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First-Line Treatment for MM Patients

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. Disclosures.

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First-Line Treatment for MM Patients

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  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

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

  4. Gompertzian Growth 1012 Precursor Disorders MGUS Smoldering Renal Failure Myelosuppression Bone disease Hypercalcemia 109 Mol CR, IF CR: MRD 105 Surviving clone Surviving clone

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

  6. Smoldering Myeloma

  7. Smoldering Myeloma 100 p < 0.001 Gr 1:TTP 1.9 y 80 Gr 2: TTP: 5 y 60 Gr 3: TTP 10 y Probability of Progression (%) 40 No. of risk factors No. Rel risk 1 81 1 2 114 1.9 (1.2–2.9) 3 78 4.0 (2.6–6.1) 20 0 0 5 10 15 Years • PCsBM Infiltration ≥ 10% • Serum M protein ≥ 3 g/dL • Serum FLC ratio < 1/8 or > 8 Kyle RA, et al. N Engl J Med. 2007; 356:2582-90 Dispenzieri A, et al. Blood. 2008;111:785-9.

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

  9. QuiRedex Objectives • Primaryobjective • Time toprogressiontosymptomatic MM • Secondaryobjectives • Response rates • Duration of response • Safety and tolerability • Progression-free survival, overallsurvival External CRO: monitorization of data Independent Data MonitoringCommittee: Inclusioncriteria & primaryendpoint

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

  11. 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 Proportion of patients alive 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

  12. Len-dex vs. No Treatment: OS FromInclusion (n = 119) Median follow-up: 32 months (range 12–49) Lenalidomide + Dex 1.0 No treatment 0.8 0.6 Proportion of patients alive p=0.04 0.4 Lenalidomide + Dex: 93% at 3 years No treatment: 76% at 3 years 0.2 0.0 0 5 10 15 20 25 30 35 40 45 50 Time from inclusion

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

  14. Myeloma Treatment Younger Induction Transplant Consolidation Maintenance Older Induction Consolidation Maintenance

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

  16. 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 CR in Transplant Setting van de Velde et al. Haematologica 2007

  17. Impact of CR + VGPR on Outcome IFM90 IFM99 Double ASCT 100 1.00 p= .0007 0.75 p = 7 x 10-5 75 Survival Distribution Function (%) 0.50 ≥ 90% (n = 51) PR: 290 0.25 CR + VGPR: 440 50 0.00 ≥ 50% (n = 81) 0 250 500 750 1,000 1,250 1,500 1,750 2,000 2,250 25 EFS < 50% (n = 46) 1.00 p = 7 x 10-5 0.75 0 0 22 44 66 88 Survival Distribution Function (%) 0.50 PR: 290 0.25 CR + VGPR: 440 0.00 0 250 500 750 1,000 1,250 1,500 1,750 2,000 2,250 OS EFS = event-free survival. Moreau et al, 2008; Attal et al. 1996, 2006.

  18. Hematologic CR Correlates With Long-Term PFS and OS in Elderly Patients Treated With Novel Agents • 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 OS PFS CR CR VGPR Probability Probability VGPR PR PR P<0.001 P<0.001 Gay et al. Blood 2011; 117(11):3025-31

  19. The Better the Quality of the Response the Longer the Survival (Immunophenotypic CR): GEM2005>65y PFS Immunophenotypic CR 90% at 3y “Stringent CR”38% at 3y Conventional CR57% at 3y PR (≥70% reduction)28% at 3y 100 80 60 40 20 P =0.001 0 0 10 20 30 40 50 60 Paiva et al; J Clin Oncol. 2011;29(12):1627-33. Months

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

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

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

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

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

  25. BiRD (Clarithromycin/lenalidomide/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. 2008; 111: 1101-1109Prepublished 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, FaizaZafar, 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, MadhuMazumdar, Selina Chen-Kiang and Morton Coleman

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

  27. Sustained Responses to BiRD Over Time

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

  29. Progression-Free Survival is not Affected by Transplant After Lenalidomide No Transplant Transplant 1.00 0.75 Proportion of Patients 0.50 P=0.61 by log-rank test 0.25 0.00 100 200 300 0 Time (weeks) 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%) 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%) Rossi et al. Blood 2013 Jan 8 Epub

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

  31. 73 74 61 76 • Niesvizky et al Blood. 111, 1101-1109; 2008. • Richardson et al. ASH 2008, Abstract 92 3. Reeder et al.Leukemia2009, 23:1337-41 4. Bensinger et al. ASH 2008, Abstract 94

  32. 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%

  33. 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

  34. 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 MyelomaCenter. org NCI K23 Award: CA109260-01

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