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

Treatment Decision in Older 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 Variable HR (CI 95%) P SCORE AGE Age <75 years 1 - Age 75-80 years 1.37 (0.93-2.03) 0.114 Age >80 years 2.75 (1.81-4.18) <0.001 2 CHARLSON INDEX Charlson <1 Charlson >2 1.6 (1.07-2.39) 0.021 ADL SCORE ADL >4 ADL<4 1.76 (1.14-2.71) 0.01 IADL SCORE IADL >5 IADL<5 1.53 (1.03-2.27) 0.036 ADDITIVE TOTAL SCORE PATIENT STATUS FIT 1 UNFIT >2 FRAIL Slide courtesy of Palumbo, ASH 2013

Fit vs. Unfit vs. Frail Overall Survival Multivariate Analysis 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) 1-yr OS Fit 96% Unfit 93% Frail 78% Patients (%) Lower risk Death FIT ISS 1-2 FISH neg 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 Fit defined as: score=0 Unfit defined as: score=1 Frail defined as: score>2 Slide courtesy of Palumbo, ASH 2013

Slide courtesy of Palumbo, ASH 2013

Treatment algorithm for elderly MM PATIENT STATUS ASSESSMENT Age (score 0 – 1 – 2) Charlson (score 0 – 1) ADL (score 0 – 1) IADL (score 0 – 1) FIT UNFIT FRAIL Additive total score = 0 Additive total score = 1 Additive total score ≥ 2 GO-GO MODERATE-GO SLOW-GO Full-dose Reduced-dose Further reduced dose Dose level 0 Dose level -1 Dose level -2 Lenalidomide 25 mg/d 15 mg/d 10 mg/d Bortezomib 1.3 mg/m2/wk 1.0 mg/m2/wk 1.3 mg/m2/2wk Dexamethasone 40 mg/wk 20 mg/wk 10 mg/wk Cyclophosphamide 300 mg/m2 d 1,8,15 50 mg/d 50 mg/qod Slide courtesy of Palumbo, ASH 2013

Unanswered Question for Transplant Ineligible Patients Frailty-Adjust Treatment Intensity Melphalan ??? Doublets ??? Triplets ??? Maintenance ???

Progression-free survival Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials 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) Fayers P M et al. Blood 2011;118:1239-1247

Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials MPT MP mOS 39.3 m 32.7 m mPFS 20.3 m 14.9 m 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

Initial Therapy in Older Adults With MM: Randomized Trials of MP With or Without the Addition of Novel Agents 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. Wildes T M et al. JCO 2014;32:2531-2540

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 Best 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

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 ???

FIRST Trial: Study Design Screening Active Treatment + PFS Follow-up Phase LT Follow-Up RANDOMIZATION 1:1:1 LEN + Lo-DEX Continuously LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 PD or Unacceptable Toxicity Subsequent anti-MM Tx PD, OS and Arm A Continuous Rd Arm B Rd18 LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 MEL + PRED + THAL 12 Cycles1 (72 wks) MELPHALAN 0.25mg/kg D1-4/42 PREDNISONE 2mg/kg D1-4/42 THALIDOMIDE 200mg D1-42/42 Arm C MPT Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL2 0.2 mg/kg D1–4 Stratification: age, country and ISS stage ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival 1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70. Facon T, et al. Blood. 2013;122:abstract 2. Benboubker L et al. N Engl J Med 2014;371:906-917.

FIRST Trial: Final Progression-free Survival 28% reduced risk of disease progression Median PFS Rd (n=535) 25.5 mos Rd18 (n=541) 20.7 mos MPT (n=547) 21.2 mos 100 80 60 40 20 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 Patients (%) 72 wks 6 12 18 24 30 36 42 48 54 60 Time (months) Rd 535 400 319 265 218 168 105 55 19 2 Rd18 541 391 167 108 56 30 7 MPT 547 380 304 244 170 116 58 28 6 1 mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone. Benboubker L et al. N Engl J Med 2014;371:906-917.

FIRST Trial: Overall Survival Interim Analysis Overall survival (months) 100 80 60 40 20 6 12 18 24 30 36 42 48 54 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 4-year OS Rd (n= 535) 59% Rd18 (n= 541) 56% MPT (n= 547) 51% Patients (%) 574 deaths (35% of ITT) 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 5 6 3 Benboubker L et al. N Engl J Med 2014;371:906-917.

FIRST Trial: Response Endpoints Responsea (%) Continuous Rd (n=535) Rd18 (n=541) MPT (n=547) ORR (≥ PR)b 75 73 62 CR 15 14 9 VGPR 28 19 PR 32 31 34 SD 21 27 VGPR or better 43 42 Time to response (median, mos) 1.8 2.8 Duration of response (median, mos) 35.0 22.1 22.3 aIMWG 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;371:906-917.

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 !!

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 Palumbo A et al. JCO 2014;32:634-640

Survival outcomes in the intention-to-treat population, according to study group. TNT PFS OS after Relapse OS Palumbo A et al. JCO 2014;32:634-640

VT-Maintenance for Non-Transplant Patients 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 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 !!

Thank You !!