Presentation on theme: "Update on transplant- ineligible patients: Which regimens are best? Suzanne Lentzsch MD, PhD Columbia University, New York."— Presentation transcript:
Update on transplant- ineligible patients: Which regimens are best? Suzanne Lentzsch MD, PhD Columbia University, New York
Disclosures for Suzanne Lentzsch, MD, PhD Honoraria Scientific Advisory Board Speakers Bureau No relevant conflicts of interest to declareMajor Stockholder Consultant No relevant conflicts of interest to declareEmployee CelgeneResearch Support/P.I. No relevant conflicts of interest to declare Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx No relevant conflicts of interest to declare
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
Treatment Decision in Transplant Ineligible Patients Frailty ??? Melphalan based regimens ??? Doublets ??? Triplets ??? Maintenance ???
Frailty score VariableHR (CI 95%)PSCORE AGEAge <75 years1-0 Age 75-80 years1.37 (0.93-2.03)0.1141 Age >80 years2.75 (1.81-4.18)<0.0012 CHARLSON INDEXCharlson <11-0 Charlson >21.6 (1.07-2.39)0.0211 ADL SCOREADL >41-0 ADL<41.76 (1.14-2.71)0.011 IADL SCOREIADL >51-0 IADL<51.53 (1.03-2.27)0.0361 ADDITIVE TOTAL SCOREPATIENT STATUS 0FIT 1UNFIT >2>2FRAIL Slide courtesy of Palumbo, ASH 2013
Patients (%) Overall Survival Multivariate Analysis Lower risk Death FIT ISS 1-2 FISH neg Fit vs. Unfit vs. Frail Fit defined as: score=0 Unfit defined as: score=1 Frail defined as: score>2 1-yr OS Fit96% Unfit93% Frail78% Unfit vs Fit Frail vs Fit ISS 3 vs ISS 1-2 HR vs SR Fish ECOG 2-3 vs 0-1 1.24 (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) Higher risk Death FRAIL ISS 3 FISH pos Unfit vs Fit, HR=1.61 p=0.042 Frail vs Fit, HR=3.57 p<0.001 Slide courtesy of Palumbo, ASH 2013
PATIENT STATUS ASSESSMENT Age (score 0 – 1 – 2) Charlson (score 0 – 1) ADL (score 0 – 1) IADL (score 0 – 1) FITUNFITFRAIL Additive total score = 0Additive total score = 1Additive total score ≥ 2 GO-GOMODERATE-GOSLOW-GO Full-doseReduced-doseFurther reduced dose Dose level 0Dose level -1Dose level -2 Lenalidomide25 mg/d15 mg/d10 mg/d Bortezomib1.3 mg/m 2 /wk1.0 mg/m 2 /wk1.3 mg/m 2 /2wk Dexamethasone40 mg/wk20 mg/wk10 mg/wk Cyclophosphamide300 mg/m 2 d 1,8,1550 mg/d50 mg/qod Treatment algorithm for elderly MM Slide courtesy of Palumbo, ASH 2013
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
MPTMP mOS39.3 m32.7 m mPFS20.3 m14.9 m 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
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
Wildes T M et al. JCO 2014;32:2531-2540 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. Initial Therapy in Older Adults With MM: Randomized Trials of MP With or Without the Addition of Novel Agents
Unanswered Question for Transplant Ineligible Patients Frailty – Adjust Treatment Intensity Melphalan or Novel Drugs ??? Doublets or Triplets ??? Maintenance ???
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
RESULTS Patients 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
Response* 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) Best confirmed response after 8 (induction) and 13 (induction + maintenance) cycles Slide Courtesy Niesvizky, R; ASH 2013
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
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
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
Unanswered Question for Transplant Ineligible Patients Frailty – Adjust Treatment Intensity Melphalan or Novel Drugs! Doublets! or Triplets Maintenance ???
Facon T, et al. Blood. 2013;122:abstract 2. RANDOMIZATION 1:1:1 Arm B Rd18 Arm C MPT LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 MEL + PRED + THAL 12 Cycles 1 (72 wks) MELPHALAN 0.25mg/kg D1-4/42 PREDNISONE 2mg/kg D1-4/42 THALIDOMIDE 200mg D1-42/42 PD, OS and Subsequent anti-MM Tx PD or Unacceptable Toxicity Active Treatment + PFS Follow-up Phase ScreeningLT Follow-Up Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL 2 (100 mg D1-42/42); MEL 2 0.2 mg/kg D1–4 Stratification: age, country and ISS stage 1 Facon T, et al. Lancet 2007;370:1209-18; 2 Hulin C, et al. JCO. 2009;27:3664-70. FIRST Trial: Study Design LEN + Lo-DEX Continuously LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 Arm A Continuous Rd ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival Benboubker L et al. N Engl J Med 2014;371:906-917.
mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone. Median PFS Rd (n=535)25.5 mos Rd18 (n=541)20.7 mos MPT (n=547)21.2 mos Rd535400319265218168105551920 Rd185413913192651671085630720 MPT5473803042441701165828610 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 Time (months) Patients (%) 100 80 60 40 20 0 06121824303642485460 72 wks FIRST Trial: Final Progression-free Survival 28% reduced risk of disease progression Benboubker L et al. N Engl J Med 2014;371:906-917.
FIRST Trial: Overall Survival Interim Analysis Patients (%) 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 563563 000000 4-year OS Rd (n= 535)59% Rd18 (n= 541)56% MPT (n= 547)51% Overall survival (months) 100 80 60 40 20 0 06121824303642485460 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 Benboubker L et al. N Engl J Med 2014;371:906-917. 574 deaths (35% of ITT)
Response a (%) Continuous Rd (n=535) Rd18 (n=541) MPT (n=547) ORR (≥ PR) b 757362 CR 15149 VGPR 28 19 PR 323134 SD 192127 VGPR or better 434228 Time to response (median, mos) 1.8 2.8 Duration of response (median, mos) 35.022.122.3 FIRST Trial: Response Endpoints FIRST Trial: Response Endpoints a IMWG Criteria; CR, complete response; mos, months ORR, overall response rate; PR, partial response; SD, stable disease; VGPR, very good PR. b Response 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.
FIRST Trial: Conclusions Continuous Rd significantly extended PFS and 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.
Unanswered Question for Transplant Ineligible Patients Frailty – Adjust Treatment Intensity Melphalan or Novel Drugs !! Doublets or Triplets !! Maintenance !!
Palumbo A et al. JCO 2014;32:634-640 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
Survival outcomes in the intention-to-treat population, according to study group. PFS OS TNT OS after Relapse Palumbo A et al. JCO 2014;32:634-640
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 including neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). Conclusion Bortezomib and thalidomide maintenance significantly improved OS in multiple myeloma patients VT-Maintenance for Non-Transplant Patients Palumbo A et al. JCO 2014;32:634-640
UnAnswered Question for Transplant Ineligible Patients? Frailty –Adjust Treatment Intensity –Determine the goals of care !! Melphalan or Novel Drugs !! Doublets or Triplets !! –Less toxic treatment allows longer treatment Maintenance !!