Disclosures for Palumbo Antonio, MD

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Presentation transcript:

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

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

Early vs late ASCT 3

402 NDMM patients < 65 years 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 PFS HR 0.55 P< .0001 0.00 0.25 0.50 0.75 1.00 10 20 30 40 50 60 3 - years PFS MPR MEL200 36% 60% Median Not reached 25.88 months OS HR 0.868 P = 0.542 0.00 0.25 0.50 0.75 1.00 10 20 30 40 50 60 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

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

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 0.00 0.25 0.50 0.75 1.00 12 HR 0.39; P=.026 MEL200 MPR 24 36 48 60 HR 0.55; P=.032 0.00 0.25 0.50 0.75 1.00 PAD MEL100 VMP+VMPT 12 24 36 48 60 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

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 Unpublished data.

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 Unpublished data.

Standard of Care for Elderly Patients 9

which is the right T dosage? MPT meta-analysis: which is the right T dosage? MP better MPT better Progression-free survival Overall survival NOTE: weights are from random effects analysis Overall (I-squared = 61.7%, p = 0.023) FR < 75 NMSG HOVON Italy Fr ≥ 75 Turkey Study 0.67 (0.55– 0.80) 0.50 (0.39– 0.65) 0.89 (0.70–1.13) 0.79 (0.62–1.00) 0.62 (0.48–0.80) 0.61 (0.46–0.82) 0.59 (0.35–0.99) HR (95% CI) 1 0.5 0.75 1.5 Overall (I-squared = 60.6%, p = 0.026) Fr ≥ 75 0.82 (0.66–1.02) 1.12 (0.85–1.47) 1.04 (0.75–1.44) 0.61 (0.45– 0.81) 0.75 (0.57–1.00) 0.68 (0.48– 0.96) 0.87 (0.46–1.67) MPT MP mOS 39.3 m 32.7 m mPFS 20.3 m 14.9 m Fayers PM, et al. Blood. 2011;118:1239-47

VMPT-VT versus VMP in newly diagnosed elderly patients Median follow-up: 54 mos VMPT-VT VMP P PFS 35.3 mos 24.8 mos < 0.0001 TTNT 46.6 mos 27.8 mos Landmark analysis 4-year PFS Median PFS 33% 31.5 mos 16% 17.8 mos 5-year OS 61% 51% 0.01 Median OS Not reached 60.6 mos 4-year OS 67% 55% 54.2 mos 0.006 OS from relapse 3-year OS 47% 46% 27.3 mos Palumbo et al. ASH 2012 (Abstract 200), oral presentation

VMPT-VT versus VMP in newly diagnosed elderly patients Dear opponent: Randomized study Follow-up 54 mos Age 71 yrs PFS 35.3 mos TTNT 46.6 mos Median follow-up: 54 mos VMPT-VT VMP P PFS 35.3 mos 24.8 mos < 0.0001 TTNT 46.6 mos 27.8 mos Landmark analysis 4-year PFS Median PFS 33% 31.5 mos 16% 17.8 mos 5-year OS 61% 51% 0.01 Median OS Not reached 60.6 mos 4-year OS 67% 55% 54.2 mos 0.006 OS from relapse 3-year OS 47% 46% 27.3 mos Palumbo et al. ASH 2012 (Abstract 200), oral presentation

Melphalan limitations? 13

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

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

Cumulative incidence per 100 at 60 months SPM and SAE Cumulative incidence per 100 at 60 months No Lenalidomide studies Dear opponent: You start to have: …some… right Lenalidomide studies

Alternatives? 17

VCD vs VRD vs VCRD Progression free survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Proportion of patients VDCR (N = 48) VDC (N = 33) VDR (N = 42) VDC-mod (N = 17) Censored VDCR Censored VDC Censored VDR Censored VDC-mod 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 Time (days) Subjects at risk: 48 45 42 40 37 35 33 28 26 25 21 20 19 17 16 10 9 7 4 3 2 41 38 36 31 29 27 18 15 14 11 8 5 1 30 23 13 12 6 VDCR (n = 48) VDR (n = 42) VDC (n = 33) VDC-mod (n = 17) Median PFS, days (range) 710 (1*–802*) NE (1*–800*) NE (41–825*) NE (178*–515*) PFS at 1 year, % 85 83 93 100 *censored observation

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 1-year rate 100% 20 6% 0% 60 120 180 240 300 360 420 480 540 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.

Carfilzomib, Cyclophosphamide, Dexamethasone (CCyd) 58 newly diagnosed elderly MM patients enrolled at 10 Italian centers C Until progression/intolerance C: 36 mg/m2 d 1,2,15,16 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 Progression-free survival Best response sCR sCR/nCR/CR ≥VGPR ≥PR 25 50 75 100 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 1-year rate 86% 13 15 24 41 46 64 63 72 76 89 94 96 20 40 60 80 100 Cycle 2 Cycle 6 Cycle 9 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.

Frail condition 21

New treatment algorithm for elderly MM PATIENT STATUS ASSESSMENT - Age - ADL - IADL - Charlson co-morbidity score FIT UNFIT FRAIL Age <80 yr ADL 6 IADL 8 Charlson 0 Fit >80 yr ADL 5 IADL 6-7 Charlson 1 Unfit >80 yr ADL ≤4 IADL ≤5 Charlson ≥2 Full-dose regimens Dose level 0 Reduced-dose regimens Dose level -1 Reduced-dose Palliative approach Dose level -2 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

Subgroup analyses OS: age >75 or <75 years PFS: fit vs. frail 25 50 75 100 5 10 15 20 25 25 50 75 100 5 10 15 20 Patients (%) Age < 75 years Age > 75 years fit frail p=0.27 p=0.02 OS: Age >80 or <80 years OS: fit vs. frail p=0.58 25 50 75 100 5 10 15 20 100 75 Patients (%) 50 Age < 80 years Age > 80 years 25 fit frail p=0.001 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)

Dose adjustment recommendations for the treatment of frail elderly patients Agent Dose level 0 Dose level – 1 Dose level – 2 Bortezomib 1.3 mg/m2 twice / week d 1,4,8,11 / 3 wks 1.3 mg/m2 once / week d 1,8,15,22 / 5 weeks 1.0 mg/m2 once / week Thalidomide 100 mg/d 50 mg/d 50 mg qod Lenalidomide 25 mg/d d 1-21 / 4 weeks 15 mg/d 10 mg/d Dexamethasone 40 mg/d d 1,8,15,22 / 4 week 20 mg/d Melphalan 0.25 mg/kg d 1-4 / 4-6 weeks 0.18 mg/kg 0.13 mg/kg Prednisone 25 mg qod 12.5 mg qod Cyclophosphamide Palumbo et al. BLOOD, 27 OCTOBER 2011 118 (17):4519-4529

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

RP-MPR-RP Phase 2 Study Two drugs Three drugs Maintenance Induction Consolidation Maintenance 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/week Len: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

Conclusions FIT PATIENTS Triplets should be considered standard Melphalan too toxic Cyclophosphamide better tolerated UNFIT PATIENTS Doublet preferred 27

Thank you 29