1. First-Line Treatment for MM Patients Ruben Niesvizky Department of Medicine, Division of Hematology/Oncology, Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA Myelomacenter.org run9001@med.cornell.edu

2. Disclosures Speaker’s bureau: Celgene, Millennium, Onyx

6. Egan et al. Blood vol. 120 no. 5

7. Gompertzian Growth Renal Failure Myelosuppression Bone disease Hypercalcemia Mol CR, IF CR: MRD 10 5 10 9 10 12 Surviving clone Precursor Disorders MGUS Smoldering

8. Criteria for Diagnosis of Myeloma MGUS <3 g M-spike <10% PC AND Smoldering MM  3 g M-spike OR  10% PC Active MM Increased PC Any M-spike + AND AND Kyle RA, et al. N Engl J Med. 2002;346:564-569. C - High calcium R - Renal dysfunction A - Anemia B - Bone lesions NO (also hyperviscosity, amyloidosis, recurrent infections) YES

9. Smoldering Myeloma

10. Kyle RA, et al. N Engl J Med. 2007; 356:2582-90 Dispenzieri A, et al. Blood. 2008;111:785-9. Gr 1:TTP 1.9 y Gr 2: TTP: 5 y Gr 3: TTP 10 y p < 0.001 100 80 60 40 20 0 051015 Probability of Progression (%) Years No. of risk factorsNo.Rel risk 1811 21141.9 (1.2–2.9) 3784.0 (2.6–6.1) PCsBM Infiltration ≥ 10% Serum M protein ≥ 3 g/dL Serum FLC ratio 8 Smoldering Myeloma

11. ORIGINAL ARTICLE Lenalidomide plus Dexamethasone for High-Risk Smoldering Multiple Myeloma María-Victoria Mateos et al. N Engl J Med. 2013; 369:438-447.

12. Primary objective  Time to progression to symptomatic MM Secondary objectives  Response rates  Duration of response  Safety and tolerability  Progression-free survival, overall survival Objectives QuiRedex External CRO: monitorization of data Independent Data Monitoring Committee: Inclusion criteria & primary endpoint

13. Lenalidomide 25 mg/daily during 21d every 28 d Dexamethasone 20 mg D1-D4 and D12-D15 every 28 d Therapeutic abstention Induction Nine 4-week cycles Maintenance Lenalidomide 10 mg/daily during 21 d every month* Therapeutic abstention Schedule of Therapy (n:126 pts) Treatment arm (n = 60) Control arm (n = 66) * Low-dose Dex will be added at the moment of biological progression Ammendment on August 2011: Stop treatment at 2 years of treatment

14. Len-dex vs. No Treatment: TTP to Active Disease (n = 119) ITT analysis Median follow-up: 32 months (range 12–49) Lenalidomide + dex Median TTP: NR 9 Progressions (15%) 5 pts:early disc followed by DP 4 pts:symptomatic DP No treatment Median TTP: 23m 37 Progressions (59%) 20 patients: bone disease 7 patients: renal failure HR: 6.0; 95% IC (2.9–12.6); p < 0.0001 Time from inclusion Proportion of patients alive

15. Len-dex vs. No Treatment: OS From Inclusion (n = 119) Median follow-up: 32 months (range 12–49)

16. Carfilzomib, Lenalidomide, and Dexamethasone for Smoldering Multiple Myeloma Biomarker Study of Elotuzumab in High Risk Smoldering Myeloma

17. Myeloma Treatment Consolidation InductionTransplant Maintenance Induction Maintenance Younger Older Consolidation

18. Quality of Response: Survival Niesvizky et al. Br J Haematol. 2008 Oct;143(1):46-53

19. CR in Transplant Setting van de Velde et al. Haematologica 2007 Outcomes of 4990 HDT/SCT patients (21 studies) according to best response were reported Majority of these studies show correlation between maximal response (CR/nCR/VGPR) and long-term outcomes (OS & EFS/PFS) Two meta-analyses: both show highly significant associations – One based on p-values reported – One based on primary response and outcome data

20. EFS p =.0007 p = 7 x 10-5 IFM99 Double ASCTIFM90 CR + VGPR: 440 022446688 0 25 50 75 100 ≥ 90% (n = 51) ≥ 50% (n = 81) < 50% (n = 46) 02501,5007501,0001,2505001,7502,0002,250 0.00 Survival Distribution Function (%) 1.00 0.75 0.50 0.25 PR: 290 OS CR + VGPR: 440 0 2501,5007501,0001,2505001,7502,0002,250 0.00 Survival Distribution Function (%) 1.00 0.75 0.50 0.25 PR: 290 Impact of CR + VGPR on Outcome EFS = event-free survival. Moreau et al, 2008; Attal et al. 1996, 2006. p = 7 x 10-5

21. Hematologic CR Correlates With Long-Term PFS and OS in Elderly Patients Treated With Novel Agents Gay et al. Blood 2011; 117(11):3025-31 PFS OS P<0.001 CR VGPR PR CR VGPR PR Probability Retrospective analysis: 3 randomized European trials of GIMEMA and HOVON groups (N=1175) First-line treatment MP (n=332), MPT (n=332), VMP (n=257), VMPT-VT (n=254) Significant benefit also seen when analysis is restricted to patients >75 years old

22. 6050403020100 100 80 60 40 20 0 Months P =0.001 PFS Immunophenotypic CR 90% at 3y “Stringent CR”38% at 3y Conventional CR57% at 3y PR (≥70% reduction) 28% at 3y Paiva et al; J Clin Oncol. 2011;29(12):1627-33. The Better the Quality of the Response the Longer the Survival (Immunophenotypic CR): GEM2005>65y

23. Martinez-Lopez et al. Blood. 2011;118(3):529-534 Abstract

24. Martinez-Lopez et al. Blood. 2011;118(3):529-534 Abstract

25. Martinez-Lopez et al. Blood. 2011;118(3):529-534 CR vs. nCR/VGPR/PR vs. Less

26. Advancing Outcomes With Total Therapy Barlogie Leukemia, 22:1633 –1636; 2008 Years from date of first complete response

27. Stewart et al, 2009. Combinations in the Upfront Treatment of MM

28. BiRD (Clarithromycin/lenalidomide/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. 2008; 111: 1101-1109 Prepublished online Nov 7, 2007; doi:10.1182/blood-2007-05-090258 Ruben Niesvizky, David S. Jayabalan, Paul J. Christos, Jessica R. Furst, Tara Naib, Scott Ely, Jessica Jalbrzikowski, Roger N. Pearse, Faiza Zafar, Karen Pekle, April LaRow, Richard Lent, Tomer Mark, Hearn J. Cho, Tsiporah Shore, Jeffrey Tepler, John Harpel, Michael W. Schuster, Susan Mathew, John P. Leonard, Madhu Mazumdar, Selina Chen-Kiang and Morton Coleman

29. Maximum Response to BiRD (n = 72, 69 evaluable) Median time on treatment: 368 days (29-944) Niesvizky et al. Blood. 2008;111:1101-1109.

30. Sustained Responses to BiRD Over Time

31. UPDATE BiRD BiRD, clarithromycin, lenalidomide, dexamethasone; CI, confidence interval; EFS, event-free survival; SPM, second primary malignancy; NR, not reached; PFS, progression-free survival. PFS for Patients Receiving BiRD Proportion of Patients Time (Weeks) Median PFS: 70.8 months (range, 47.6-NR) 5-year PFS rate: 54.5% (95% CI: 40.5%-66.4%) 4-year OS rate: 82.2% (95% CI: 70.7%-89.5%) Median 5-year OS has not been reached OS for Patients Receiving BiRD Time (Weeks) Rossi et al. Blood 2013 Jan 8 Epub

32. No Transplant: N=36 patients, 15 progressions Median PFS = 307.9 weeks (95% CI 207 - NR) 5-year PFS = 60.7% (95% CI = 41.5% - 75.2%) Progression-Free Survival is not Affected by Transplant After Lenalidomide No TransplantTransplant 1.00 P=0.61 by log-rank test 0.75 0.50 0.25 0.00 0 100200300 Time (weeks) Transplant: N=32 patients, 15 progressions Median PFS = 259.4 weeks (95% CI 146.9 - NR) 5-year PFS = 48.0% (95% CI = 27.5% - 65.8%) Proportion of Patients Rossi et al. Blood 2013 Jan 8 Epub

33. PCR Analysis pre post Pt. #15Pt. #40Pt. #43Pt. #59 No new clones were identified and the primary clone was undetectable in 5/7 tested pairs

34. CyBORD 3 N=35 BCD + BDT 4 N=65 BiRD 1 N=72 VRD 2 N=65 CR 392838.926 nCR NA1813.918 VGPR 223020.830 PR 27NA16.725 MR 1NA5.6NA Refractory 1NA00 Overall 8810090.3100 1.Niesvizky et al Blood. 111, 1101-1109; 2008. 2.Richardson et al. ASH 2008, Abstract 92 6176 73 74 3. Reeder et al. Leukemia 2009, 23:1337-41 4. Bensinger et al. ASH 2008, Abstract 94

35. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma Jakubowiak, et al. Blood, 2013 CR 42% >VGPR 62%

36. Summary / Conclusions Novel agents can increase CR/VGPR CR should be the goal, but….. Improvement in induction reached top numbers….what’s next –Consolidation post transplant –Transplant as salvage, improve on conditioning regimens SC collection ?MRD Car Dex 20-27-45-52 BiRd ? Other IMiDs

37. Morton Coleman Faiza Zafar Roger N Pearse Tomer Mark Adriana C Rossi Karen Pekle Arthur Perry Tsiporah Shore Koen Van Besien Linda Tangenstam Kathleen Pogonowski Selina Chen-Kiang Monica Guzman Scott Ely Yashpal Agrawal David S. Jayabalan Stanley Goldsmith Maureen Lane Paul Christos Susan Mathew NCI K23 Award: CA109260-01 MyelomaCenter. org