlesner, Tobias Arkenau, HenkLokhorst, Peter Gimsing, JakubKrejcik, Charlotte Lemech, Monique C. Minnema, UlrikLassen, Andrew Cakana, Nikolai ConstantinBrun, Linda Basse, Antonio Palumbo, and Paul G. Richardson

36. Response Data

37. Adverse Events

38. 2013 ASH Abstract 284SAR650984, a CD38 Monoclonal Antibody in Patients with Selected CD38+ Hematological Malignancies- Data from a Dose-Escalation Phase I StudyThomas G Martin III, Stephen A. Strickland, Martha Glenn, Wei Zheng, Nikki Daskalakis, and Joseph R. Mikhael

39. Response Data CR PR • Binds different epitope than daratumumab MR Median prior therapies = 6 Patients treated > 10 mg/kg Q2W >PR 30.8% SD 1 mg/kg Q2W 3 mg/kg Q2W 5 mg/kg Q2W PD 10 mg/kg Q2W 10 mg/kg QW 20 mg/kg Q2W NA 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 Week

40. 2013 ASH Abstract 283Novel AKT Inhibitor Afuresertibin Combination with Bortezomib and Dexamethasone Demonstrates Favorable Safety Profile and Significant Clinical Activity in Patients with Relapsed/Refractory Multiple Myeloma Peter M Voorhees, Andrew Spencer, Heather J. Sutherland, Michael E O'Dwyer, Shang-Yi Huang, Keith Stewart, AjaiChari, Michael Rosenzwieg, Ajay K. Nooka, Cara A Rosenbaum, Craig C Hofmeister, Deborah A Smith, Joyce M Antal, Ademi Santiago-Walker, Jennifer Gauvin, Joanna B Opalinskaand Suzanne Trudel

41. Analysis After Relapse

42. Activity by Prior Bortezomib Exposure • Akt inhibition may be attractive in myeloma!

43. 2013 ASH Abstract 285Prolonged Survival and Improved Response Rates with ARRY-520 in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with Low α-1 Acid Glycoprotein (AAG) Levels: Results From a Phase 2 Study SagarLonial, JatinJ. Shah, Jeffrey Zonder, William I. Bensinger, Adam D. Cohen, Jonathan L. Kaufman, Ajay K. Nooka, Donna M. Weber, Brandi Hilder, Selena A Rush, Ann Ptaszynski, Duncan Walker, and Robert Z. Orlowski

44. Mechanism of Action

45. Study Design

46. Response Data

47. AAG and Outcomes

48. 2013 ASH Abstract 123Identification of Tight Junction Protein (TJP)-1 as a Modulator and Biomarker of Proteasome Inhibitor Sensitivity in Multiple Myeloma Xing-Ding Zhang, VerrabhadranBaladandayuthapani, Heather Lin, George Mulligan, Bin Li, Dixie-Lee Esseltine, Lin Qi, Jian-Liang Xu, Walter Hunziker, Bart Barlogie, SaadUsmani, Qing Zhang, John Crowley, Bing-ZongLi, Hui-Han Wang, Jie-XinZhang, Isere Kuiatse, Jin-Le, Tang, HuaWang, Richard Eric Davis, Wen-CaiMa, Zhi-QiangWang, Lin Yang, and Robert Z. Orlowski

49. TJP1 Sensitizes to Bortezomib • High TJP1 = Good response to bortezomib

50. CRBN and IMiDs Thalidomide LEN DDB1 Teratogenicity CRBN Cul4A ? Multiple Myeloma Roc1 Lenalidomide E3 Ubiquitin Ligase Zhu et al, Blood 2011 Lopez-Girona et al, Leukemia 2012 Ito et al, Science 2010 Pomalidomide ? Proteasomal Degradation Courtesy of Monica Schenone