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Debate: What is the best induction therapy for transplant-eligible patients? Sequential therapy.

Debate: What is the best induction therapy for transplant-eligible patients? Sequential therapy. Tomer M. Mark Department of Medicine, Division of Hematology / Oncology Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA Lymphoma & Myeloma 2013. Disclosures.

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Debate: What is the best induction therapy for transplant-eligible patients? Sequential therapy.

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  1. Debate: What is the best induction therapy for transplant-eligible patients? Sequential therapy. Tomer M. Mark Department of Medicine, Division of Hematology / Oncology Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA Lymphoma & Myeloma 2013

  2. Disclosures Research Funding: CelgeneInc.; Onyx Inc. Speakers Bureau: Celgene Corp; Millenium Inc.; Onyx Inc. Membership on an entity's advisory committees: Celgene Corp., Millenium Inc. Off-label usage of bortezomib, lenalidomide, and carfilzomib are discussed.

  3. How do we best treat a chronic malignancy? • Cure versus control: improved survival is the goal • Regimen tolerability • Regimen cost • Do we burn bridges by using combination therapy? • Do patients benefit more from deeper response or longer duration of therapy?

  4. Not for debate: combination therapy gives deeper responses Stewart et al, 2009.

  5. What do we “know” ? • Therapy has become better • Survival now approaches a decade • Although growing, therapy options are limited • Myeloma is not curable • More chemo is more toxic than less chemo • Deeper response to therapy does not always translate into longer survival • We need to look at long-term follow up to see this.

  6. How do you maximize a limited arsenal? Lenalidomide Bortezomib Thalidomide Carfilzomib Corticosteroids Alkylators

  7. Goals of induction: quick reversal of symptoms & obtain disease control to lead to extended survival PFS Death Dx OS

  8. Possible Treatment Scenarios:a) combination therapy adds to OS; salvage is just as effective PFS Dx Death OS Dx Death

  9. Possible Treatment Scenarios:b) combination therapy prolongs PFS but not OS due to less efficacious salvage PFS Dx Death OS Death Dx

  10. Which scenario fits the MM model better? Ineffective treatment Dexamethasone Alkylators Tumor Volume → High-Dose Therapy Limit ofdetection Goal of newertherapy options Time → Ultimate goal: Cure

  11. Natural History of MM: 100 Symptomatic Asymptomatic Active Myeloma Relapse 50 M Protein (g/l) Refractory Relapse MGUS* or SmolderingMyeloma Plateau Remission 20 Therapy Therapy Therapy *Monoclonal gammopathy of uncertain significance ~11,000 Annual deaths in U.S.2 ~20,000 New cases in U.S.2 ~60,000 Prevalence in the U.S.

  12. Response is not everything… • In TT-2, OS not increased in thal arm, but CR frequency was higher1 • SUS-CR at 3 yrs predicted increased OS • Achievement, then LOSS of CR predicted worse OS. • Loss of CR correlates with negative prognostic factors (high ISS, IgA) • Benefit of CR may be limited to high-GEP risk group.2 • Pts with MGUS or SMM may not benefit from getting to CR.3 Barlogie B. et al. Cancer. 2008.113;2:355-359 Haessler J. et al. Clin Cancer Res. 2007.13:7073-7079 Pineda-Roman M. et al. Br J Haematol. 2007.136:393-399.

  13. Update of IFM 2005/01: Bortezomib/Dexamethasone (VD) vs. VAD Induction in Newly Diagnosed MM • VAD: Vincristine 0.4 mg/m2 + doxorubicin 9 mg/m2 Days 1–4 continuous infusion; Dexamethasone 40 mg Days 1–4 (Cycles 1–4) and Days 9–12, 17–20 (Cycles 1–2) • VD: Bortezomib 1.3 mg/m2 Days 1, 4, 8, 11; Dexamethasone 40 mg Days 1–4(Cycles 1–4) and Days 9–12 (Cycles 1–2) • DCEP: Dexamethasone 40 mg Days 1–2; Cyclophosphamide 15 mg/m2, etoposide400 mg/m2, and cisplatin 10 mg/m2 Days 1–4 continuous infusion 4 cycles Melphalan 200 mg/m2 + ASCTa VAD 28-day/cycle DCEP Two 28-day cycles VAD 28-day/cycle Untreated MM patients ≤ 65 years N = 482 VD 21-day/cycle DCEP Two 28-day cycles VD 21-day/cycle aSecond ASCT or reduced-intensity conditioning allogeneic transplantation if < VGPR. DCEP = dexamethasone, cyclophosphamide, etoposide, cisplatin; IFM = Intergroupe Francophone du Myelome. HarousseauJL et al. J ClinOncol. 2010. 28;30:4621-4629.

  14. VD vs. VAD as Induction Therapy: Efficacy • Harousseau JL et al. J ClinOncol. 2010. 28;30:4621-4629.

  15. CRs and PFS does not translate into OS! • Median PFS: 29.7m VAD vs. 36m BD • Median OS: NR. At 32m: 81% VAD vs. 83% BD alive • Harousseau JL et al. J ClinOncol. 2010. 28;30:4621-4629.

  16. VTD vs. Thalidomide/Dexamethasone (TD) → Double ASCT in Newly Diagnosed MM VTD CONSOLIDATION N = 474 Bort: 1.3 mg/m2 Days 1, 4, 8, 11 Thal: 200 mg Days 1–63 Dex: 320 mg/cycle Bort: 1.3 mg/m2 Days 1, 8, 15, 22 Thal: 100 mg/day, Days 1–70 Dex: 320 mg/cycle RANDOM I ZE 3 x 21-day cycles PBSC collection cyclophosphamide Transplantation Mel200 x 2 2 x 35-day cycles ≤ 65 years TD Thal: 200 mg Days 1–63 Dex: 320 mg/cycle Thal: 100 mg/day, Days 1–70 Dex: 320 mg/cycle • Primary end point: CR/nCR after 3 cycles of induction CavoM. et al. Lancet. 2010. 476: 2075-2085

  17. VTD vs. TD Induction → ASCT: Efficacy CavoM. et al. Lancet. 2010. 476: 2075-2085

  18. Thal-Dex vs. MP in elderly NDMM • TD vs. MP in 268 pts ≥ 65 with NDMM • Thal 200 daily, dex 40mg days 1-4 & 15-18 (odd cycles only) of 28-day cycles. • Mel 0.25mg/kg and prednisolone 2mg/kg on days 1-4 of a 28-42 day cycle. Ludwig H et al. Blood 2009;113:3435-3442

  19. TD vs. MP Ludwig H et al. Blood 2009;113:3435-3442

  20. VTD vs. CVTD in NDMM Pts not eligible for ASCT or in CR post-induction received 4 more cycles, with Dex 20. VTD Bort: 1.3 mg/m2 Days 1, 4, 8, 11 Thal:100 mg Days 1–21 Dex:40 mg Days 1-4, 9-12 RANDOM I ZE 4x 21-day cycles PBSC collection Transplantation Mel200 x 1 or 2 CVTD Bort: 1.3 mg/m2 Days 1, 4, 8, 11 Thal: 100 mg Days 1–21 Dex: 40 mg Days 1-4, 9-12 CTX: 400mg/m2 IV on Days 1,8 Ludwig H et al. JCO 2013;31:247-255

  21. VTD vs. CVTD Ludwig H et al. JCO 2013;31:247-255

  22. Ld vs. CRD vs. CyBorD: retrospective comparison of 3 phase 2 studies Khan M. et al. Br J of Haematol. 2011. 156:326-333.

  23. No phase 3 studies for 2 vs. 3-drug lenalidomide combinations We are left to compare phase 2 + retrospective data

  24. Phase 2: 2 vs. 3 drug regimens 73 74 33.3 61 • Niesvizky et al. Blood. 2008. 111;3:1101-1109. • Richardson et al. Blood. 2010. 116;5:679-686. 3. Reeder et al.Leukemia. 2009. 23:1337-41 4. Gay et al. Am J Jematol. 2010. 85;9:669-669.

  25. Possible Treatment Scenarios:b) combination therapy prolongs PFS but not OS due to less efficacious salvage PFS Dx Death OS Death Dx

  26. Conclusions • There is no clear evidence that combination therapy improves OS compared to a sequential approach. • There IS clear evidence that combination therapy is more toxic.

  27. Thank you

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