Bahlis, Nizar Jacques

8044 Background: In the phase 3 MAIA study, adding DARA to Rd improved progression-free survival (primary endpoint), overall survival, duration of response, and PROs in transplant-ineligible pts with NDMM. We report a MAIA subgroup analysis of time to response, duration of response, and PROs. Methods: Transplant-ineligible pts with NDMM received 28-day cycles of Rd (R 25 mg PO on Days 1-21; d 40 mg PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter) until disease progression or unacceptable toxicity. Secondary endpoints included time to response and duration of response. PROs were measured using the EORTC QLQ-C30, with treatment effects assessed via mixed-effects model with repeated measures. Results: In total, 368 pts were assigned to the D-Rd group and 369 pts to the Rd group; 162 (44%) D-Rd pts and 142 (38%) Rd pts had renal impairment (defined as baseline CrCl ≤60 mL/min). At a 56.2-mo median follow-up, median times to very good partial response or better (≥VGPR) and complete response or better (≥CR) were shorter with D-Rd vs Rd in the overall study population and in the subgroups of pts with and without renal impairment (Table). Among pts who achieved ≥CR or partial response or better (≥PR), higher proportions of D-Rd vs Rd pts had not experienced disease progression at 48 mo (Table). Among pts with renal impairment, greater improvements from baseline in pt-reported pain, fatigue, and nausea and vomiting symptom scores were observed with D-Rd vs Rd across most timepoints; a notably greater meaningful reduction in pain symptom score was seen with D-Rd vs Rd as early as Cycle 6 Day 1 (least squares mean change from baseline, −14.9 vs −7.0; P=0.0241). Analyses for additional pt subgroups will be presented. Conclusions: In transplant-ineligible pts with NDMM, D-Rd showed more rapid deep responses as well as more durable responses vs Rd, regardless of renal function. Improvements in pt-reported symptoms were generally greater with D-Rd vs Rd in pts with renal impairment. Our results support the use of D-Rd in transplant-ineligible pts with NDMM. Clinical trial information: NCT02252172. [Table: see text]

Abstract Introduction: Multiple myeloma (MM) is a chronic hematologic malignancy with a high symptom burden that can have a substantial negative impact on patients' (pts) health-related quality of life (HRQoL). The introduction of novel triplet regimens for newly diagnosed MM (NDMM) has extended progression-free survival (PFS) and overall survival (OS); however, adverse events and demanding administration and monitoring schedules have a further negative effect on HRQoL, especially among pts who are transplant ineligible (TIE) due to older age and/or frailty. Optimizing initial treatment is particularly important in older pts, many of whom receive only 1 line of therapy. The phase 3 MAIA trial compared daratumumab, lenalidomide, and dexamethasone (D-Rd) vs lenalidomide and dexamethasone (Rd) in TIE pts with NDMM. At a median follow-up of 28 months, D-Rd significantly prolonged PFS and was associated with faster and sustained clinically meaningful improvements in patient-reported outcomes (PROs) vs Rd. Results of an updated analysis with longer follow-up recently confirmed a significant benefit in OS with D-Rd vs Rd as well as a continued significant PFS benefit and higher rates of complete response or better and very good partial response or better. Here we present an update of the HRQoL analysis with additional follow-up. Methods: MAIA (NCT02252172) is a randomized, open-label, active controlled, multicenter, phase 3 study of TIE pts with NDMM who were randomly assigned 1:1 to receive D-Rd or Rd until disease progression (PD) or unacceptable toxicity. PROs were recorded using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EQ-5D-5L visual analog scale. EORTC QLQ-C30 has 30 items comprising 5 functional scales (physical, role, emotional, cognitive, and social functioning), 1 global health status (GHS) scale, 3 symptom scales (fatigue, nausea and vomiting, and pain) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Questionnaires were completed at baseline, on day 1 of cycles 3, 6, 9, and 12 for year 1, and every 6 months thereafter until PD. Analyses were conducted on all pts with a baseline and ≥1 post-baseline PRO assessment. Pts were censored at PD or discontinuation of study treatment. Thresholds for meaningful improvement and worsening were defined a priori based on published literature (≥10-point change). Treatment effect was analyzed using a mixed-effects model for repeated measurements including baseline value, visit, treatment, visit by treatment interaction, and randomization stratification factors as fixed effects and individual subject as random effect. Results: At a median follow-up of 56.2 months, discontinuation rates were lower with D-Rd than Rd (56.8% vs 80.8%). For GHS, physical functioning, fatigue, pain, and dyspnea, PROs that are particularly relevant to pts with MM, a numerically greater proportion of pts achieved a meaningful improvement with D-Rd vs Rd (Table 1). Differences were significant for physical functioning, fatigue, and dyspnea. The proportion of pts achieving a meaningful worsening on therapy was similar in both treatment groups (Table 1). The median time to improvement was numerically shorter with D-Rd vs Rd for physical functioning and pain and with Rd vs D-Rd for GHS and fatigue; differences were not significant (Table 2). The median time to worsening of fatigue was similar between groups, numerically longer for D-Rd vs Rd for GHS, and significantly longer with D-Rd than Rd for physical functioning, pain, and dyspnea (Table 2). Median time to worsening of pain with D-Rd vs Rd was 39.43 vs 17.97 months, reflective of an additional ~21 months without worsening pain among pts treated with D-Rd. Between-group differences for least squares mean change from baseline for these 5 PROs favored D-Rd vs Rd at all assessment time points except cycle 3 for physical functioning and cycle 6 for fatigue; differences were significant at ≥1 timepoint for each scale. Conclusions: These updated PRO analyses from the MAIA study demonstrate sustained and clinically meaningful improvements in HRQoL with D-Rd vs Rd with almost 5 years of follow-up. These results are consistent with the clinical benefits of superior PFS, OS, and deep responses observed with D-Rd compared with Rd and support the use of D-Rd in older pts. Figure 1 Figure 1. Disclosures Perrot: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kumar: Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Bluebird Bio: Consultancy; Tenebio: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Beigene: Consultancy; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner: Takeda: Research Funding; Oncopeptides: Other: Advisor, Research Funding; Genentech: Other: Advisor, Research Funding; CSL Behring: Other: Advisor; AbbVie: Other: Advisor, Research Funding; Celgene: Other: Advisor, Research Funding; Janssen: Other: Advisor, Research Funding; Genmab: Research Funding. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Moreau: Oncopeptides: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Celgene BMS: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Bahlis: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Nahi: XNK Therapeutics AB: Consultancy. Hulin: Takeda: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; abbvie: Honoraria. Quach: CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, 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; Karyopharm: 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; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Goldschmidt: Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant; Molecular Partners: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; GSK: Honoraria; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. O'Dwyer: ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Bristol Myers Squibb: Research Funding. Venner: BMS: Honoraria; Amgen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Weisel: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, 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; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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, Research Funding; Roche: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Macro: Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; Celgen/BMS: Honoraria. Leleu: Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria. Liu: Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau: Janssen: Current Employment, Current equity holder in publicly-traded company. Gries: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Ho: DRG Abacus: Consultancy; Janssen: Consultancy; Emalex Biosciences: Consultancy. Mistry: Janssen: Current Employment, Current equity holder in publicly-traded company. Tromp: Janssen: Current Employment, Current equity holder in publicly-traded company. Delioukina: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Usmani: Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau.

Abstract Introduction: The phase 3 MAIA study (NCT02252172) evaluated the addition of daratumumab (D) to lenalidomide and dexamethasone (Rd) in patients (pts) with transplant-ineligible newly diagnosed multiple myeloma (NDMM). At a median follow-up of 56.2 months, D-Rd prolonged progression-free survival (PFS) and overall survival (OS) versus Rd alone, despite almost half of the pts in the Rd arm who received subsequent therapy receiving a daratumumab-containing regimen as any subsequent line of therapy (Facon T, et al. Presented at: European Hematology Association 2021 Virtual Congress. Abstract LB1901). Approximately 20% to 50% of pts with MM have baseline renal impairment that can affect the choice and efficacy of therapy (Dimopoulos MA, et al. Journal of Clinical Oncology. 2016;34[13]:1544-1557). Here, we report results from MAIA for D-Rd vs Rd in pts with impaired renal function based on lenalidomide starting dose at a median follow-up of 56.2 months. Methods: Pts with NDMM ineligible for high-dose chemotherapy and autologous stem-cell transplantation due to age ≥65 years or comorbidities were randomized 1:1 to receive D-Rd or Rd. Pts in both arms received 28-day cycles of oral Rd (R: 25 mg [10 mg recommended if creatinine clearance (CrCl) was 30-50 mL/min] on Days 1-21; d: 40 mg [20 mg if aged >75 years or body-mass index <18.5 kg/m 2] on Days 1, 8, 15, 22). Pts in the D-Rd arm also received intravenous D (16 mg/kg once weekly for Cycles 1-2, once every 2 weeks for Cycles 3-6, and once every 4 weeks thereafter). Pts in both arms were treated until disease progression or unacceptable safety events. The primary endpoint was PFS, and a secondary endpoint was OS. Renal impairment was defined as a baseline CrCl of ≤60 mL/min. Results: 737 pts were randomized (D-Rd, n=368; Rd, n=369); 162 (44%) pts in the D-Rd arm and 142 (38%) pts in the Rd arm had renal impairment as defined. At a median follow-up of 56.2 months, in pts with renal impairment who received a lenalidomide starting dose of 25 mg (25 mg subgroup; D-Rd, n=60 [37%]; Rd, n=62 [44%]), a PFS and OS advantage was observed with D-Rd versus Rd (Table). In pts with renal impairment who received a lenalidomide starting dose of <25 mg (<25 mg subgroup; D-Rd, n=98 [60%]; Rd, n=75 [53%]), median PFS and OS were prolonged with D-Rd versus Rd (Table). Among pts in the 25 mg subgroup who died (D-Rd, n=12; Rd, n=29), disease progression was the primary cause of death in 6 (50%) pts in the D-Rd arm and 10 (34%) pts in the Rd arm. Among pts in the <25 mg subgroup who died (D-Rd, n=44; Rd, n=37), disease progression was the primary cause of death in 16 (36%) pts in the D-Rd arm and 11 (30%) pts in the Rd arm. Conclusion: After ~5 years of follow-up, D-Rd showed a PFS improvement versus Rd in transplant-ineligible pts with NDMM and renal impairment regardless of lenalidomide starting dose. An OS advantage for D-Rd versus Rd was observed in pts with renal impairment who received a lenalidomide starting dose of 25 mg; in pts with renal impairment who received a lenalidomide starting dose of <25 mg, median OS was prolonged for D-Rd versus Rd, but the OS benefit was less pronounced. Overall, among pts with renal impairment, PFS and OS benefits of D-Rd versus Rd were observed regardless of lenalidomide starting dose; however, dose recommendations per the lenalidomide prescribing information should be followed. Many transplant-ineligible pts with NDMM may not receive a second line of therapy; our results support the frontline use of D-Rd to provide prolonged disease control in transplant-ineligible pts with NDMM and renal impairment. Figure 1 Figure 1. Disclosures Usmani: Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau. Kumar: Novartis: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Antengene: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Oncopeptides: Consultancy; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Plesner: CSL Behring: Other: Advisor; Genentech: Other: Advisor, Research Funding; Oncopeptides: Other: Advisor, Research Funding; Takeda: Research Funding; Celgene: Other: Advisor, Research Funding; AbbVie: Other: Advisor, Research Funding; Janssen: Other: Advisor, Research Funding; Genmab: Research Funding. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Bahlis: Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Genentech: Consultancy; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Nahi: XNK Therapeutics AB: Consultancy. Hulin: Janssen: Honoraria; Celgene/BMS: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; abbvie: Honoraria. Quach: GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, 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; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: 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. Goldschmidt: Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Mundipharma: Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; Johns Hopkins University: Other: Grant; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; GSK: Honoraria; Incyte: Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. O'Dwyer: ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Janssen: Consultancy. Perrot: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; GSK: 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; BMS Celgene: 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; Abbvie: Honoraria. Venner: Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Research Funding; Pfizer: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Amgen: Research Funding. Weisel: Novartis: Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Roche: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Macro: Janssen: Honoraria, Other: Travel accomodation, Research Funding; GSK: Honoraria; Sanofi: Honoraria; Celgen/BMS: Honoraria; Takeda: Honoraria, Other: Travel accomodation, Research Funding. Leleu: Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Pei: Janssen: Current Employment, Current equity holder in publicly-traded company. Van Rampelbergh: Janssen: Current Employment. Tromp: Janssen: Current Employment, Current equity holder in publicly-traded company. Delioukina: Janssen: Current Employment.

Abstract Multiple myeloma (MM) is an incurable form of plasma cell cancer in which primary and secondary chromosomal translocations routinely juxtapose oncogenes to plasma cell-specific super-enhancers. Coincidentally, drugs which target super-enhancers have had success clinically. For example, immunomodulatory imide drugs (IMiDs) degrade super-enhancer-binding pioneer factors IKAROS and AIOLOS, while glucocorticoids (Dexamethasone) and proteasome inhibitors (Bortezomib) have the ability to transrepress or block the processing of super-enhancer-forming NF-κB proteins, respectively. Currently, alternative enhancer-targeting drugs are also in clinical development, like p300 inhibitors which target the acetyl-binding bromodomains and/or histone acetyl transferase activity of the chromatin-regulating coactivator homologs CBP and EP300. Despite showing therapeutic promise, our understanding of how these drugs function, alone or together, remains incomplete. Case in point, we find that IMiD-induced degradation of its target proteins IKAROS and AIOLOS does not guarantee a therapeutic response in vitro, and patients successfully treated with IMiDs eventually relapse; meanwhile, coactivator-targeting therapies like p300 inhibitors are often too toxic in vivo, and lack a therapeutic window. To improve the outcomes of MM patients we need to understand the heterogeneous genetics and transcription-factor milieus of the myeloma enhancer landscape, as well as how to increase the precision of enhancer-disrupting drugs. To accomplish this, our lab utilizes more than 60 human myeloma cell lines that have been extensively characterized at the genetic, proteomic, and drug-therapeutic-response levels. Additionally, we have generated a highly-predictive immunocompetent mouse model (Vk*MYC hCRBN+) that develops human-like MM and is sensitive to both IMiDs and a new class of therapeutics termed "degronimids" (normal mice do not respond to IMiDs or degronimids). Our central hypothesis is that combining a broad coactivator-targeting drug (e.g., the p300 inhibitor GNE-781), with a MM-specific transcription factor-targeting drug (e.g., IMiDs) restricts toxicities to myeloma cells and thus improves the therapeutic window. Currently, we are testing a variety of coactivator-targeting compounds alongside traditional IMiD therapies and other preclinical transcription factor-targeting drugs both in vivo and in vitro. We show that Vk*MYC hCRBN+ mice are exquisitely sensitive to GNE-781, requiring one fourth of the dose needed to treat other cancers and therefore avoiding the neutropenia and thrombocytopenia seen at higher doses. Second, we show that although IMiDs and GNE-781 induce an effective but transient response in vivo as single agents, the combination of the two drugs proved curative, with a progressive deepening of the anti-tumor response occurring even after therapy is discontinued. Ongoing experiments aim to determine how this drug combination, and other coactivator + transcription factor-targeting combinations, permanently disrupt myeloma-specific super-enhancers. Disclosures Neri: BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Bahlis: Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy. Boise: AstraZeneca: Honoraria, Research Funding; AbbVie/Genentech: Membership on an entity's Board of Directors or advisory committees. Chesi: Abcuro: Patents & Royalties: Genetically engineered mouse model of myeloma; Pi Therapeutics: Patents & Royalties: Genetically engineered mouse model of myeloma; Pfizer: Consultancy; Novartis: Consultancy, Patents & Royalties: human CRBN transgenic mouse; Palleon Pharmaceuticals: Patents & Royalties: Genetically engineered mouse model of myeloma.

Abstract Introduction: Depth of response is associated with long-term outcomes in multiple myeloma (MM); however, the effect of response kinetics on outcomes in NDMM is variable and less clear. Although some studies have shown that achieving a ≥very good partial response (VGPR) at 4 months (mos) from diagnosis is associated with increased overall survival (Garderet Leukemia 2018), other reports have shown worse outcomes in pts with early vs late responses (Yan Blood Adv 2019). The double-blind, randomized TOURMALINE-MM2 (NCT01850524) trial (Facon Blood 2021) showed a clinical meaningful progression-free survival (PFS) benefit with IRd vs pbo-Rd (median 35.3 vs 21.8 mos; hazard ratio, 0.830; 95% confidence interval, 0.676-1.018; P=0.073; median follow-up, 53.3 and 55.8 mos, respectively) in NDMM pts. Safety data were consistent with the established toxicity profile of IRd. We evaluated PFS and duration of response (DOR) by depth of best confirmed response and time to best response in TOURMALINE-MM2. Methods: Pts were randomized to receive oral ixazomib 4 mg (n=351) or placebo (n=354) on days 1, 8, and 15, plus oral lenalidomide 25 mg (10 mg if creatinine clearance ≤60 mL/min) on days 1-21 and oral dexamethasone 40 mg (20 mg in pts aged >75 years) on days 1, 8, 15, and 22 in 28-day cycles. After 18 cycles, treatment was continued without dexamethasone and reduced doses of ixazomib (3 mg) and lenalidomide (10 mg) until progressive disease (PD)/toxicity. Response assessments were performed every cycle until PD, or every 4 weeks in pts who discontinued treatment prior to PD. PFS and DOR were analyzed post-hoc in subgroups defined by depth of response and in subgroups defined by time to best confirmed response; 'early' and 'late' responses were defined by time to best confirmed response of 0-4 and >4 mos, respectively (additional analyses were performed by time to best confirmed response of 0-6 and >6 mos). Pts in either subgroup could have recorded an initial response prior to their best response. PFS and DOR were evaluated from randomization to progression and time of initial response to progression, respectively. To address potential guarantee-time bias in the PFS analysis, and to eliminate potential bias due to transient responses in DOR analysis, sensitivity analyses were conducted in pts with PFS / DOR of ≥6 mos. Results: Among the 705 pts in the intention-to-treat (ITT) population, 20% (26% IRd vs 14% placebo-Rd) had a best confirmed response of complete response (CR) or stringent CR, 35% (37 vs 34%) had VGPR, 26% (19 vs 32%) had PR, 10% (9 vs 10%) had stable disease (SD), 3% (1 vs 4%) had PD. 7% (8 vs 6%) of pts were not evaluable. In a pooled analysis of both arms, achieving a deeper response was associated with longer PFS (Figure, A) and DOR (median not reached [NR], 42.8, and 15.0 mos for pts with ≥CR, VGPR, and PR, respectively). In 570 pts with ≥PR (288 IRd; 282 pbo-Rd), 152 (53%) and 136 (47%) in the IRd arm and 143 (51%) and 139 (49%) pts in the pbo-Rd arm were defined as early (0-4 mos) and late (>4 mos) responders, respectively. For early vs late responders, 46% vs 40% were aged ≥75 years, 21% vs 12% had International Staging System stage III MM, and 44% vs 33% had expanded high-risk cytogenetic abnormalities. Median PFS was prolonged among late vs early responders with IRd (65.7 vs 21.2 mos) and pbo-Rd (62.6 vs 18.2 mos), as was median DOR (IRd, NR vs 22.6 mos; pbo-Rd, 64.1 vs 17.2 mos). The PFS sensitivity analysis among pts with PFS of ≥6 mos confirmed the association of late response with improved outcomes; among late vs early responders achieving ≥PR, median PFS was 65.7 vs 23.9 mos with IRd and 62.6 vs 18.4 mos with pbo-Rd (Figure, B), and among late vs early responders achieving ≥VGPR, median PFS was 65.7 vs 35.3 mos with IRd and 64.4 vs 21.7 with pbo-Rd. Conclusions: Achieving a deeper response was associated with prolonged PFS and DOR in NDMM patients in TOURMALINE-MM2. PFS benefit on the ITT analysis was driven by the higher rates of deep responses (≥VGPR) with IRd vs pbo-Rd. PFS and DOR were also longer in pts achieving a late vs early best confirmed response of ≥PR or ≥VGPR. Consistent with results from a similar analysis in relapsed/refractory MM in the TOURMALINE-MM1 trial (Garderet Leukemia 2018), our findings support the continuation of therapy with the aim of achieving a deeper response over time. Additional sensitivity analyses will be presented. Figure 1 Figure 1. Disclosures Richardson: Sanofi: Consultancy; AstraZeneca: Consultancy; Celgene/BMS: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Oncopeptides: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Venner: Takeda: Honoraria; BMS: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; GSK: Honoraria. Bahlis: GlaxoSmithKline: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Genentech: Consultancy; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. White: Amgen: Consultancy, Honoraria; Antengene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Forus: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Karlin: Celgene-BMS: Honoraria, Other: member of advisory board; Sanofi: Honoraria; oncopeptide: Honoraria; Janssen: Honoraria, Other: member of advisory board, travel support; Abbvie: Honoraria; GSK: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Takeda: Honoraria, Other: member of advisory board. Rigaudeau: Takeda: Membership on an entity's Board of Directors or advisory committees. Suzuki: Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; ONO: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Abie: Honoraria; Janssen: Consultancy, Honoraria. Shibayama: Mundi Pharma: Honoraria; Otsuka: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Nippon Shinyaku: Honoraria; Fujimoto: Honoraria; Daiichi Sankyo: Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Essentia Pharma Japan: Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Avvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Research Funding. Zhang: Takeda: Current Employment. Kumar: Takeda: Current Employment, Current holder of stock options in a privately-held company. Twumasi-Ankrah: Takeda: Current Employment. Labotka: Takeda: Current Employment. Rifkin: Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Coherus: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Lonial: AMGEN: Consultancy, Honoraria; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria. Kumar: Antengene: Consultancy, Honoraria; Carsgen: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Moreau: Amgen: Honoraria; Oncopeptides: Honoraria; Janssen: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib in newly diagnosed multiple myeloma patients who are ineligible for transplant.

Abstract Introduction: In oncology clinical trials, overall survival (OS) is considered the gold standard efficacy endpoint. However, in multiple myeloma, the prolonged survival times and availability of multiple salvage therapies render it difficult to rely on OS as a primary endpoint. Instead, progression-free survival (PFS) or clinical response can be a relevant biomarker. At the same time, some health technology assessment bodies will only consider evidence based on patient-relevant endpoints, such as morbidity, mortality, and health-related quality of life (HRQoL), within their benefit assessments. Patient-reported outcomes (PROs) provide insights into how a treatment affects HRQoL, including symptoms and functioning. In the phase 3 MAIA trial, daratumumab, lenalidomide, and dexamethasone (D-Rd) demonstrated a significantly prolonged PFS and rapid and sustained improvements in PROs compared with lenalidomide and dexamethasone (Rd) alone at a median follow-up of 28 months. Updated results with longer follow-up confirmed a continued PFS benefit, deepening best clinical responses, and a significant OS benefit with D-Rd. Here, we report the results of analyses exploring the relationship between clinical efficacy endpoints and PROs in the MAIA trial. Methods: In MAIA (NCT02252172), TIE patients with NDMM were randomized to D-Rd or Rd until disease progression (PD) or unacceptable side effects. Clinical response and PD were defined per the International Myeloma Working Group uniform response criteria. PROs were assessed at baseline, on day 1 of cycles 3, 6, 9, and 12 for year 1, every 6 months thereafter until PD, or at end of treatment and at 8 and 16 weeks post-progression using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30). The current analyses were conducted on patients with a baseline PRO assessment and ≥1 post-baseline PRO assessment using a clinical cutoff date of February 19, 2021. Patients from both treatment groups were pooled and stratified by best clinical response. For PROs, the threshold for clinically meaningful change from baseline was defined a priori as ≥10 points based on published literature. Analyses were conducted for the global health status (GHS), fatigue, and pain scales of the EORTC QLQ-C30. The proportions of patients with clinically meaningful improvement in these PROs from baseline at any time while on treatment were calculated for and compared across best clinical response subgroups. For this analysis, patients were censored at the time of PD or discontinuation of therapy. Results were summarized with odds ratios and 95% confidence intervals. Additionally, the proportions of patients with clinically meaningful worsening in PROs from baseline at the time of and post-progression were also calculated for those who had PD. No adjustments were made for multiplicity. Nominal P-values are presented. Results: Best clinical response at a median follow-up of 56.2 months for the 710 patients included in this analysis is shown in the Table. For GHS, fatigue, and pain, the proportion of patients who reported clinically meaningful improvement from baseline increased with increasing depth of best clinical response. Odds ratios comparing best clinical response vs stable disease reflect this relationship and are shown in the Figure. Of the 264 patients who experienced PD and had PRO data at the time of or post-progression, 38.6%, 54.9%, and 39.4% reported meaningful worsening of GHS, pain, and fatigue, respectively, at the time of or post-progression. Conclusions: Patients with deeper best clinical response were more likely to report meaningful improvements in PROs. Patients who experienced PD reported worsening of GHS and symptoms at the time of or following progression. These analyses provide evidence of the association between key clinical efficacy endpoints and PROs and demonstrate the patient relevance of these clinical endpoints. Figure 1 Figure 1. Disclosures Perrot: Abbvie: Honoraria; BMS Celgene: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kumar: Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; Takeda: Consultancy, 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; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Plesner: Takeda: Research Funding; Genentech: Other: Advisor, Research Funding; Oncopeptides: Other: Advisor, Research Funding; AbbVie: Other: Advisor, Research Funding; CSL Behring: Other: Advisor; Janssen: Other: Advisor, Research Funding; Celgene: Other: Advisor, Research Funding; Genmab: Research Funding. Orlowski: Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Moreau: Abbvie: Honoraria; Oncopeptides: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Bahlis: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Honoraria. Nahi: XNK Therapeutics AB: Consultancy. Hulin: abbvie: Honoraria; Celgene/BMS: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Quach: Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, 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; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldschmidt: GSK: Honoraria; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; Johns Hopkins University: Other: Grant; Mundipharma: Research Funding; MSD: Research Funding; Molecular Partners: Research Funding. O'Dwyer: Bristol Myers Squibb: Research Funding; ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Venner: Amgen: Research Funding; Celgene: Research Funding; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; BMS: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: 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, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Macro: Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; GSK: Honoraria; Celgen/BMS: Honoraria; Sanofi: Honoraria. Leleu: Sanofi: Honoraria; Roche: Honoraria; Pierre Fabre: Honoraria; Oncopeptides: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Liu: Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau: Janssen: Current Employment, Current equity holder in publicly-traded company. Gries: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Ho: DRG Abacus: Consultancy; Emalex Biosciences: Consultancy; Janssen: Consultancy. Mistry: Janssen: Current Employment, Current equity holder in publicly-traded company. Tromp: Janssen: Current Employment, Current equity holder in publicly-traded company. Delioukina: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Usmani: Amgen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; SkylineDX: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding.

Abstract We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10−5 sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172.

Abstract In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10−5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE).

PURPOSE The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS). PATIENTS AND METHODS Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 v 2 or 3), previous proteasome inhibitor (PI) exposure (yes v no), and International Staging System disease stage (I or II v III). OS (intent-to-treat population) was a key secondary end point. RESULTS With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; P = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% v 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns. CONCLUSION Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.

Abstract Background: Immunoglobulin (IGH, IGL, IGK) and non-immunoglobulin (PVT1, TXNDC5, FAM46C, DUSP22, etc.) enhancers hijacking by variable genes (MYC, MAF, MAFB, CCND1/2/3, MMSET, IRF4) is a recognized oncogenic driver event in MM. However, the identity of the transcription factors (TFs) or transcriptional regulatory complexes binding and regulating the activity of these enhancers remains to be fully elucidated and may yield valuable therapeutic targets. As such the discovery of the BET family member BRD4 as the master histone acetyl mark reader at enhancers loci regulating MYC lead to promising therapeutic developments in MM and numerous other cancers. Immunomodulatory drugs (IMiDs) promote the proteasomal degradation of IKAROS (IKZF1) and AIOLOs (IKZF3) leading to the transcriptional repression of MYC and the suppression of MM cells survival and proliferation. However, acquired resistance to IMIDs and the loss of the transcriptional repression of MYC are nearly universal and occur in spite of sustained IKZF1/3 degradation suggesting that transcriptional rewiring may be sustaining hijacked enhancers activity and transcription of driver oncogenes. Methods and Results: In order to define how IMiDs repress MYC transcription, we first defined IKZF1, BRD4, the lysine acetyl transferase P300 and the mediator complex subunit MED1 mapping within the MM genome using ChIPseq. In MM cell lines (MM1S, RPMI8226, ARP1 and AMO1), IKZF1 predominantly mapped to intronic and intergenic loci which are typically enriched with enhancer and superenhancer elements. Indeed, IKZF1 mapping to the genome nearly completely (96.5%) overlapped that of P300, MED1 and BRD4 co-occupied enhancer and superenhancer loci. We also confirmed that in the MM1S sensitive cell lines IMiDs (lenalidomide 10 μM, 24h) exposure efficiently depleted IKZF1, BRD4, P300 and MED1 at enhancer loci with ensuing MYC (and MAF) downregulation. In contrast, in resistant cell lines (RPMI8226) and in spite efficient IKZF1 displacement, BRD4, P300 and MED1 were retained at the oncogenic enhancer (IGLL5) driving MYC (and MAF). These findings lead us to postulate that in IMiDs resistant cells retention of BRD4 and MED1 at oncogenic enhancers in the absence of IKZF1 likely results from rewiring of the TFs regulating MYC. To identify TFs that may co-localize with BRD4 and IKZF1, we analyzed the enrichment of DNA motifs at IKZF1and BRD4 co-occupied enhancers using the MEME suite motif-finding algorithms. This computational analysis revealed a strong enrichment at these MM enhancers of the GGAA motif recognized by the ETS family of TFs (P= 3.2 e-743) and other motifs boxes for the RUNX (P= 9.6 e-725), MYC/MYB ( P= 8.8 e-52) and interferon regulatory (IRF) (P= 3.1 e-293) TFs. We next confirmed that the ETS family TF ETV4 was indeed expressed in IMiDs resistant, but not sensitive, MM cell lines. ChiPseq occupancy profiles in IMiDs resistant RPMI8226 cell line revealed co-localization of ETV4 with IKZF1, P300 and BRD4. As predicted, lenalidomide treatment induced global depletion of IKZF1 but not ETV4 at BRD4 occupied enhancers in resistant cell lines (RPMI8226 and ARP1). Importantly, Cas9-mediated knock out of ETV4 in RPMI8226 cells sensitized them to lenalidomide with ensuing MYC downregulation and cell death. Confirming its role in MM, ETV4 transcript was indeed detectable in primary patients' samples in the CoMMpass data repository (ETV4 FPKM >1.0 in 112/724) and its expression was associated with significantly reduced survival outcomes (HR 0.64; P=0.0008). Similarly, high expression (top quartiles) of RUNX2 or MYB, TFs with enriched motifs at IKZF1 co-occupied enhancer loci, was also associated with decreased survival. Of note RNAseq analysis of paired patient samples pre- and post-IMiDs treatment (n=14 pairs) revealed significant upregulation of ETV4 at the time of acquired IMiDs resistance (7/14). Lastly transcriptome analysis of 101 patients enrolled in the RD arm (lenalidomide and dexamethasone) of the POLLUX trial (NCT02076009) confirmed the reduced survival of patients with top quartiles expression of ETV4 as well as MYB and RUNX2 (Fig.1) Conclusion: Transcriptional plasticity with expression of extra-lineage TFs such as the ETS family member ETV4 sustains oncogenic enhancers in MM overcoming IKAROS and AIOLOS dependency and promoting IMiDs resistance. Figure 1 Figure 1. Disclosures Neri: Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Soong: Jannsen: Employment. Chiu: Janssen: Employment. Bahlis: Takeda: 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, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.