Citations

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).

Objectives Betaine‐homocysteine methyltransferase (BHMT) catalyzes the remethylation of homocysteine. BHMT in the human liver is responsible for up to 25% of homocysteine metabolism. Knowledge of the relationship between genetic polymorphisms and BHMT phenotypes could enhance our understanding of the role of this reaction in drug metabolism. Methods Levels of BHMT enzyme activity and immunoreactive protein were measured in 268 human liver biopsies. Twelve tag BHMT SNPs from our own gene resequencing and HapMap data were used to genotype DNA from these samples. Genotype‐phenotype association analysis was then performed. BHMT enzyme activity averaged 0.077 ± 0.028 units/μg, with a 12 fold variation. Results BHMT protein levels averaged 6.9 ± 3.3 units/μg, with a 50‐fold variation. Three SNPs (rs41272270, rs16876512, and rs6875201), located 28kb upstream, in the 5′‐UTR and in intron 1 of BHMT , respectively, were significantly correlated with both phenotypes (p<10 −8 for enzyme activity and p<10 −5 for protein level). rs41272270 was associated with altered protein binding during electrophoresis mobility shift assay. Conclusions Three tag SNPs were significantly associated with human hepatic BHMT enzyme activity and immunoreactive protein. These observations may help us understand the regulation of BHMT in the human liver and its role in drug metabolism. Supported by NIH U01 GM61388, R01 GM28157, R01 CA132780.

Abstract Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming radiation (RT) resistance. To discover genotype-independent mediators of RT resistance, we correlated RT resistance with the concentration of approximately 700 metabolites across 23 GBM cell lines. Purine metabolites, especially those containing the base guanine, were most correlated with RT resistance. Similarly, increased abundance of tumor purines was associated with decreased survival in GBM patients treated with RT. This relationship is causal. Purine supplementation protected RT-sensitive GBMs from RT and promoted the repair of RT-induced double strand DNA breaks (DSBs). In vitro and in vivo stable isotope tracing confirmed that GBM cell lines and orthotopic patient-derived xenografts primarily generated purines through the de novo synthetic pathway. RT treatment further increased de novo purine synthesis in GBM through signaling via the DNA damage response. Inhibition of de novo GTP synthesis with mycophenolic acid (MPA) sensitized multiple GBM cell lines and neurospheres to RT by slowing the repair of RT-induced DSBs. MPA-induced radiosensitization was GTP-dependent as it was rescued by nucleoside supplementation. Modulating pyrimidine metabolism affected neither RT resistance nor DSB repair, suggesting these GTP-specific effects are due to active signaling rather than its ability to act as a physical substrate for DNA repair and candidate signaling molecules have been identified. These results were recapitulated in vivo with mycophenolate mofetil (MMF), the orally bioavailable FDA-approved prodrug of MPA. MMF potentiated RT efficacy, reduced tumor guanylates and slowed the repair of RT-induced DSBs across multiple models. Because de novo purine synthesis is activated by many of the oncogenic alterations that drive GBM, its inhibition is a promising genotype-independent strategy to overcome GBM RT resistance. We have now begun a clinical trial to determine whether combining MMF and RT is safe and potentially efficacious in patients with GBM.

PURPOSE To evaluate the effects of daratumumab, lenalidomide, and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) on patient-reported outcomes (PROs) in the phase III MAIA study. PATIENTS AND METHODS PROs were assessed on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item and the EuroQol 5-dimensional descriptive system at baseline and every 3 months during treatment. By mixed-effects model, changes from baseline are presented as least squares means with 95% CIs. RESULTS A total of 737 transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma were randomly assigned to D-Rd (n = 368) or Rd (n = 369). Compliance with PRO assessments was high at baseline (> 90%) through month 12 (> 78%) for both groups. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item global health status scores improved from baseline in both groups and were consistently greater with D-Rd at all time points. A global health status benefit was achieved with D-Rd, regardless of age (< 75 and ≥ 75 years), baseline Eastern Cooperative Oncology Group (ECOG) performance status score, or depth of response. D-Rd treatment resulted in significantly greater reduction in pain scores as early as cycle 3 ( P = .0007 v Rd); the magnitude of change was sustained through cycle 12. Reductions in pain with D-Rd were clinically meaningful in patients regardless of age, ECOG status, or depth of response. Similarly, PRO improvements were observed with D-Rd and Rd on the EuroQol 5-dimensional descriptive system visual analog scale score. CONCLUSION D-Rd compared with Rd was associated with faster and sustained clinically meaningful improvements in PROs, including pain, in transplant-ineligible patients with newly diagnosed multiple myeloma regardless of age, baseline ECOG status, or depth of treatment response.

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, and has been approved across lines of therapy for the treatment of multiple myeloma. The addition of DARA to standard-of-care (SoC) regimens, lenalidomide and dexamethasone (D-Rd) and bortezomib, melphalan, and prednisone (D-VMP), in the phase 3 MAIA and ALCYONE clinical studies reduced the risk of disease progression or death by ≥44%, nearly doubled the rate of complete response (CR) or better, and induced a &gt;3-fold increase in MRD-negativity rates (10-5 sensitivity threshold) vs SoC alone in pts with TIE NDMM. In both MAIA and ALCYONE, MRD negativity was associated with longer progression-free survival (PFS), irrespective of trial treatments. MRD negativity provides an index of deep clinical response and may be a more robust evaluation of disease control if sustained over time. Here, we evaluate MRD negativity, including sustained MRD negativity, in pts with TIE NDMM from MAIA and ALCYONE and its association with PFS with longer follow-up. Methods: Pts with NDMM ineligible for high-dose chemotherapy with stem cell transplantation due to age (≥65 years) or unacceptable coexisting conditions in MAIA and ALCYONE were randomized (1:1) to SoC ± DARA. Pts in MAIA 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 for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter). ALCYONE pts received up to nine 6-week cycles of VMP (V: 1.3 mg/m2 SC twice weekly during Weeks 1, 2, 4, and 5 of Cycle 1 and QW during Weeks 1, 2, 4, and 5 of Cycles 2-9; M: 9 mg/m2 PO on Days 1-4 of Cycles 1-9; and P: 60 mg/m2 PO on Days 1-4 of Cycles 1-9) ± DARA (16 mg/kg IV QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+). Study treatments continued until progressive disease or unacceptable toxicity. MRD was assessed in MAIA and ALCYONE in all pts who achieved a CR or stringent CR. For ≥CR pts, additional MRD assessments occurred at 12, 18, 24, and 30 months after the first dose in ALCYONE and at 12, 18, 24, 30, 36, 48, and 60 months in MAIA. MRD was assessed via next-generation sequencing using the clonoSEQ® assay (v.2.0; Adaptive Biotechnologies, Seattle, WA) at the 10-5 sensitivity threshold. Sustained MRD negativity was defined as the maintenance of MRD negativity confirmed ≥6 or ≥12 months apart with no MRD positive test in between and was evaluated in the intention-to-treat (ITT) population. Results: A total of 737 (D-Rd, n=368; Rd, n=369) pts in MAIA and 706 (D-VMP, n=350; VMP, n=356) pts in ALCYONE were randomized; median duration of follow-up was 36.4 months in MAIA and 40.1 months in ALCYONE. In both studies, DARA-based therapy improved MRD negativity vs SoC in the ITT population (D-Rd, 28.8% vs Rd, 9.2%, P&lt;0.0001; D-VMP, 28.3% vs VMP, 7.0%, P&lt;0.0001). MRD-negative pts had improved PFS vs MRD-positive pts in the ITT population, regardless of treatment arm. In a pooled analysis of pts from DARA (D-Rd/D-VMP) and SoC (Rd/VMP) treatment groups, MRD-negative pts had improved PFS vs pts who were MRD positive, irrespective of treatment arm. In general, baseline characteristics were comparable among pts in DARA and control treatment groups with sustained MRD negativity. A higher proportion of pts in the ITT populations of MAIA (D-Rd, n=368; Rd, n=369) and ALCYONE (D-VMP, n=350; VMP, n=356) achieved sustained MRD negativity with DARA-based therapy vs SoC for ≥6-months (D-Rd, 14.9% vs Rd, 4.3%, P&lt;0.0001; D-VMP, 15.7% vs VMP, 4.5%, P&lt;0.0001) and ≥12-months (D-Rd, 10.9% vs Rd, 2.4%; P&lt;0.0001; D-VMP, 14.0% vs VMP, 2.8%, P&lt;0.0001). PFS was prolonged in pts with sustained MRD negativity for ≥6-months and ≥12-months vs pts without sustained MRD negativity in the pooled ITT populations, regardless of treatment arm (Figure). Conclusions: DARA-based combination regimens induce higher rates of MRD-negativity and sustained MRD negativity in pts with TIE NDMM, which are associated with deep responses and improved PFS. Disclosures San-Miguel: Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Avet-Loiseau:Celgene and Janssen: Research Funding; Celgene, Amgen, Bristol-Myers Squibb, Sanofi, and Janssen;: Honoraria, Speakers Bureau. Paiva:Takeda: Consultancy, Honoraria, Research Funding; SkylineDx: Consultancy; Kite: Consultancy; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Honoraria; Adaptive: Honoraria; Roche: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding. Kumar:Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy, Research Funding; MedImmune: Research Funding; Sanofi: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Carsgen: Other, Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Tenebio: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria. Dimopoulos:Beigene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mateos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Pharmamar: Consultancy; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; EDOMundipharma: Consultancy; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Touzeau:Sanofi: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; GlaxoSmithKline: Honoraria, Research Funding. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Usmani:Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; GSK: Consultancy, Research Funding; Array Biopharma: Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Incyte: Research Funding; SkylineDX: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding. Cook:Karyopharm: Honoraria; Celgene, Janssen, Takeda: Research Funding; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, Roche, Sanofi: Honoraria. Cavo:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: 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, Other: Travel accomodations, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Quach:GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria; Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Ramaswami:Janssen: Current equity holder in publicly-traded company. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Sun:Janssen: Current Employment, Current equity holder in publicly-traded company. Wang:Janssen: Current Employment. Krevvata:Janssen: Current Employment. DeAngelis:Janssen: Current Employment, Current equity holder in publicly-traded company. Heuck:Christoph Heuck: Current Employment, Current equity holder in publicly-traded company. Van Rampelbergh:Janssen: Current Employment. Kudva:Janssen: Current Employment, Current equity holder in publicly-traded company; Memorial Sloan Kettering Cancer Center: Other: non-paid consultancy. Kobos:Janssen: Current Employment, Current equity holder in publicly-traded company. Qi:Janssen: Current Employment, Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company. Bahlis:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; GSK: Consultancy, Honoraria.

Introduction: Daratumumab (DARA) is a human, CD38-targeting, IgG1κ monoclonal antibody approved as monotherapy in relapsed/refractory multiple myeloma (RRMM) and in combination with standard of care for RRMM and NDMM. The addition of DARA to standard-of-care regimens in phase 3 studies has consistently improved progression-free survival (PFS) and led to deep and durable responses, including higher rates of minimal residual disease (MRD) negativity compared with standard of care. In the primary analysis of the phase 3 MAIA study (median follow-up, 28.0 mo), D-Rd vs Rd significantly improved PFS and MRD-negativity rates in transplant-ineligible NDMM (Facon T, N Engl J Med 2019). With longer follow-up (36.4 mo), D-Rd maintained a PFS benefit and deeper and more durable responses vs Rd alone (Bahlis N, Blood 2019. 134[Suppl 1]:1875). Here, we report updated efficacy and safety findings from MAIA after approximately 4 years of follow-up. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age ≥65 years or comorbidities were randomly assigned (1:1) to receive Rd ± DARA. Stratification factors included International Staging System stage (ISS [I vs II vs III]), region (North America vs other), and age (&lt;75 vs ≥75 years). All patients received 28-day cycles of Rd (R: 25 mg orally once daily on Days 1-21; d: 40 mg orally on Days 1, 8, 15 and 22). In the D-Rd arm, DARA (16 mg/kg intravenously) was given weekly for Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter. Patients were treated until disease progression or unacceptable toxicity in both treatment arms. The primary endpoint was PFS. Key secondary endpoints included overall response rate (ORR), MRD-negativity rate (10‒5 sensitivity, clonoSEQ® version 2.0), and safety. PFS on the next line of therapy (PFS2), defined as the time from randomization to progression on the next subsequent line of therapy or death, was also measured. Results: A total of 737 patients were randomized (D-Rd, n = 368; Rd, n = 369). Patient baseline characteristics were well balanced between the two treatment arms. Median (range) age was 73 (45-90) years, with 44% of patients ≥75 years of age. 27%, 43%, and 29% of all patients were ISS stage I, II, and III, respectively. Among 642 patients evaluable for FISH/karyotyping analysis, 86% had standard and 14% had high cytogenetic risk. After a median follow-up of 47.9 months, 176 (48%) and 273 (75%) patients discontinued study treatment in the D-Rd vs Rd groups, respectively, with 85 (23%) and 113 (31%) patients discontinuing treatment due to progressive disease. PFS remained improved for D-Rd vs Rd (median, not reached [NR] vs 34 mo; HR, 0.54; 95% CI, 0.43-0.67; P&lt;0.0001; Figure). The estimated 48-month PFS rate was 60% with D-Rd vs 38% with Rd. The PFS benefit of D-Rd in prespecified subgroups, including patients with high cytogenetic risk, was generally consistent with overall results. Adding DARA to Rd continued to result in deeper responses with higher rates of ≥CR and ≥very good partial response (VGPR; Table). Median duration of response among responders was NR with D-Rd vs 44 months with Rd. Median PFS2 was NR vs 51 months with D-Rd vs Rd, respectively (HR, 0.65; 95% CI, 0.52-0.83; P=0.0005); follow up is ongoing. 107 (29%) patients in the D-Rd group and 132 (36%) in the Rd group have discontinued the study due to death. Grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) occurring in ≥10% of patients were neutropenia (53%/37%), pneumonia (18%/11%), anemia (16%/21%), lymphopenia (16%/11%), hypokalemia (12%/10%), leukopenia (11%/6%), and cataract (11%/10%); grade 3/4 infection rates were 40%/29%. The most common serious TEAE was pneumonia (17%/11%). 11% of patients in the D-Rd arm and 22% in the Rd arm discontinued treatment due to an adverse event. The complete updated data set will be presented at the meeting with additional efficacy endpoints, including MRD-negativity rate. Conclusion : After 48 months follow up, the addition of DARA to Rd continues to demonstrate a superior PFS benefit. More patients continued to have deeper and more durable responses with D-Rd vs Rd alone. No new safety concerns were observed with longer follow-up. These results continue to support the use of D-Rd in the first line of treatment for patients with transplant-ineligible NDMM. Disclosures Kumar: Sanofi: Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Karyopharm: Consultancy; Merck: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; MedImmune: Research Funding; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Adaptive Biotechnologies: Consultancy. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Usmani:Abbvie: Consultancy; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Other; GSK: Consultancy, Research Funding; Merck: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Array Biopharma: Research Funding. Plesner:Janssen: Consultancy. Orlowski:Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding. Bahlis:BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Genentech: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Goldschmidt:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Incyte: Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Mundipharma GmbH: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Molecular Partners: Research Funding; Merck Sharp and Dohme (MSD): Research Funding. O'Dwyer:Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Research Funding; Carrick Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy; ONK Therapeutics: Consultancy, Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Weisel:Adaptive: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Karlin:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; Sanofi: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Preis:Janssen: Other: for factor XI inhibitor. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Hansson:Amgen, Celgene, Takeda, Janssen Cilag: Consultancy. Krevvata:Janssen: Current Employment. Wang:Janssen: Current Employment. Van Rampelbergh:Janssen: Current Employment. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Uhlar:Janssen: Current Employment, Current equity holder in publicly-traded company. Kobos:Janssen: Current Employment, Current equity holder in publicly-traded company. Perrot:Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding.

8035 Background: D-Rd significantly reduced the risk of progression/death by 44% in transplant-ineligible NDMM pts vs Rd in the phase 3 MAIA study. To examine the impact of age on efficacy/safety of D-Rd vs Rd in this population, a subgroup analysis was conducted in pts <75 and ≥75 y of age. Methods: Transplant-ineligible NDMM pts were randomized 1:1 to Rd ± DARA; stratification was based on age (<75 vs ≥75 y), ISS (I, II, III), and region (North America vs Other). Pts received 28-day cycles of either R 25 or 10 mg (based on renal function) PO QD on Days 1-21 and either d 40 or 20 mg (based on age or BMI) PO/IV weekly until progression. In the D-Rd arm, pts received daratumumab 16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter until progression. PFS is the primary endpoint. Results: Among 737 randomized pts (D-Rd, n=368; Rd, n=369), 321 (44%) were ≥75 y of age. For D-Rd vs Rd, relative median dose intensity for R was 79% vs 93% for <75 y subgroup and 66% vs 89% for ≥75 y subgroup, respectively. After median follow-up of 28 mo, significant PFS benefit of D-Rd vs Rd was maintained in both <75 and ≥75 y subgroups (Table). Deeper responses and MRD-negative rate (10-5 threshold) remained higher with D-Rd vs Rd in both subgroups (Table). Most common (≥10%; D-Rd/Rd) grade 3/4 TEAEs in ≥75 y pts were neutropenia (60%/41%), lymphopenia (19%/12%), anemia (16%/22%), pneumonia (15%/10%), leukopenia (12%/6%), and thrombocytopenia (8%/11%). Fewer pts receiving D-Rd vs Rd discontinued treatment due to TEAEs (<75 y: 5% vs 12%; ≥75 y: 10% vs 21%). Conclusions: D-Rd pts received less R vs Rd group regardless of age. Efficacy of D-Rd in <75 and ≥75 y pts was consistent with the ITT population, and D-Rd demonstrated acceptable tolerability regardless of age. Together with the phase 3 ALCYONE study, these studies confirm clinical benefit of daratumumab plus standard-of-care in transplant-ineligible NDMM pts ≥75 y of age. Clinical trial information: NCT02252172. [Table: see text]

Introduction: Daratumumab (DARA) is a human, CD38-targeted, IgG1κ monoclonal antibody approved as monotherapy in heavily pretreated relapsed/refractory multiple myeloma (RRMM) and in combination with standard-of-care regimens for transplant-ineligible NDMM and RRMM. The addition of DARA to standard-of-care regimens in phase 3 studies has consistently demonstrated a near doubling of complete response (CR) rates, tripling of minimal residual disease (MRD)-negativity rates, and reduction in the risk of disease progression or death by ≥44% in patients with transplant-ineligible NDMM or RRMM. In the primary analysis of the phase 3 MAIA study (median follow-up: 28.0 months), a significant progression-free survival (PFS) benefit (median not reached [NR] vs 31.9 months; hazard ratio [HR], 0.56; P<0.001) and a >3-fold increase in MRD-negativity rates (10-5 sensitivity threshold; 24.2% vs 7.3%; P<0.001) were observed for D-Rd vs Rd in patients with transplant-ineligible NDMM (Facon T, N Engl J Med 2019). Here, we report updated efficacy and safety findings from MAIA after 9 months of additional follow-up. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age ≥65 years or comorbidities were randomly assigned (1:1) to receive Rd ± DARA. Stratification factors included International Staging System stage (ISS [I vs II vs III]), region (North America vs other), and age (<75 vs ≥75 years). All patients received 28-day cycles of Rd (R: 25 mg orally once daily on Days 1-21; d: 40 mg orally on Days 1, 8, 15 and 22). In the D-Rd arm, DARA (16 mg/kg intravenously) was given weekly for Cycles 1-2, bi-weekly for Cycles 3-6, and every 4 weeks thereafter. Patients were treated until disease progression or unacceptable toxicity in both treatment arms. The primary endpoint was PFS. Key secondary endpoints included overall response rate (ORR), MRD-negativity rate (10-5 sensitivity, clonoSEQ® version 2.0), and safety. PFS on the next line of therapy (PFS2), defined as the time from randomization to progression on the next line of therapy or death, was also measured. Results: A total of 737 patients were randomized (D-Rd, N = 368; Rd, N = 369). Patient baseline characteristics were well balanced between the two treatment arms. Median (range) age was 73 (45-90) years, with 44% of patients ≥75 years of age. 27%, 43%, and 29% of all patients were ISS stage I, II, and III, respectively. Among 642 patients evaluable for FISH/karyotyping analysis, 86% had standard and 14% had high cytogenetic risk. After a median follow-up of 36.4 months, median PFS was NR with D-Rd vs 33.8 months with Rd (HR, 0.56; 95% confidence interval [CI], 0.44-0.71; P<0.0001; Figure). The estimated 36-month PFS rate was 68% with D-Rd vs 46% with Rd. The PFS benefit of D-Rd vs Rd was observed in all prespecified subgroups, except for patients with impaired hepatic function. Adding DARA to Rd continued to result in deeper responses with higher rates of ≥CR and ≥very good partial response (VGPR; Table). Median duration of response among responders was NR with D-Rd vs 40.7 months with Rd. Median PFS2 was NR vs 47.3 months with D-Rd vs Rd, respectively (HR, 0.69; 95% CI, 0.53-0.91; P=0.0079); follow up is ongoing. 143 (39%) vs 233 (64%) patients with D-Rd vs Rd, respectively, have discontinued treatment. 85 (23%) patients with D-Rd vs 103 (28%) patients with Rd have discontinued the study due to death. Grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) occurring in ≥10% of patients were neutropenia (51%/35%), lymphopenia (15%/11%), pneumonia (15%/9%), anemia (14%/21%), leukopenia (11%/6%), and hypokalemia (10%/10%); grade 3/4 infection rates were 36%/27%. The most common serious TEAE was pneumonia (14%/9%). 9% of patients in the D-Rd arm and 18% of patients in the Rd arm discontinued treatment due to TEAEs. The complete updated data set will be presented at the meeting with additional efficacy endpoints, including MRD-negativity rate. Conclusion: After longer follow up, the addition of DARA to Rd continues to demonstrate a significant PFS benefit and improved rates of deeper and more durable responses vs Rd alone in patients with transplant-ineligible NDMM. The longer follow-up also demonstrated a significant improvement in PFS2 favoring D-Rd, and no new safety concerns were observed. These results continue to support the use of D-Rd in the first line of treatment for transplant-ineligible patients with NDMM. Disclosures Bahlis: Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: 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; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Usmani:Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Plesner:Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genmab: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Quach:Sanofi: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldschmidt:ArtTempi: Honoraria; John Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product; Mundipharma: Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Molecular Partners: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding. O'Dwyer:GlycoMimetics Inc: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy. Venner:Janssen: Honoraria; J&J: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Weisel:GSK: Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Celgene Corporation: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Krevvata:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Wang:Janssen: Employment. Van Rampelbergh:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Uhlar:Janssen: Employment. Kobos:Janssen: Employment. Perrot: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; Takeda: Honoraria; Amgen: Honoraria; Sanofi: Honoraria.