Presentation on theme: "Update on transplant-ineligible patients: Which regimens are best?"— Presentation transcript:
1Update on transplant-ineligible patients: Which regimens are best? Suzanne Lentzsch MD, PhDColumbia University, New York
2Disclosures for Suzanne Lentzsch, MD, PhD HonorariaScientific Advisory BoardSpeakers BureauNo relevant conflicts of interest to declareMajor StockholderConsultantEmployeeCelgeneResearch Support/P.I.No relevant conflicts of interest to declareNo relevant conflicts of interest to declareAmgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx
3Treatment Decision in Older Patients ADLIADLComorbiditiesHospitalizationMedicationsSocial SupportMultiple MyelomaCytogeneticsStageTumor burdenOptimal ChemoSupportive medsGoals of Care (CR vs Disease Control?)ExpectationsUnderstandingLife Expectancy
4Treatment Decision in Transplant Ineligible Patients Frailty ???Melphalan based regimens ???Doublets ???Triplets ???Maintenance ???
5Frailty score Variable HR (CI 95%) P SCORE AGE Age <75 years 1 - Age years1.37 ( )0.114Age >80 years2.75 ( )<0.0012CHARLSON INDEXCharlson <1Charlson >21.6 ( )0.021ADL SCOREADL >4ADL<41.76 ( )0.01IADL SCOREIADL >5IADL<51.53 ( )0.036ADDITIVE TOTAL SCOREPATIENT STATUSFIT1UNFIT>2FRAILSlide courtesy of Palumbo, ASH 2013
6Fit vs. Unfit vs. Frail Overall Survival Multivariate Analysis Unfit vs FitFrail vs FitISS 3 vs ISS 1-2HR vs SR FishECOG 2-3 vs 0-11.24 (0.74, 2.08)3.11 (1.97, 4.90)1.77 (1.23, 2.54)1.83 (1.26, 2.63)1.19 (0.81, 1.76)1-yr OSFit96%Unfit93%Frail78%Patients (%)Lower risk DeathFITISS 1-2FISH negHigher risk DeathFRAILISS 3FISH posUnfit vs Fit, HR=1.61 p=0.042Frail vs Fit, HR=3.57 p<0.001Fit defined as: score=0 Unfit defined as: score=1 Frail defined as: score>2Slide courtesy of Palumbo, ASH 2013
10Progression-free survival Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trialsMP betterMPT betterProgression-free survivalOverall survivalNOTE: weights are from random effects analysisOverall (I-squared = 61.7%,p = 0.023)FR < 75NMSGHOVONItalyFr ≥ 75TurkeyStudy0.67 (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)10.50.751.5Overall (I-squared = 60.6%, p = 0.026)Fr ≥ 750.82 (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)Fayers P M et al. Blood 2011;118:
11Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trialsMPTMPmOS39.3 m32.7 mmPFS20.3 m14.9 mFayers P M et al. Blood 2011;118:
12Overall survival in patients randomized to bortezomib-melphalan-prednisone (VMP) or melphalan-prednisone (MP) after a median follow-up of 5 yearsSan Miguel J F et al. JCO 2013;31:
13Initial Therapy in Older Adults With MM: Randomized Trials of MP With or Without the Addition of Novel AgentsAbbreviations: 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:
14Unanswered Question for Transplant Ineligible Patients Frailty – Adjust Treatment IntensityMelphalan or Novel Drugs ???Doublets or Triplets ???Maintenance ???
15Efficacy 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 StudySlide Courtesy Niesvizky, R; ASH 2013
16RESULTS Patients 502 patients were randomized to VD (n=168),VTD (n=167),VMP (n=167)Baseline characteristics were well balanced across the treatment armsMedian age was 73 years (range 38–91)48% of patients had comorbidities at baselineThe most common were diabetes mellitus (21%), renal disease (15%), and chronic pulmonary disease (8%)Slide Courtesy Niesvizky, R; ASH 2013
17Response*ORRs after 13 cycles were 73% (VD), 80% (VTD), and 70% (VMP) including:30%, 40%, and 32% CR/nCR, respectively37%, 51%, and 41% ≥VGPR, respectivelyBest confirmed response after 8 (induction) and 13 (induction + maintenance) cycles*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
18PFS (intent-to-treat population) After a median follow-up of 42.7 months, 265 (53%) patients had progressed and/or diedMedian 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
19OS (intent-to-treat population) Median OS (95% CI) was 49.8 months (35.7, not estimable [NE]), 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
20UPFRONT TRIAL CONCLUSIONS After ~3.5 years’ follow-up, no significant differences in PFS or OS were seen among armsVTD had the highest toxicity rates and the lowest mean bortezomib dose intensity among the armsVD 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
21Unanswered Question for Transplant Ineligible Patients Frailty – Adjust Treatment IntensityMelphalan or Novel Drugs!Doublets! or TripletsMaintenance ???
22FIRST Trial: Study Design ScreeningActive Treatment + PFS Follow-up PhaseLT Follow-UpRANDOMIZATION 1:1:1LEN + Lo-DEX ContinuouslyLENALIDOMIDE mg D1-21/28Lo-DEX mg D1,8,15 & 22/28PD or Unacceptable ToxicitySubsequent anti-MM TxPD, OS andArm AContinuous RdArm BRd18LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE mg D1-21/28Lo-DEX mg D1,8,15 & 22/28MEL + PRED + THAL 12 Cycles1 (72 wks)MELPHALAN mg/kg D1-4/42PREDNISONE mg/kg D1-4/42THALIDOMIDE mg D1-42/42Arm CMPTPts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL mg/kg D1–4Stratification: age, country and ISS stageISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival1Facon T, et al. Lancet 2007;370: ; 2Hulin C, et al. JCO. 2009;27:Facon T, et al. Blood. 2013;122:abstract 2.Benboubker L et al. N Engl J Med 2014;371:
23FIRST Trial: Final Progression-free Survival 28% reduced risk of disease progressionMedian PFSRd (n=535)25.5 mosRd18 (n=541)20.7 mosMPT (n=547)21.2 mos10080604020Hazard ratioRd vs. MPT: 0.72; P =Rd vs. Rd18: 0.70; P =Rd18 vs. MPT: 1.03; P =Patients (%)72 wks6121824303642485460Time (months)Rd53540031926521816810555192Rd1854139116710856307MPT547380304244170116582861mos, 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:
24FIRST Trial: Overall Survival Interim Analysis Overall survival (months)1008060402061218243036424854Hazard ratioRd vs. MPT: 0.78; P = 0.02Rd vs. Rd18: 0.90; P = 0.31Rd18 vs. MPT: 0.88; P = 0.184-year OSRd (n= 535)59%Rd18 (n= 541)56%MPT (n= 547)51%Patients (%)574 deaths (35% of ITT)RdRd18MPT535541547488505484457465448433425418403393375338324312224209205121124106434430563Benboubker L et al. N Engl J Med 2014;371:
25FIRST Trial: Response Endpoints Responsea (%)Continuous Rd(n=535)Rd18(n=541)MPT(n=547)ORR (≥ PR)b757362CR15149VGPR2819PR323134SD2127VGPR or better4342Time to response (median, mos)1.82.8Duration of response (median, mos)35.022.122.3aIMWG 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:
26FIRST Trial: Conclusions Continuous Rd significantly extended PFS and OS vs. MPTPFS:HR= 0.72 (P= )Consistent benefit across most subgroupsRd better than Rd18 (HR= 0.70, P= )3 yr PFS: 42% Rd vs 23% Rd18 and MPTPlanned interim OS: HR= 0.78 (P= )Rd was superior to MPT across all other efficacy secondary endpointsSafety profile with continuous Rd was manageableHematological and non-hematological AEs were as expected for Rd and MPTIncidence of hematological SPM was lower with continuous Rd vs. MPTIn NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of careBenboubker L et al. N Engl J Med 2014;371:
27Unanswered Question for Transplant Ineligible Patients Frailty – Adjust Treatment IntensityMelphalan or Novel Drugs !!Doublets or Triplets !!Maintenance !!
28Bortezomib-Melphalan-Prednisone Followed by Maintenance With Bortezomib-Thalidomide (VMP-VT) Compared With Bortezomib-Melphalan-Prednisone (VMP) for Initial Treatment of Multiple MyelomaN=511Palumbo A et al. JCO 2014;32:
29Survival outcomes in the intention-to-treat population, according to study group. TNTPFSOS after RelapseOSPalumbo A et al. JCO 2014;32:
30VT-Maintenance for Non-Transplant Patients VMP vs. VMPT-VT:3-year PFS: 41% vs 56%median PFS: vs 35.3 months (P .001)TNT 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 including neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%).ConclusionBortezomib and thalidomide maintenance significantly improved OS in multiple myeloma patientsPalumbo A et al. JCO 2014;32:
31UnAnswered Question for Transplant Ineligible Patients? FrailtyAdjust Treatment IntensityDetermine the goals of care !!Melphalan or Novel Drugs !!Doublets or Triplets !!Less toxic treatment allows longer treatmentMaintenance !!