Facon, Thierry T.F.

Abstract Background: In the pivotal FIRST trial, at the pre-specified planned analysis for progression-free survival (PFS), treatment (Tx) with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) improved outcomes for transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM) compared with melphalan, prednisone, and thalidomide (MPT), as well as Rd for 18 cycles (Rd18; Benboubker, NEJM 2014). Rd18 was added as a third arm to investigate whether Rd continuous Tx would control progression of NDMM longer than Rd18. Here, we present the final analysis of the overall survival (OS) data from the trial. Methods: Transplant-ineligible pts with NDMM were randomized 1:1:1 to Rd continuous (with lenalidomide given on days 1-21 of 28-day cycles until disease progression), Rd18 (with lenalidomide given on days 1-21 of eighteen 28-day cycles), or MPT (twelve 42-day cycles); both Rd18 and MPT were 72 weeks in duration. The primary endpoint was PFS and the key secondary endpoint was OS; the primary comparison was Rd continuous vs MPT. Other secondary endpoints included time to second therapy (TTST) and safety. Time from randomization to second progression or death (PFS2) was an exploratory analysis. Response assessment used for PFS and PFS2 analysis was determined by investigators based on International Myeloma Working Group criteria. Results: At the time of cutoff for the final OS analysis (January 21, 2016), 52 of the 535 pts in the Rd continuous arm and none of the pts in the Rd18 (n = 541) and MPT (n = 547) arms continued to receive Tx. The median follow-up for surviving pts was 67.0 months (range, 0-86.8 months). In the pre-specified final OS analysis for the primary comparison, a statistically significant advantage in OS was shown with Rd continuous over MPT (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.92; P = .00234; Table). OS for Rd continuous vs Rd18 was evaluated (HR, 1.02; 95% CI, 0.86-1.20). In this updated analysis, a PFS advantage continued to be seen for Rd continuous vs MPT (HR, 0.69; 95% CI, 0.59-0.79; P < .00001) and vs Rd18 (HR, 0.70; 95% CI, 0.60-0.81). Median TTST was longer for Rd continuous vs MPT (HR, 0.63; 95% CI, 0.54-0.73; Table). More pts in the Rd18 and MPT arms started second-line therapy (n = 377 and 381, respectively) compared with the Rd continuous arm (n = 299). Pts received a variety of Tx at progression, with bortezomib-based regimens the most common in the Rd continuous (n = 179; 59.9%), Rd18 (n = 208; 55.2%), and MPT (n = 170; 44.6%) arms. Pts who received bortezomib after Rd continuous or Rd18 had better outcomes than those who received it after MPT. PFS2 for Rd continuous was improved vs MPT (HR, 0.74; 95% CI, 0.64-0.85). Grade 3/4 adverse events (AEs) occurred in 86.3%, 80.2%, and 88.7% of the 532, 540, and 541 pts in the safety populations of the Rd continuous, Rd18, and MPT arms, respectively; the most common grade 3/4 AEs were neutropenia (29.5%, 26.5%, and 44.9%) and infections (31.6%, 21.9%, and 17.2%), and no new safety signals were seen compared with earlier analyses. Study discontinuation was most commonly due to disease progression and was less common in the Rd continuous vs Rd18 and MPT arms (50.7% vs 66.9% and 61.6%, respectively). Discontinuation due to AEs was similar across the Rd continuous, Rd18, and MPT arms (12.0%, 13.1%, and 13.9%). Solid tumor second primary malignancies (SPMs) occurred in 6.0, 6.9%, and 5.9% of pts, and hematologic malignancies occurred in 0.8%, 0.4%, and 2.6% of pts in the Rd continuous, Rd18, and MPT arms, respectively. Conclusions: Rd continuous significantly prolonged PFS and OS, and improved other secondary endpoints compared with MPT in transplant-ineligible pts with NDMM. Rd continuous also showed a PFS benefit compared with Rd18, delaying the time to next Tx. PFS2 outcomes suggest that Rd does not induce resistant relapses. Few hematologic malignancies occurred in the Rd arms, and the incidence of SPMs was similar between Rd continuous and Rd18. Rd continuous remains a standard of care for transplant-ineligible pts with NDMM. Disclosures Facon: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel and expense, Speakers Bureau. Dimopoulos:Genesis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene: Research Funding. Belch:Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria. Weisel:BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Bahlis:BMS: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria. Delforge:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Cavenagh:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Geraldes:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Oriol:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. De La Rubia:Amgen, Bristol, Celgene, Janssen: Consultancy, Speakers Bureau. White:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria. Attal:janssen: Consultancy, Research Funding; amgen: Consultancy, Research Funding; celgene: Consultancy, Research Funding; sanofi: Consultancy. Ervin-Haynes:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment, Equity Ownership. Houck:Celgene: Employment. Hulin:celgene: Honoraria; Bristol: Honoraria; Janssen: Honoraria; Amgen: Honoraria; takeda: Honoraria. Benboubker:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival. Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecular inhibitor of BCL-2. When combined with bortezomib, which can inhibit MCL-1, VEN can enhance the activity of bortezomib in MM cell lines and xenograft models. Methods: In this Phase 1b, open label, dose escalation study, patients with relapsed/refractory (R/R) MM received daily VEN (50 - 1200 mg per designated dose cohort) with bortezomib and dexamethasone. The objectives of the study were to assess the safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose (R2PD), and efficacy (objective response rate [ORR], time to progression [TTP], and duration of response [DoR]) of combination therapy in this patient population. Results: As of 01July2016, 66 patients were enrolled, with 54 in the dose escalation cohort and 12 in the safety expansion at R2PD of 800 mg. The median age was 64 years and 39 (59%) were ISS stage II/III. The median number of prior therapies was 3 (range: 1 - 13), and 21 (32%) were refractory to prior bortezomib, 37 (56%) were refractory to prior lenalidomide, and 41 (62%) had prior stem cell transplant. Forty-three (65%) patients discontinued the study for the following primary reasons: 33 related to disease progression, 5 due to AEs (1 each: respiratory failure and cardiac failure, lung adenocarcinoma, sepsis, renal impairment, and Guillain-Barre syndrome; none were considered by the investigator as related to VEN), 2 withdrew consent, and 3 for other reasons not specified. Adverse events (AEs) were reported in 65 (99%) patients, with common AEs in ≥20% of patients being diarrhea (41%), thrombocytopenia (39%), constipation (38%), nausea (36%), insomnia (32%), peripheral neuropathy (30%), peripheral edema (29%), anemia (27%), peripheral sensory neuropathy (27%), dyspnea (24%), fatigue (24%), and asthenia (24%). Grade 3/4 AEs in ≥10% of patients included thrombocytopenia (29%), anemia (15%) and neutropenia (14%). Serious AEs in ≥2 patients were febrile neutropenia, thrombocytopenia, cardiac failure, pyrexia, influenza, lower respiratory tract infection, pneumonia, sepsis, acute kidney injury, respiratory failure, embolism, and hypotension. One dose-limiting toxicity of lower abdominal pain was reported for a patient who received 1200 mg VEN. Five deaths were reported during the study, 4 due to disease progression and 1 due to respiratory syncytial virus infection (not considered by the investigator as related to VEN). After co-administration with bortezomib and dexamethasone, dose-normalized VEN exposure at steady-state appeared to be within the exposure range observed with VEN monotherapy in patients with MM. The ORR for all evaluable patients was 68% (44/65) and 26 (40%) achieved very good partial response (VGPR) or better (3 stringent complete response [sCR], 8 CR, 15 VGPR) (Figure). For all patients, median DoR was 8.8 months (95% CI: 7.2, 15.8) and TTP was 8.6 months (95% CI: 5.7, 10.2), with a median follow up of 4.9 months (range: .03 - 26.7). High ORR of 89% was seen in patients who were non-refractory to prior bortezomib (39/45) or who had 1 - 3 prior therapies (31/35). In 31 patients who were non-refractory to bortezomib and had 1 - 3 prior therapies had ORR of 94% (29/31), 68% (21/31) with VGPR or better; median DoR was 10.6 months and TTP was 11.3 months for this subgroup. Moreover, patients who were bortezomib naïve and had 1 - 3 prior lines of therapy had ORR of 100% (12/12), and median DoR was 15.8 months and TTP was 17.1 months. In patients who were non-refractory to prior bortezomib but who were refractory to lenalidomide, the ORR was 86% (19/22) as compared with 91% (20/22) in those non-refractory to lenalidomide. Clinical responses were comparable in patients with t(11;14) MM (ORR, 78% [7/9]) and without t(11;14) MM (ORR, 66% [37/56]). In the t(11;14) group, 3 patients were bortezomib-refractory, and 2 of them achieved a PR as best response. Also, 4 patients had more than 3 prior lines, with 3 of them achieving PR. Conclusions: VEN in combination with bortezomib and dexamethasone has an acceptable safety profile in patients with R/R MM. Efficacy results, including 68% ORR in all patients and 94% ORR in patients not refractory to bortezomib and who received 1 - 3 prior lines of therapy, indicates promising efficacy of this novel combination and supports the ongoing Phase 3 trial with this regimen in patients with R/R MM. Figure. Figure. Disclosures Moreau: Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Roberts:Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; AbbVie: Research Funding; Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding. Agarwal:AbbVie: Honoraria, Research Funding; Millennium: Consultancy; Amgen: Consultancy; Janssen: Speakers Bureau; Onyx: Speakers Bureau; Celgene: Speakers Bureau. Facon:Amgen: Consultancy, Speakers Bureau; Millenium/Takeda: Consultancy; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Kumar:Glycomimetics: Consultancy; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; BMS: Consultancy; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Kesios: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding. Touzeau:AbbVie: Research Funding. Cordero:AbbVie: Employment. Ross:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment. Jia:AbbVie: Employment. Salem:AbbVie: Employment. Leverson:AbbVie: Employment, Other: Shareholder in AbbVie. Maciag:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Harrison:Janssen Cilag: Research Funding, Speakers Bureau; AbbVie: Research Funding.

Abstract Introduction Lenalidomide-based therapies are a standard of care for patients with newly diagnosed, transplant-ineligible MM. Daratumumab (DARA) is a human, CD38-targeted, IgG1κ monoclonal antibody which has single-agent activity in heavily pretreated MM patients. As previously reported in 3 phase 3 studies, the addition of DARA to standards of care in both relapsed refractory (D-Rd, DARA plus bortezomib and dexamethasone [D-Vd]) or transplant-ineligible NDMM (DARA plus bortezomib, melphalan, and prednisone [D-VMP]) resulted in a ≥50% reduction in the risk of disease progression or death (Palumbo A, et al. N Engl J Med 2016;375:754-766; Dimopoulos MA, et al. N Engl J Med 2016;375:1319-1331; Mateos MV, et al. N Engl J Med 2018;378:518-528). Of these, the POLLUX study with D-Rd showed the greatest benefit with a 63% reduction in risk of disease progression or death in patients with MM who had at least one prior line of therapy. Based on the efficacy and tolerable safety profile of D-Rd, we conducted a phase 3 study (MAIA) to evaluate D-Rd vs Rd in transplant-ineligible NDMM. Here we report the prespecified interim analysis of the MAIA study. Methods Patients ineligible for high-dose chemotherapy with autologous stem cell transplantation due to age ≥65 years or comorbidities were randomized 1:1 to Rd ± DARA. Stratification was based on International Staging System stage (ISS [I, II, III]), region (North America vs other), and age (<75 vs ≥75 years). All patients received 28-day cycles of treatment with Rd ± DARA. R: 25 mg (oral) QD on Days 1-21; d: 40 mg (oral) on Days 1, 8, 15 and 22. In the D-Rd arm, DARA was given at 16 mg/kg (intravenously) QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter. In both arms, patients were treated until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), minimal residual disease (MRD)-negativity rate (10-5 sensitivity, clonoSEQ® version 2.0), and safety. Results This international study randomized 737 patients (368 to D-Rd; 369 to Rd) from 14 countries. Key baseline characteristics were well balanced between the two arms. The median (range) age was 73 (45-90) years with 44% of patients ≥75 years, and 52% were male. Two thirds of patients had ECOG scores ≥1: ECOG score 0, 34%; 1, 50%; ≥2, 17%. Overall, 27%, 43%, and 29% were ISS stage I, II, and III, respectively. Of 642 patients evaluable for FISH/karyotyping analysis, 86% and 14% were standard and high cytogenetic risk, respectively. The prespecified interim analysis occurred after 239 PFS events on 24 September 2018 with a median follow up of 28 months. For the primary endpoint, the hazard ratio was 0.55 (95% CI, 0.43 to 0.72; P <0.0001), representing a 45% reduction in the risk of progression or death in patients treated with D-Rd (Figure). The median PFS for the Rd arm was 31.9 months and not reached for the D-Rd arm. Adding DARA to Rd resulted in deeper responses with a complete response (CR) or better rate of 47.6% in the D-Rd arm compared with 24.7% in the Rd arm (odds ratio [OR] 2.75, 95% CI, 2.01 to 3.76; P <0.0001). The very good partial response (VGPR) or better rate was 79.3% in the D-Rd arm compared with 53.1% in the Rd arm (OR 3.4, 95% CI, 2.45 to 4.72; P <0.0001). A total of 19% of patients have died and the HR for OS was 0.78 (95% CI, 0.56 to 1.1); follow-up is ongoing. Higher rates (5% or more difference) of grade 3/4 pneumonia, neutropenia, and leukopenia were observed in the D-Rd arm. The safety profile is consistent with previously reported DARA studies. The complete topline data set will be presented with additional efficacy endpoints, including MRD negativity rate. Conclusion The addition of DARA to Rd in patients with transplant-ineligible NDMM significantly reduced the risk of progression or death by 45%. There are no new safety signals using DARA plus Rd in NDMM. These data together with the phase 3 ALCYONE study (D-VMP vs VMP) support the addition of DARA to standard of care combinations in patients with NDMM ineligible for transplant. Disclosures Facon: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner:Celgene: Other: Independent Response Assessment Comittee; Janssen: Consultancy. Orlowski:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioTheryX: Research Funding; Spectrum Pharma: Research Funding. Moreau:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bahlis:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hulin:Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Research Funding. Goldschmidt:Adaptive Biotechnology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; ArtTempi: Honoraria. O'Dwyer:Janssen: Consultancy. Perrot:Janssen: Consultancy, Equity Ownership, Honoraria. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Weisel:Celgene: Consultancy; Angeb: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding; Bristol Myers SquibbMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Ahmadi:Genmab: Employment, Equity Ownership. Chiu:Janssen Research & Development, LLC: Employment, Equity Ownership. Wang:Janssen Research & Development, LLC: Employment. Van Rampelbergh:Janssen: Employment. Uhlar:Janssen: Employment. Kobos:Janssen Research & Development: Employment. Qi:Janssen Research & Development, LLC: Employment. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding.

Background:Carfilzomib (CFZ) combined with dexamethasone is approved to treat patients (pts) with relapsed and/or refractory multiple myeloma (RRMM), with CFZ given once‐weekly at 70 mg/m2 (Kd70 QW) or twice‐weekly at 56 mg/m2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW.Aims:We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION‐1 trials.Methods:Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION‐1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION‐1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW.Results:Among BTZ non‐refractory pts with 2–3 lines of prior therapy, median progression‐free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well‐tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69).Summary/Conclusion:This post hoc analysis suggests that once‐weekly Kd70 has a comparable benefit‐risk profile to twice‐weekly Kd56.© 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO Annual Meeting. All rights reserved.

Background:MAIA, an ongoing phase 3 trial of transplant‐ineligible patients with NDMM, demonstrated significant improvement in progression‐free survival with D‐Rd vs Rd alone. Assessment of patient‐reported outcomes (PRO) alongside efficacy endpoints provides patient perspective on their quality of survival and overall value of health‐related quality of life (HRQoL) while on treatments.Aims:To utilize PRO assessments as a tool in capturing the patient perspective on quality of survival and HRQoL changes in MAIA.Methods:The EORTC QLQ‐C30 and EQ‐5D‐5L questionnaires were completed by patients using an electronic device at baseline and every 3 months during treatment; interim results are presented for first 12 months. Treatment effects were assessed using repeated measures, mixed effects models and thresholds for clinically meaningful benefit were based on established criterion from the literature.Results:Compliance rates in completing the assessment tools were high and comparable at baseline (>90%) and through month 12 (>80%) for both groups (D‐Rd [n = 368]; Rd [n = 369]). Improvement in Global Health Status (GHS) occurred in both groups; however, for D‐Rd, significantly greater improvement was observed at cycle 3 (LS mean change; D‐Rd: 4.5 [95% CI: 2.4, 6.6], Rd: 1.5 [95% CI: −0.7, 3.7]; [p = 0.0454]) and increasing improvement occurred across all time points. Significant improvement and clinically meaningful benefit in HRQoL for D‐Rd was also observed in EQ‐5D‐5L Visual Analog Scale (VAS) scores (LS mean change; D‐Rd: 10.1 [95% CI: 8.1, 12.1], Rd: 4.9 [95% CI: 2.8, 7.0]; [p = 0.0002]). The VAS median time to worsening was 10 mo longer for D‐Rd. Of note, meaningful differences were observed between the treatment groups in two subscale scores, pain symptoms and cognitive functioning. Statistically significant less pain was reported early with D‐Rd (LS mean change at cycle 3; D‐Rd: −17.9 [95% CI: −20.7, −15.0], Rd: −11.0 [95% CI: −14.0, −8.1]; [p = 0.0007]); clinically meaningful reduction in pain symptoms was sustained with D‐Rd. There was a decline in cognitive functioning through Cycle 12 in both treatment arms with the peak difference occurring at Cycle 9, but mean differences between groups were not statistically significant.Summary/Conclusion:Faster and sustained improvement in patients treated with D‐Rd was observed using HRQoL assessments compared with Rd, with similar findings reflected across the pain subscale.

Background:The pivotal FIRST trial, the largest study conducted in transplant‐ineligible (TNE) patients (pts) with newly diagnosed multiple myeloma (NDMM), examined lenalidomide plus low‐dose dexamethasone until disease progression (Rd continuous), Rd for 18 cycles (Rd18), and melphalan, prednisone, and thalidomide (MPT). The study, conducted in 18 countries in Europe, North America, and Asia Pacific, demonstrated that Rd continuous significantly improved progression‐free survival (PFS) vs MPT (median 26.0 vs 21.9 mos; HR, 0.69; 95% CI, 0.59‐0.79; P < .00001). PFS was similarly extended for Rd continuous vs Rd18 (median 21.0 mos; HR, 0.70; 95% CI, 0.60‐0.81). Furthermore, median overall survival (OS) was significantly longer with Rd continuous vs MPT (median 59.1 vs 49.1 mos; HR, 0.78; 95% CI, 0.67‐0.92; P = .0023). These results support the use of frontline oral, alkylator‐free continuous therapy for TNE NDMM pts and established Rd continuous as a standard of care as reflected by clinical guidelines in Canada, the US, and Europe.Aims:To report outcomes in the subset of patients from Canada and the US.MethodsPts with TNE NDMM were randomized 1:1:1 to Rd continuous (with lenalidomide given on days 1‐21 of 28‐day cycles until disease progression), Rd18 (with lenalidomide given on days 1‐21 of eighteen 28‐day cycles), or MPT (twelve 42‐day cycles). Rd18 and MPT were both 72 weeks in duration. Stratification factors included country and Rd continuous vs MPT was the primary comparison. The primary endpoint was PFS and secondary endpoints included OS, time to next therapy (TTNT) and safety. Time from randomization to second progression or death (PFS2) was an exploratory analysis. Response assessment used for PFS and PFS2 analysis was determined by investigators based on International Myeloma Working Group criteria. Data is presented as of the January 21, 2016 cutoff used for the final OS analysis.Results:A total of 312 pts from Canada (n = 252) and the US (n = 60) were enrolled (104 in each arm). Consistent with results from the intent‐to‐treat (ITT) analysis, the Canada/US subgroup also demonstrated a significant improvement in PFS with Rd continuous vs MPT (median 29.3 vs 20.2 mos; HR, 0.69; 95% CI, 0.49‐0.97; P = .03326) and an improvement vs Rd18 (median 21.9 mos; HR, 0.72; 95% CI, 0.51‐1.02; Table). Median OS was 56.9 vs 46.8 mos for Rd continuous vs MPT (HR, 0.77; 95% CI, 0.53‐1.11; P = .15346). Median PFS2 was longer for Rd continuous vs MPT (median 39.3 vs 35.1 mos; HR, 0.69; 95% CI 0.50‐0.95) as was TTNT (median 39.1 vs 24.6 mos; HR, 0.54; 95% CI, 0.37‐0.78). Additional details, including safety data, will be presented at the meeting.Summary/Conclusion:In the Canada/US subpopulation of pts from FIRST, Rd continuous extended median PFS by 9 mos vs MPT and > 7 mos vs Rd18. Rd continuous also delayed median TTNT > 14 mos and resulted in a longer PFS2 vs MPT, suggesting that the benefit from frontline Rd continuous is maintained at relapse. These results are consistent with that from the ITT population confirming the advantage of Rd continuous vs MPT in the Canada/US subgroup and supporting the role of Rd continuous as a standard of care for TNE pts with NDMM. The efficacy observed with Rd continuous raises the question on the role of immunostimulatory effects by the immunomodulatory agents in NDMM.image