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Disclosures for Palumbo Antonio, MD

Disclosures for Palumbo Antonio, MD. Research Support/P.I. No relevant conflicts of interest to declare. Employee. No relevant conflicts of interest to declare. Consultant. Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx. Major Stockholder.

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Disclosures for Palumbo Antonio, MD

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  1. Disclosures for Palumbo Antonio, MD Research Support/P.I. No relevant conflicts of interest to declare Employee No relevant conflicts of interest to declare Consultant Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx Major Stockholder No relevant conflicts of interest to declare No relevant conflicts of interest to declare Speakers Bureau Honoraria Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx No relevant conflicts of interest to declare Scientific Advisory Board Presentation includes discussion of the off-label use of a drug or drugs

  2. Improving Outcomes in Myeloma Should alkylators be used upfront in transplant-ineligible patients? Yes/May be Antonio Palumbo University of Torino, Italy, EU 25min

  3. Early vs late ASCT

  4. PFS 1.00 1.00 0.75 0.75 0.50 0.50 3 3 - - years PFS years PFS Median Median PFS PFS 0.25 Not Not reached reached MEL200 MEL200 60% 60% 0.25 HR 0.55 HR 0.868 MPR MPR 36% 36% 25.88 25.88 months months P< .0001 P = 0.542 0.00 0.00 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Early vs late ASCT MPR vs MEL 200 402 NDMM patients < 65 years MPR six 28-day courses M: 0.18 mg/Kg/d, days 1-4 P: 2 mg/Kg/d, days 1-4 R: 10 mg/d, days 1-21 NO MAINTENANCE Rd four 28-day courses R: 25 mg/d, days 1-21 d: 40 mg/d, days 1,8,15,22 1° R 2° R MEL200 two courses M: 200 mg/m2 day -2 Stem cell support day 0 R MAINTENANCE 28-day courses until relapse R: 10 mg/day, days 1-21 Median follow-up 38 months OS Months Months NDMM, newly diagnosed multiple myeloma; Rd, lenalidomide plus low-dose dexamethasone; MPR, melphalan-prednisone-lenalidomide; R, lenalidomide maintenance; MEL200, melphalan 200 mg/m2 Cavallo F, et al. EHA 2012;97:1142

  5. 100 100 MEL200-R 75 MPR-R 75 MEL200 50 MPR 50 MEL200-R MEL200 25 25 MPR-R MPR 0 0 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 Months MPR vs MEL200 vs MPR-R vs MEL200-R Progression-free survival Overall survival Months MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; R, lenalidomide maintenance

  6. 1.00 1.00 PAD MEL100 0.75 MEL200 0.75 0.50 0.50 VMP+VMPT MPR 0.25 0.25 HR 0.55; P=.032 HR 0.39; P=.026 0.00 0.00 12 24 36 48 60 12 24 36 48 60 Early vs late ASCT Role of CR after induction MPR vs MEL200 Random PAD MEL100 vs VMP+VMPT No random 1-year landmark PFS CR patients only 1-year landmark PFS CR patients only Months Months Palumbo A, et al. Gr. Emat. Milano 19 November 2012 MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; MEL100, melphalan 100 mg/m2; VMP, bortezomib-melphalan-prednisone; VMPT, VMP plus thalidomide; PAD, bortezomib-pegylated doxorubicin-dexamethasone; CR, complete response; PFS, progression-free survival

  7. Progression-free survival according to quality of response +12 m maint Pre maint +3 m maint +6 m maint +18 m maint Dia +12 m maint Pre maint +3 m maint +6 m maint +18 m maint Dia MRD - CR + Progression-free survival 100 MRD - CR + 80 60 Percent survival 40 MRD+ CR + MRD + CR + 20 0 0 10 20 30 40 50 Months MRD, minimal residual disease; CR complete response Palumbo A, et al. Unpublished data.

  8. Progression-free survival according to quality of response +12 m maint Pre maint +3 m maint +6 m maint +18 m maint Dia +12 m maint Pre maint +3 m maint +6 m maint +18 m maint Dia MRD - CR + Progression-free survival 100 • PLEASE • Do not compare CR rates • Do compare PFS rates MRD - CR + 80 60 Percent survival 40 MRD+ CR + MRD + CR + 20 0 0 10 20 30 40 50 Months MRD, minimal residual disease; CR complete response Palumbo A, et al. Unpublished data.

  9. Standard of Care for Elderly Patients

  10. MPT meta-analysis: which is the right T dosage? 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 PM, et al. Blood. 2011;118:1239-47

  11. VMPT-VT versus VMP in newlydiagnosedelderlypatients • Median follow-up: 54 mos Palumbo et al. ASH 2012 (Abstract 200), oral presentation

  12. VMPT-VT versus VMP in newlydiagnosedelderlypatients • Dearopponent: • Randomizedstudy • Follow-up 54 mos • Age 71 yrs • PFS 35.3 mos • TTNT 46.6 mos • Median follow-up: 54 mos Palumbo et al. ASH 2012 (Abstract 200), oral presentation

  13. Melphalan limitations?

  14. Hematologic SPMs Lenalidomide only Lenalidomide + cyclophosphamide Lenalidomide + melphalan Melphalan only 0 0,5 1 1,5 2 Solid SPMs Lenalidomide only Lenalidomide + cyclophosphamide Lenalidomide + melphalan Melphalan only 0 0,5 1 1,5 2 Incidence Rate per 100 per year Incidence rate per 100 per year Different lenalidomide combinations

  15. SPM and SAE Cumulative incidence per 100 at 60 months No Lenalidomide studies Lenalidomide studies

  16. SPM and SAE Cumulative incidence per 100 at 60 months No Lenalidomide studies Dearopponent: You start tohave: …some… right Lenalidomide studies

  17. Alternatives?

  18. VCD vs VRD vs VCRDProgression free survival 0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 510 540 570 600 630 660 690 720 750 780 810 840 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Proportion of patients Censored VDCR Censored VDC Censored VDR Censored VDC-mod VDCR (N = 48) VDC (N = 33) VDR (N = 42) VDC-mod (N = 17) Time (days) *censored observation

  19. Bortezomib-Cyclophosphamide-Dexamethasone • 17 newly diagnosed transplant eligible and ineligible MM patients VCDmod For 8 three-week cycles V: 1.3 mg/m2 d 1,4,8,11 C: 500 mg/m2 d 1,8,15 D: 40 mg d 1,8,15 MAINTENANCE V For 4 six-week cycles V: 1.3 mg/m2 d 1,8,15,22 For ASCT eligible: Stem cell collection after cycle 4 Progression-free survival Best response 100% 100 100 80 80 60 60 47% Patients (%) Patients (%) 40 40 29% 20 20 1-year rate 100% 6% 0% 0 0 420 480 540 0 120 180 240 300 360 60 PD VGPR sCR CR ≥PR Time (days) VCDmod, bortezomib-cyclophosphamide-dexamethasone modified schedule; PR, partial response; VGPR, very good partial response; CR, complete response; sCR, stringent complete response; PD, progressive disease; V, bortezomib. Kumar S, et al. Blood 2012.

  20. Carfilzomib, Cyclophosphamide, Dexamethasone (CCyd) MAINTENANCE CCyd Cycles 1-9 C: 20 mg/m2 d 1,2 followed by 36 mg/m2 d 8,9,15,16,22 (cycle 1); 36 mg/m2 d 1,2,8,9,15,16,22 (cycle 2-9); Cy: 300 mg/m2 d 1,8,15 d: 40 mg d 1,8,15,22 C Until progression/intolerance C: 36 mg/m2 d 1,2,15,16 sCR sCR/nCR/CR ≥VGPR ≥PR 96 94 100 89 100 76 80 72 64 63 75 60 46 41 50 40 24 15 13 20 25 1-year rate 86% 0 0 Cycle 2 Cycle 6 Cycle 9 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 • 58 newly diagnosed elderly MM patients enrolled at 10 Italian centers Progression-free survival Best response Patients (%) Patients (%) Time (months) CCyd, cyclophosphamide-cyclophosphamide-dexamethasone; C, carfilzomib; PR, partial response; VGPR, very good partial response; CR, complete response; sCR, stringent complete response; nCR, near complete response.

  21. Frailcondition

  22. New treatment algorithm for elderly MM Go-go moderate-go slow-go ADL, Activity of Daily Living; IADL, Instrumental Activity of Daily Living; ASCT, autologous stem cell transplantation Palumbo A. IMW 2013, oral presentation

  23. Subgroup analyses OS: Age >80 or <80 years OS: age >75 or <75 years 100 100 75 75 50 50 25 25 0 0 0 5 10 15 20 25 0 5 10 15 20 25 100 75 50 25 p=0.58 0 0 5 10 15 20 25 PFS: fit vs. frail Patients (%) fit frail Age < 75 years Age > 75 years p=0.27 p=0.02 OS: fit vs. frail 100 75 Patients (%) 50 Age < 80 years Age > 80 years fit frail 25 p=0.001 0 0 5 10 15 20 25 Time (months) Time (months) *Frail defined as: ADL <4 or IADL <5 or Charlson >2 or unfit patient >80 yr (Unfit defined as: ADL 5 or IADL 6-7 or Charlson 1 or fit patient >80 y)

  24. Dose adjustment recommendations for the treatment of frail elderly patients Palumbo et al. BLOOD, 27 OCTOBER 2011 118 (17):4519-4529

  25. Progression-free survival Rd vs. CPR vs. MPR CVP vs. VMP vs. VP VD vs. VTD vs. VMP 1.0 1.00 1.00 0.8 0.6 0.75 0.75 0.4 0.50 0.50 0.2 0.25 0.25 0 0 4 8 12 16 20 24 28 32 36 40 44 0.00 0.00 0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 Rd, len-dex CPR, cyclophosphamide MPR, melphalan VP, bort-prednisone CVP, cyclophosphamide VMP, melphalan; VD, bort-dex VTD, thalidomide VMP, melphalan Rd, lenalidomide-dexamethasone; CPR, cyclophosphamide-prednisone-lenalidomide; MPR, melphalan-prednisone-lenalidomide; CVP, cyclophosphamide-bortezomib-prednisone; VMP, bortezomib-melphalan-prednisone; VP, bortezomib-prednisone; VD, bortezomib-dexamethasone; VTD, bortezomib-thalidomide-dexamethasone. Larocca A, et al. Gr. Emat. Milano 2012 Larocca A, et al. IMW 2013 Niesvizky R, et al. EHA 2010

  26. RP-MPR-RP Phase 2 Study Consolidation Maintenance Induction Two drugs Three drugs Maintenance RP: Pred:50 mg/day, 3x/week Len: 25 mg/day, d1–21 Four 28-day cycles MPR: Mel:2 mg, 3x/week Pred:50 mg/day, 3x/weekLen:10–15 mg/day, d1–21 Six 28-day cycles RP: Len:10 mg/day, d1–21 Pred: 25 mg/day, 3x/week 28-day cycles until PD MPR, melphalan, prednisone, Lenalidomide; RP, Lenalidomide, prednisone;RP-MPR-RP, Lenalidomide-prednisone induction followed by melphalan-prednisone-Lenalidomide consolidation and Lenalidomide-prednisone maintenance. Falco P, et al. Leukemia. 2013;27:695-701

  27. Conclusions • FIT PATIENTS • Tripletsshouldbeconsidered standard • Melphalantootoxic • Cyclophosphamidebettertolerated • UNFIT PATIENTS • Doubletpreferred

  28. Thank you

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