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Update on transplant-ineligible patients: Which regimens are best?

Update on transplant-ineligible patients: Which regimens are best?. Suzanne Lentzsch MD, PhD Columbia University, New York. Research Support/P.I. Celgene. Employee. No relevant conflicts of interest to declare. Consultant. Major Stockholder. No relevant conflicts of interest to declare.

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Update on transplant-ineligible patients: Which regimens are best?

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  1. Update on transplant-ineligible patients: Which regimens are best? Suzanne Lentzsch MD, PhD Columbia University, New York

  2. Research Support/P.I. Celgene Employee No relevant conflicts of interest to declare Consultant Major Stockholder No relevant conflicts of interest to declare No relevant conflicts of interest to declare Speakers Bureau Honoraria Scientific Advisory Board Disclosures for Suzanne Lentzsch, MD, PhD No relevant conflicts of interest to declare No relevant conflicts of interest to declare Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx

  3. Treatment Decision in Older Patients Patients • ADL • IADL • Comorbidities • Hospitalization • Medications • Social Support • Multiple Myeloma • Cytogenetics • Stage • Tumor burden • Optimal Chemo • Supportive meds • Goals of Care (CR vs Disease Control?) • Expectations • Understanding • Life Expectancy

  4. Treatment Decision in Transplant Ineligible Patients • Frailty ??? • Melphalan based regimens ??? • Doublets ??? • Triplets ??? • Maintenance ???

  5. Frailty score Slide courtesy of Palumbo, ASH 2013

  6. OverallSurvival Multivariate Analysis Fit vs. Unfit vs. Frail Patients (%) Lower risk Death FIT ISS1-2 FISH neg Higherrisk Death FRAIL ISS 3 FISH pos Unfit vsFit, HR=1.61 p=0.042 Frail vsFit, HR=3.57 p<0.001 Fit defined as: score=0 Unfit defined as: score=1 Frail defined as: score>2 Slide courtesy of Palumbo, ASH 2013

  7. Slide courtesy of Palumbo, ASH 2013

  8. Treatment algorithm for elderly MM Slide courtesy of Palumbo, ASH 2013

  9. Unanswered Question for Transplant Ineligible Patients • Frailty-Adjust Treatment Intensity • Melphalan ??? • Doublets ??? • Triplets ??? • Maintenance ???

  10. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials Progression-free survival Overall survival Study HR (95% CI) HR (95% CI) Study HR (95% CI) HR (95% CI) MPT better MP better MPT better MP better FR < 75 0.50 (0.39– 0.65) FR < 75 0.61 (0.45– 0.81) Fr≥ 75 0.68 (0.48– 0.96) Turkey 0.59 (0.35–0.99) HOVON 0.75 (0.57–1.00) Fr ≥ 75 0.61 (0.46–0.82) Italy 0.62 (0.48–0.80) Turkey 0.87 (0.46–1.67) HOVON 0.79 (0.62–1.00) Italy 1.04 (0.75–1.44) NMSG 1.12 (0.85–1.47) NMSG 0.89 (0.70–1.13) Overall (I-squared = 60.6%, p = 0.026) 0.82 (0.66–1.02) Overall (I-squared = 61.7%, p = 0.023) 0.67 (0.55– 0.80) 0.5 0.75 1 1.5 0.5 0.75 1 1.5 NOTE: weights are from random effects analysis NOTE: weights are from random effects analysis Fayers P M et al. Blood 2011;118:1239-1247

  11. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials Fayers P M et al. Blood 2011;118:1239-1247

  12. Overall survival in patients randomized to bortezomib-melphalan-prednisone (VMP) or melphalan-prednisone (MP) after a median follow-up of 5 years San Miguel J F et al. JCO 2013;31:448-455

  13. Initial Therapy in Older Adults With MM: Randomized Trials of MP With or Without the Addition of Novel Agents • Abbreviations: MM, multiple myeloma; MP, melphalan and prednisone; MPR, melphalan, prednisone, and lenalidomide; MPR-R, melphalan, prednisone, and lenalidomide with lenalidomide maintenance; MPT, melphalan, prednisone, and thalidomide; MPV, melphalan, prednisone, and bortezomib; NR, not reported; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide and low-dose dexamethasone; RD, lenalidomide and high-dose dexamethasone. • ↵* Discontinuation rate because of toxicity, specifically during induction where applicable. Global (ie, “any” or “nonhematologic”) toxicity incidence not reported. • ↵† Statistically significant for MPR-R v MP and MPR-R v MPR only. Wildes T M et al. JCO 2014;32:2531-2540

  14. Unanswered Question for Transplant Ineligible Patients • Frailty – Adjust Treatment Intensity • Melphalan or Novel Drugs ??? • Doublets or Triplets ??? • Maintenance ???

  15. Efficacy and Safety of Three Bortezomib-Based Induction and Maintenance Regimens in Previously Untreated, Transplant-Ineligible Multiple Myeloma Patients: Final Results from the Randomized, Phase 3b, US Community-Based UPFRONT Study Slide Courtesy Niesvizky, R; ASH 2013

  16. RESULTSPatients 502 patients were randomized to • VD (n=168), • VTD (n=167), • VMP (n=167) Baseline characteristics were well balanced across the treatment arms • Median age was 73 years (range 38–91) • 48% of patients had comorbidities at baseline • The most common were diabetes mellitus (21%), renal disease (15%), and chronic pulmonary disease (8%) Slide Courtesy Niesvizky, R; ASH 2013

  17. Response* Best confirmed response after 8 (induction) and 13 (induction + maintenance) cycles ORRs after 13 cycles were 73% (VD), 80% (VTD), and 70% (VMP) including: • 30%, 40%, and 32% CR/nCR, respectively • 37%, 51%, and 41% ≥VGPR, respectively *Response-evaluable population (n=425 patients who received at least one dose of study drug, had measurable disease at baseline, and had at least one post-baseline M-protein measurement) Slide Courtesy Niesvizky, R; ASH 2013

  18. PFS (intent-to-treat population) After a median follow-up of 42.7 months, 265 (53%) patients had progressed and/or died Median PFS (95% CI) was 14.7 months (12.0, 18.6), 15.4 months (12.6, 24.2), and 17.3 months (14.8, 20.3), for VD, VTD, and VMP, respectively, with no global difference among arms (p=0.458) Slide Courtesy Niesvizky, R; ASH 2013

  19. OS (intent-to-treat population) Median OS (95% CI) was 49.8 months (35.7, not estimable [NE]), 51.5 months (38.5, NE), and 53.1 months (41.1, NE) for VD, VTD, and VMP, respectively, with no global difference among arms (p=0.789) Slide Courtesy Niesvizky, R; ASH 2013

  20. UPFRONT TRIAL CONCLUSIONS After ~3.5 years’ follow-up, no significant differences in PFS or OS were seen among arms VTD had the highest toxicity rates and the lowest mean bortezomib dose intensity among the arms VD doublet therapy may be as effective as VTD or VMP triplet therapy in elderly pat (due less toxicity with higher bortezomib intensity?) In accordance with: • Recent analysis of VMP data from VISTA suggests that a higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, is associated with superior OS (Mateos MV, et al. ASH 2013, abstract #2155) Slide Courtesy Niesvizky, R; ASH 2013

  21. Unanswered Question for Transplant Ineligible Patients • Frailty – Adjust Treatment Intensity • Melphalan or Novel Drugs! • Doublets! or Triplets • Maintenance ???

  22. FIRST Trial: Study Design Active Treatment + PFS Follow-up Phase Screening LT Follow-Up PD or Unacceptable Toxicity RANDOMIZATION 1:1:1 PD, OS and Subsequent anti-MM Tx LEN + Lo-DEX Continuously LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 Arm A Continuous Rd LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 Arm B Rd18 MEL + PRED + THAL 12 Cycles1 (72 wks) MELPHALAN 0.25mg/kg D1-4/42 PREDNISONE 2mg/kg D1-4/42 THALIDOMIDE 200mg D1-42/42 Arm C MPT Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL2 0.2 mg/kg D1–4 • Stratification: age, country and ISS stage ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival 1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70. Facon T, et al. Blood. 2013;122:abstract 2. Benboubker L et al. N Engl J Med 2014;371:906-917.

  23. 100 80 60 40 20 0 FIRST Trial: Final Progression-free Survival 28% reduced risk of disease progression Hazard ratio Rd vs. MPT: 0.72; P = 0.00006 Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349 Patients (%) 72 wks 6 12 18 24 30 36 42 48 54 60 0 Time (months) mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone. Benboubker L et al. N Engl J Med 2014;371:906-917.

  24. FIRST Trial: Overall Survival Interim Analysis 100 80 60 40 20 0 6 12 18 24 30 36 42 48 54 60 0 Rd Rd18 MPT 535 541 547 488 505 484 457 465 448 433 425 418 403 393 375 338 324 312 224 209 205 121 124 106 43 44 30 5 6 3 0 0 0 Patients (%) Hazard ratio Rd vs. MPT: 0.78; P = 0.02 Rd vs. Rd18: 0.90; P = 0.31 Rd18 vs. MPT: 0.88; P = 0.18 574 deaths (35% of ITT) Overall survival (months) Benboubker L et al. N Engl J Med 2014;371:906-917.

  25. FIRST Trial: Response Endpoints aIMWG Criteria; CR, complete response; mos, months ORR, overall response rate; PR, partial response; SD, stable disease; VGPR, very good PR. bResponse assessment for Rd obtained every 4 wks and for MPT every 6 wks; Response and progression rate based on IRAC assessment. Benboubker L et al. N Engl J Med 2014;371:906-917.

  26. FIRST Trial: Conclusions Continuous Rd significantly extended PFSand OS vs. MPT PFS: HR= 0.72 (P= 0.00006) Consistent benefit across most subgroups Rd better than Rd18 (HR= 0.70, P= 0.00001) 3 yr PFS: 42% Rd vs 23% Rd18 and MPT Planned interim OS: HR= 0.78 (P= 0.0168) Rd was superior to MPT across all other efficacy secondary endpoints Safety profile with continuous Rd was manageable Hematological and non-hematological AEs were as expected for Rd and MPT Incidence of hematological SPM was lower with continuous Rd vs. MPT In NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of care Benboubker L et al. N Engl J Med 2014;371:906-917.

  27. Unanswered Question for Transplant Ineligible Patients • Frailty – Adjust Treatment Intensity • Melphalan or Novel Drugs !! • Doublets or Triplets !! • Maintenance !!

  28. Bortezomib-Melphalan-Prednisone Followed by Maintenance With Bortezomib-Thalidomide (VMP-VT) Compared With Bortezomib-Melphalan-Prednisone (VMP) for Initial Treatment of Multiple Myeloma N=511 Palumbo A et al. JCO 2014;32:634-640

  29. Survival outcomes in the intention-to-treat population, according to study group. TNT PFS OS after Relapse OS Palumbo A et al. JCO 2014;32:634-640

  30. VT-Maintenance for Non-Transplant Patients • VMP vs. VMPT-VT: • 3-year PFS: 41% vs 56% • median PFS: 24.8 vs 35.3 months (P .001) • TNT 27.8 vs 46.6 months (P .001) • 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P .01). • VMPT-VT group, more grade 3 to 4 adverse events includingneutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). • Conclusion • Bortezomib and thalidomide maintenance significantly improved OS in multiple myeloma patients Palumbo A et al. JCO 2014;32:634-640

  31. UnAnswered Question for Transplant Ineligible Patients? • Frailty • Adjust Treatment Intensity • Determine the goals of care !! • Melphalan or Novel Drugs !! • Doublets or Triplets !! • Lesstoxic treatment allowslonger treatment • Maintenance !!

  32. Thank You !!

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