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Introduction Two phase 3 studies demonstrated superior efficacy of intravenous daratumumab (DARA IV) plus bortezomib/melphalan/prednisone (ALCYONE) or lenalidomide/dexamethasone (Rd; MAIA) versus standard-of-care regimens for transplant-ineligible newly diagnosed multiple myeloma. In these studies, patients could switch from DARA IV to subcutaneous daratumumab (DARA SC) while receiving daratumumab monotherapy in ALCYONE (as of Cycle 11) or daratumumab plus Rd in MAIA. The phase 3 COLUMBA study demonstrated noninferiority of DARA SC to DARA IV. DARA SC reduced administration time, allowing patients to spend less time in healthcare settings, a relevant practical consideration for patient care in the COVID-19 pandemic/settings of limited healthcare resources. Methods DARA SC 1800 mg was administered every 4 weeks, per approved dosing schedules. We evaluated safety and patient-reported experience (ALCYONE only) among patients who switched from DARA IV to DARA SC. Results Fifty-seven patients in ALCYONE and 135 in MAIA switched to DARA SC. Three (2.2%; MAIA) patients reported injection-site reactions, all of which were mild. No infusion-related reactions occurred with DARA SC. In ALCYONE, >80% of patients preferred DARA SC over DARA IV. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 5.3% of patients in ALCYONE and 25.9% in MAIA; one (0.7%; MAIA) patient experienced a TEAE with an outcome of death. Conclusion For transplant-ineligible newly diagnosed multiple myeloma, DARA SC (monotherapy/with Rd) was safe and preferred over DARA IV. ClinicalTrials.gov, NCT02195479/NCT02252172.

What is this summary about? This is a summary of a clinical trial called MAIA. The trial tested 2 combinations of cancer drugs (daratumumab plus lenalidomide and dexamethasone compared with lenalidomide and dexamethasone) in people with newly diagnosed multiple myeloma. None of the participants who took part in the study had been treated before or were eligible to receive stem-cell transplants. How was the study in this summary conducted? A total of 737 participants took part. Half of the participants took daratumumab plus lenalidomide and dexamethasone, while the other half of the participants took only lenalidomide and dexamethasone. Once participants started taking the drugs, the cancer was monitored for improvement (response to treatment), worsening (disease progression), or no change. Participants' blood and urine were tested for myeloma protein to measure response to the treatment. Participants were also monitored for side effects. What were the results of the study? After approximately 56 months of follow-up, more participants who took daratumumab plus lenalidomide and dexamethasone were alive and had decreased myeloma protein levels (indicating improvement of cancer) than participants who took only lenalidomide and dexamethasone. The most common side effects were abnormally low white and red blood cell counts and increased lung infections. What do the results of the study mean? In the MAIA study, participants with multiple myeloma who took daratumumab plus lenalidomide and dexamethasone lived longer and had decreased myeloma protein levels than participants who took only lenalidomide and dexamethasone, indicating survival could be more likely with daratumumab added. Clinical Trial Registration: NCT02252172 (Phase 3 MAIA study)

What is this summary about? This is a summary of a phase 1–2 clinical trial called MajesTEC-1. This trial tested the cancer drug teclistamab in people with relapsed or refractory multiple myeloma, a cancer that forms in a certain type of white blood cells known as plasma cells. Most participants who took part in the study had at least 3 prior treatments for multiple myeloma before their cancer came back. How was the study in this summary conducted? A total of 165 participants from 9 countries were included in this study. All participants were given teclistamab once per week and monitored for side effects. Once participants started taking teclistamab, they were checked regularly to monitor if their cancer had no change, improved (responded to treatment), or worsened or spread (known as disease progression). What were the results of the study? After approximately 14.1 months of follow-up (from 2020 to 2021), 63% of participants who were given teclistamab had a decrease in myeloma burden, meaning that they responded to treatment with teclistamab. Participants who responded to teclistamab lived without their myeloma coming back for approximately 18.4 months. The most common side effects were infections, cytokine release syndrome, abnormally low white and red blood cell counts (neutropenia, lymphopenia, and anemia), and low platelet cell counts (thrombocytopenia). Approximately 65% of participants experienced serious side effects. What do the results of this study mean? Overall, more than half of the participants (63%) in the MajesTEC-1 study responded to treatment with teclistamab despite previous myeloma treatment failures. Clinical Trial Registration: NCT03145181 , NCT04557098 ( ClinicalTrials.gov )

In the phase 3 MAIA study of patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab plus lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd). We present a subgroup analysis of MAIA by frailty status. Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit, intermediate, non-frail (fit + intermediate), or frail. Of the randomized patients (D-Rd, n = 368; Rd, n = 369), 396 patients were non-frail (D-Rd, 196 [53.3%]; Rd, 200 [54.2%]) and 341 patients were frail (172 [46.7%]; 169 [45.8%]). After a 36.4-month median follow-up, non-frail patients had longer PFS than frail patients, but the PFS benefit of D-Rd versus Rd was maintained across subgroups: non-frail (median, not reached [NR] vs 41.7 months; hazard ratio [HR], 0.48; P P = 0.003). Improved rates of complete response or better and minimal residual disease (10–5) negativity were observed for D-Rd across subgroups. The most common grade 3/4 treatment-emergent adverse event in non-frail and frail patients was neutropenia (non-frail, 45.4% [D-Rd] and 37.2% [Rd]; frail, 57.7% and 33.1%). These findings support the clinical benefit of D-Rd in transplant-ineligible NDMM patients enrolled in MAIA, regardless of frailty status.

Background: In the primary analysis of the phase 3 MAIA trial (median follow-up 28·0 months), a significant improvement in progression-free survival was observed with daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in transplantation-ineligible patients with newly diagnosed multiple myeloma. Here, we report the updated efficacy and safety results from a prespecified interim analysis for overall survival. Methods: MAIA is an ongoing, multicentre, randomised, open-label, phase 3 trial that enrolled patients at 176 hospitals in 14 countries across North America, Europe, the Middle East, and the Asia-Pacific region. Eligible patients were aged 18 years or older, had newly diagnosed multiple myeloma, had an Eastern Cooperative Oncology Group performance status score of 0–2, and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation because of their age (≥65 years) or comorbidities. Patients were randomly assigned (1:1) using randomly permuted blocks (block size 4) by an interactive web response system to receive 28-day cycles of intravenous daratumumab (16 mg/kg, once per week during cycles 1–2, once every 2 weeks in cycles 3–6, and once every 4 weeks thereafter) plus oral lenalidomide (25 mg on days 1–21 of each cycle) and oral dexamethasone (40 mg on days 1, 8, 15, and 22 of each cycle; daratumumab group) or lenalidomide and dexamethasone alone (control group). Randomisation was stratified by International Staging System disease stage, geographical region, and age. Neither patients nor investigators were masked to treatment assignment. The primary endpoint was progression-free survival, which was centrally assessed, and a secondary endpoint was overall survival (both assessed in the intention-to-treat population). The safety population included patients who received at least one dose of the study treatment. The results presented here are from a prespecified interim analysis for overall survival, for which the prespecified stopping boundary was p=0·0414. This trial is registered with ClinicalTrials.gov, NCT02252172. Findings: Between March 18, 2015, and Jan 15, 2017, 952 patients were assessed for eligibility, of whom 737 patients were enrolled and randomly assigned to the daratumumab group (n=368) or the control group (n=369). At a median follow-up of 56·2 months (IQR 52·7–59·9), median progression-free survival was not reached (95% CI 54·8–not reached) in the daratumumab group versus 34·4 months (29·6–39·2) in the control group (hazard ratio [HR] 0·53 [95% CI 0·43–0·66]; p15%) grade 3 or higher treatment-emergent adverse events were neutropenia (197 [54%] patients in the daratumumab group vs 135 [37%] patients in the control group), pneumonia (70 [19%] vs 39 [11%]), anaemia (61 [17%] vs 79 [22%]), and lymphopenia (60 [16%] vs 41 [11%]). Serious adverse events occurred in 281 (77%) patients in the daratumumab group and 257 (70%) patients in the control group. Treatment-related deaths occurred in 13 (4%) patients in the daratumumab group and ten (3%) patients in the control group. Interpretation: Daratumumab plus lenalidomide and dexamethasone increased overall survival and progression-free survival in patients ineligible for stem-cell transplantation with newly diagnosed multiple myeloma. There were no new safety concerns. Our results support the frontline use of daratumumab plus lenalidomide and dexamethasone for patients with multiple myeloma who are ineligible for transplantation. Funding: Janssen Research & Development.

BACKGROUND Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma. METHODS In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better). RESULTS Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2). CONCLUSIONS Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2.

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 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 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 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.

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 ( 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 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.

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 >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 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 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.

BACKGROUND: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population.METHODS: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival.RESULTS: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; PCONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).

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.

[Background]: In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status., [Patients and Methods]: Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients., [Results]: Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10−5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%)., [Conclusion]: Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status., This study was sponsored by Janssen Research & Development, LLC.

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)., The studies were supported by Janssen Research & Development, LLC.

Introduction The objective of this study was to describe the treatment patterns among patients with newly diagnosed multiple myeloma (MM) who had not received autologous stem cell transplantation (ASCT). It further compares the safety and clinical outcomes across different frontline regimens as well as explores whether treatment duration predicts outcomes. Methods Patients with MM (> 45 years) who had not received ASCT were retrospectively identified from the US SEER-Medicare (Jan 2007–Dec 2016) and Optum (Jan 2007–Sep 2018) databases. Cox proportional hazard models were used to compare overall survival (OS) among bortezomib + lenalidomide + dexamethasone regimen (VRd), lenalidomide + dexamethasone regimen (Rd), cyclophosphamide + bortezomib + dexamethasone regimen (CyBorD), bortezomib + dexamethasone regimen (Vd), and other bortezomib-containing therapies based on propensity score matching. To address immortal time bias, time-fixed and time-dependent Cox models were employed to estimate the association of longer frontline treatment exposure with outcomes. Results Mean (standard deviation; SD) age was 71 (9.8) years; and 49.51% were women. Bortezomib and lenalidomide-based combinations were the most common treatment modalities. After matching, the HR (95% CI) of OS by frontline therapies comparing VRd with Vd was 0.76 (0.66, 0.86), CyBorD was 0.87 (0.75, 1.05), for other bortezomib-based therapies was 0.56 (0.49, 0.64), Rd was 0.83 (0.73, 0.95), and for other therapies was 0.70 (0.61, 0.80). Longer frontline treatment duration was associated with better OS for overall frontline [HR (95% CI) 0.86 (0.82, 0.90)]; Vd [0.81 (0.74, 0.89)]; CyBorD [0.79 (0.64, 0.98)] and Rd [0.86 (0.78, 0.95)]. Conclusion Results demonstrated that the frontline therapies prescribed to most patients who did not receive ASCT for MM in the United States were consistent with the NCCN guideline recommendations. Longer frontline treatment duration was associated with improved OS. Electronic Supplementary Material The online version of this article (10.1007/s12325-020-01546-0) contains supplementary material, which is available to authorized users.

Introduction: Teclistamab (JNJ-64007957) is a T-cell redirecting, bispecific IgG4 antibody that targets both B-cell maturation antigen (BCMA) and CD3 receptors to induce T-cell mediated cytotoxicity of BCMA-expressing myeloma cells. Teclistamab is under investigation in MajesTEC-1, an ongoing phase 1/2 study in patients (pts) with heavily pretreated relapsed/refractory multiple myeloma (RRMM). Results from the phase 1 study (parts 1 and 2; NCT03145181) indicated that teclistamab is well tolerated at the recommended phase 2 dose (RP2D) and has encouraging efficacy, with an overall response rate (ORR) of 65% and very good partial response or better (≥VGPR) rate of 58% in 40 pts after a median of 6.1 mo of follow-up. Here we report for the first time initial data from the phase 2 portion of MajesTEC-1 (part 3; NCT04557098) and updated results for phase 1 pts treated at the RP2D. Methods: Pts (aged ≥18 years) were diagnosed with MM per International Myeloma Working Group (IMWG) criteria, had measurable disease and were exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. In phase 1, pts were relapsed, refractory or intolerant to established therapies. In phase 2, pts received ≥3 prior lines of therapy. The primary objectives in phase 1 were to identify the RP2D and to characterize safety and tolerability of teclistamab at the RP2D. The primary objective in phase 2 is to evaluate the efficacy of teclistamab at the RP2D (primary endpoint: ORR). Pts treated at the RP2D received a weekly dose of subcutaneous teclistamab 1500 µg/kg following step-up doses of 60 and 300 µg/kg. Responses reported here were investigator-assessed per IMWG criteria. Adverse events (AEs) are graded according to CTCAE v4.03. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT criteria. Results: As of June 14, 2021, 159 pts (median age 64.0 y [range 33-84]; 15% ≥75 y; 59% male) were treated at the RP2D (phase 1: 40 pts; phase 2: 119 pts). Pts received a median of 5 prior lines of therapy (range: 2-15); 100% were triple-class exposed, 69% were penta-drug exposed, 77% were triple-class refractory, and 29% were penta-drug refractory. As of the clinical cutoff, no new safety signals were identified in phase 2. The most common nonhematologic AEs in all 159 pts treated at the RP2D were CRS (67%; grade 1/2: 99%; 1 pt had a transient grade 3 event; median time to onset 2 days [range 1-6]; median duration 2 days [range 1-9]), injection site erythema (23%; all grade 1/2), and fatigue (22%; grade 3/4: 2%). The most common hematologic AEs were neutropenia (53%; grade 3/4: 45%), anemia (41%; grade 3/4: 27%), and thrombocytopenia (33%; grade 3/4: 18%). Four pts (2.5%) developed ICANS (all grade 1/2; all resolved). Pharmacokinetic and pharmacodynamic data from phase 2 support earlier phase 1 findings. Teclistamab exposure at the RP2D was sustained across the dosing interval and exceeded target exposure levels. Pharmacodynamic data for phase 1/2 pts treated at the RP2D showed induction of proinflammatory cytokines and T-cell activation, consistent with teclistamab's mechanism of action. At clinical cutoff for this abstract, efficacy data for the phase 2 study are immature. At a median follow-up of 8.2 mo (range 1.2-15.2), response rates in the 40 phase 1 pts treated at RP2D were consistent with previously presented data (ORR: 65% [95% CI 48-79]; ≥VGPR rate: 60% [95% CI 43-75]; complete response or better rate: 40% [95% CI 25-57]). Responses deepened over time, and with longer follow-up of responders compared with previously presented data (median follow-up of 9.5 mo vs 7.1 mo) remained durable (Figure). No additional responders had disease progression, and 85% (22/26) of responders are continuing on treatment, including 1 pt with 15.2 mo of follow-up. Median duration of response (DOR) has not been reached; the 6-month DOR rate is 90% [95% CI 63-97]. The efficacy data will be updated at the time of congress to include a minimum follow-up of ~6 mo for 150 pts treated at the RP2D (prior to March 19, 2021). Conclusions: Evaluation of teclistamab at the RP2D in 159 pts provides robust data to support safety; inclusion of phase 2 pts at the time of presentation will provide more robust efficacy data. Data from MajesTEC-1 continue to show that teclistamab monotherapy induces deep and durable responses in heavily pretreated pts with RRMM with a manageable safety profile. Figure 1 Figure 1. Disclosures Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria. Usmani: Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; Abbvie: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding. Garfall: Amgen: Honoraria; Tmunity Therapeutics: Research Funding; Novartis: Research Funding; GSK: Honoraria; Janssen: Honoraria, Research Funding. van de Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy. Nahi: XNK Therapeutics AB: Consultancy. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Oriol: GSK: 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; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Nooka: GlaxoSmithKline: Consultancy, Other: Travel expenses; Bristol-Myers Squibb: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy; Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive technologies: Consultancy; Karyopharm Therapeutics: Consultancy. Martin: Amgen: Research Funding; Sanofi: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Consultancy; Oncopeptides: Consultancy. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Chari: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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; Pharmacyclics: Research Funding; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Karlin: Abbvie: Honoraria; Amgen: Honoraria, Other: travel support and advisory board ; GSK: Honoraria, Other: member of advisory board; Janssen: Honoraria, Other: member of advisory board, travel support; Takeda: Honoraria, Other: member of advisory board; Celgene-BMS: Honoraria, Other: member of advisory board; Sanofi: Honoraria; oncopeptide: Honoraria. Mateos: Regeneron: 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; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Roche: 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; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Bahlis: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Genentech: Consultancy; Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Popat: Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Janssen and BMS: Other: travel expenses. Besemer: GSK: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Sidana: Allogene: Research Funding; Janssen: Consultancy, Research Funding; Magenta Therapeutics: Consultancy, Research Funding; BMS: Consultancy. Pei: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Trancucci: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Verona: Janssen: Current Employment. Girgis: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Olyslager: Janssen: Current Employment. Jaffe: Janssen: Current Employment. Uhlar: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Stephenson: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Van Rampelbergh: Janssen: Current Employment. Banerjee: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Kobos: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Krishnan: MAGENTA: Consultancy; BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; JANSSEN: Consultancy, Research Funding; City of Hope Cancer Center: Current Employment; REGENERON: Consultancy; SANOFI: Consultancy; GSK: Consultancy; Amgen: Speakers Bureau.

Context Daratumumab plus standard-of-care (SOC) showed superior efficacy vs SOC for patients with TIE-NDMM (phase 3 ALCYONE, MAIA, and CASSIOPEIA; primary analyses). In ALCYONE, after longer follow-up, adding daratumumab to bortezomib, melphalan, and prednisone significantly reduced the risk of death by 40%. In MAIA (primary analysis), D-Rd reduced the risk of progression/death by 44% vs Rd (median follow-up, 28 months). Objective Updated efficacy and safety of D-Rd vs Rd from MAIA (NCT02252172; pre-specified interim OS analysis). Design Open-label, randomized, active-controlled. Patients Patients with TIE-NDMM were randomly assigned 1:1 to receive D-Rd (n=368) or Rd (n=369); median age: 73 years. Baseline characteristics were well balanced between arms. Interventions 28-day cycles of oral Rd (R: 25 mg QD [Days 1–21]; d: 40 mg [Days 1, 8, 15, 22]) ± IV daratumumab (16 mg/kg QW [Cycles 1–2], Q2W [Cycles 3–6], and Q4W thereafter) until progression or unacceptable toxicity. Main Outcome Measures Primary endpoint: progression-free survival (PFS); key secondary endpoints: overall response rate (ORR), OS, and safety. Results After a median follow-up of 56.2 months, the risk of death significantly reduced with D-Rd vs Rd; median OS: not reached (NR) in either arm (hazard ratio [HR], 0.68 [95% CI, 0.53–0.86]; P=0.0013). The median PFS was NR with D-Rd vs 34.4 months with Rd (HR, 0.53 [0.43–0.66]; P 15% incidence) grade 3 or 4 treatment-emergent adverse events with D-Rd/Rd were neutropenia (54.1%/37.0%), pneumonia (19.2%/10.7%), anemia (16.8%/21.6%), and lymphopenia (16.5%/11.2%). Conclusions After a median follow-up of ≈5 years, patients with TIE-NDMM had a significant and clinically meaningful OS improvement with D-Rd vs Rd. The significant PFS benefit of D-Rd was maintained, with a 47% reduction in the risk of progression/death. The favorable benefit-risk profile supports the use of D-Rd in patients with TIE-NDMM. Together with the OS benefit observed in ALCYONE, these results support using frontline daratumumab-based regimens to maximize PFS for optimal long-term outcomes.

Overcoming drug resistance is one of the greatest challenges in the treatment of multiple myeloma (MM). The interaction of myeloma cells with the bone marrow (BM) microenvironment is a major factor contributing to drug resistance. Tumour-associated macrophages (TAMs) with different polarization states constitute an important component of this microenvironment. Previous studies have revealed a role of TAMs in MM cell survival and drug resistance; however, the impact of macrophage polarization (anti-tumoural ‘M1’ versus pro-tumoural ‘M2’-like phenotype) in this process has not yet been described. Here, the presence of TAMs was confirmed in BM sections from MM patients, both at diagnosis and relapse, with two M2 markers, CD163 and CD206. By following different TAM subpopulations during disease progression in the syngeneic murine 5T33MM model, we demonstrated a decrease in the number of inflammatory monocytes and an increase in the number of M2-oriented TAMs in BM. Co-culture experiments demonstrated that macrophages provide a survival benefit to myeloma cells that is maintained after treatment with several classes of anti-myeloma agent (melphalan and bortezomib); the greatest effect was observed with M2-polarized macrophages. The pro-survival effect was associated with activation of the STAT3 pathway in 5T33MM cells, less cleavage of caspase-3, and thus less apoptosis. AZD1480, an ATP-competitive JAK2 inhibitor, abrogated the observed TAM-mediated MM cell survival, and partially inhibited resistance to bortezomib. Despite having only a small quantitative impact on myeloid cells in vivo, AZD1480 treatment alone and in combination with bortezomib significantly reduced tumour load. In conclusion, M2 TAMs are present in the MM microenvironment, and contribute to MM cell survival and protection from drug-induced apoptosis. As a result of TAM-induced activation of the STAT3 pathway, 5T33MM cells are sensitized to AZD1480 treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Introduction: Daratumumab (DARA) is a CD38-targeting monoclonal antibody approved for the treatment of MM. The addition of DARA to standard-of-care (SOC) regimens in the phase 3 ALCYONE (D-VMP vs VMP) and MAIA (D-Rd vs Rd) studies demonstrated deep and durable responses and improved progression-free survival in transplant-ineligible NDMM patients (pts). DARA-based regimens have shown increased infection rates vs SOC in both ALCYONE (grade 3/4 infections, 22% vs 15%) and MAIA (36% vs 27%). Most common (>10 pts) grade 3/4 infection(s) was pneumonia (D-VMP/VMP; 13%/4%) in ALCYONE and were pneumonia (D-Rd/Rd; 15%/9%), influenza (3%/2%), bronchitis (3%/1%), and sepsis, urinary tract and lower respiratory tract infections (3% each) in MAIA. Most common (>10 pts) serious adverse infection(s) was pneumonia (D-VMP/VMP; 12%/3%) in ALCYONE and pneumonia (D-Rd/Rd; 14%/9%), influenza (4%/2%), bronchitis (4%/2%), and upper respiratory tract infection (3%/3%) in MAIA. Using pooled data from DARA-treated pts in ALCYONE and MAIA, we report results of an analysis to identify predictive markers of grade ≥3 or serious infections that occurred during the first 6 mo of treatment. Methods: ALCYONE pts received ≥nine 6-week cycles of VMP (V: 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 of Cycles 2-9; M: 9 mg/m2 orally, and P: 60 mg/m2 orally on Days 1-4 of Cycles 1-9)±DARA (16 mg/kg IV), QW during Cycle 1, Q3W Cycles 2-9, and Q4W thereafter as maintenance therapy until disease progression or unacceptable toxicity. MAIA pts received 28-day cycles of Rd (R: 25 mg PO once daily on Days 1-21; d: 40 mg PO on Days 1, 8, 15 and 22)±DARA (16 mg/kg IV) QW Cycles 1-2, Q2W Cycles 3-6, and Q4W weeks thereafter. This analysis pooled data for DARA-treated pts in ALCYONE (median follow-up, 40.1 mo) and MAIA (median follow-up, 36.4 mo). Pooled data were randomly split into training and validation data. A predictive model was developed for time to first occurrence of treatment-emergent grade ≥3 or serious infections during the first 6 mo of study treatment. To identify the set of predictors for the Cox proportional hazard multivariate model, each candidate predictor was first assessed in a univariate model. Parameters with a P value Results: In ALCYONE, a total of 706 pts were randomized (D-VMP, 350; VMP, 356); in MAIA, a total of 737 pts were randomized (D-Rd, 368; Rd, 369). A total of 710 DARA-treated pts (D-VMP, 346; D-Rd, 364) were pooled from both studies to develop the predictive model (training data, 534 pts; validation data, 176 pts). 10 significant parameters were identified from the univariate analysis (Table): age, β2-microglobulin (β2M) level, frailty status, lactic acid dehydrogenase (LDH) level, albumin level at baseline, low albumin level, high alkaline phosphatase level, and elevated baseline alanine aminotransferase (ALT), ISS stage, and cytogenetic risk. The final predictive model included age, LDH, albumin, and elevated baseline ALT levels (Table). Based on the coefficient estimate of each predictor from the final Cox model, a scoring tool was developed with the total score ranging from 0-23; (≥8, high risk; ≤7, low risk). The scoring system was applied to the training data (n = 534); 370 pts were classified at low risk and 164 pts were at high risk for infection. The infection event rate was 15.7% for low-risk pts and 29.3% for high-risk pts (HR, 2.11; 95% CI, 1.44-3.10; P = 0.0001). In the validation data (n = 176), 130 pts were classified as low-risk and 46 pts were at high risk for infection. The infection rate was 16.2% for low-risk vs 28.3% for high-risk pts (HR, 1.91; 95% CI, 0.96-3.83; P = 0.0663). Conclusion: This analysis identified predictors of grade ≥3 or serious infections during the first 6 mo of treatment in DARA-treated NDMM pts that were used to develop a risk scoring system. These data will be useful in identifying pts most at risk of infection during DARA treatment. Disclosures van de Donk: Amgen: Other: Ad Board, Research Funding; BMS: Other: Ad Board, Research Funding; Janssen: Other: Ad Board, Research Funding; Novartis: Other: Ad Board; Bayer: Other: Ad Board; Takeda: Other: Ad Board; Genentech: Other: Ad Board; Celgene: Other: Ad Board, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: 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; Sanofi: Membership on an entity's Board of Directors or advisory committees. 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. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Cavo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Celgene: 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; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria; GlaxoSmithKline: Honoraria, 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. Suzuki:Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria; Bristol-Myers Squibb, Celgene and Amgen: Research Funding. Touzeau:Sanofi: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Usmani:Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Incyte: Research Funding; GSK: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Merck: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Research Funding; Abbvie: Consultancy. Perrot:Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Kudva:Memorial Sloan Kettering Cancer Center: Other: non-paid consultancy; Janssen: Current Employment, Current equity holder in publicly-traded company. Van Rampelbergh:Janssen: Current Employment. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Leary:Janssen: Current Employment, Current equity holder in publicly-traded company. Carson:Janssen: Current Employment. Qi:Janssen: Current Employment, Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company. Chari:Janssen, Celgene, Novartis, Amgen, Bristol-Myers Squibb, Karyopharm, Sanofi, Genzyme, Seattle Genetics, Oncopeptides, Millennium/Takeda, Antengene, Glaxo Smith Kline, Secura Bio: Consultancy; Janssen, Celgene, Novartis, Amgen, Pharmacyclics, Seattle Genetics, Millennium/Takeda: Research Funding.

Context: Daratumumab (D), is approved as monotherapy and combination therapy for MM. We report an analysis of patients who discontinued R±d in the D-Rd arm of the MAIA and POLLUX studies. Design: In MAIA and POLLUX, patients with transplant-ineligible newly diagnosed MM and relapsed/refractory MM, respectively, were randomized (1:1) to Rd (R, 25 mg orally Days 1-21 of each 28-day cycle; d, 40 mg orally QW) ±D (16 mg/kg intravenously, QW Cycles 1-2, Q2W Cycles 3-6, then Q4W). The primary endpoint was progression-free survival (PFS). Landmark PFS analyses excluding events before 12- or 24-mo were conducted for all patients and by subgroups. Results: Patients were randomized in MAIA (D-Rd, n=368; Rd, n=369) and POLLUX (D-Rd, n=286; Rd, n=283). Median follow-up was 36.4 and 54.8 months, respectively. Among all randomized patients (ITT population), PFS rates were improved for D-Rd vs Rd in MAIA (NR vs 33.8 months; 36-month PFS rates, 68% vs 46%) and POLLUX (45.0 months vs 17.5 months; 60-month PFS rates, 44% vs 17%). Among D-Rd patients, 73 and 44 discontinued R in MAIA and POLLUX, respectively; 45 and 18 discontinued both R and d, and 28 and 26 discontinued R only but continued d. Most patients discontinuing R discontinued after 6 mo of treatment (MAIA, n=63; POLLUX, n=38), mostly due to adverse events (AEs). Median PFS for R discontinuers was NR in MAIA (36-mo PFS rate, 76%) and POLLUX (60-mo PFS rate, 62%). Landmark analysis for 12 mo and 24 mo showed median PFS was NR in MAIA for the ITT population, those discontinuing R, and those discontinuing R and d; PFS was NR in all patients and subgroups in POLLUX. In both studies, most responders achieved best response before R±d discontinuation. At the time of R discontinuation, many patients showed response rates in MAIA (≥complete response [CR], 45%; ≥very good partial response [VGPR], 90%) and POLLUX (≥CR, 73%; ≥VGPR, 91%) that were consistent with the ITT populations. Conclusions: In MAIA and POLLUX, patients in ≥VGPR who received D-Rd and discontinued R±d, but remained on daratumumab, demonstrated benefits in PFS and response comparable to the overall study populations.

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; P3-fold increase in MRD-negativity rates (10-5 sensitivity threshold; 24.2% vs 7.3%; P 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 ( 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 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.

Overcoming drug resistance is one of the greatest challenges in the treatment of multiple myeloma (MM). The interaction of myeloma cells with the bone marrow (BM) microenvironment is a major factor contributing to drug resistance. Tumour-associated macrophages (TAMs) with different polarization states constitute an important component of this microenvironment. Previous studies have revealed a role of TAMs in MM cell survival and drug resistance; however, the impact of macrophage polarization (anti-tumoural 'M1' versus pro-tumoural 'M2'-like phenotype) in this process has not yet been described. Here, the presence of TAMs was confirmed in BM sections from MM patients, both at diagnosis and relapse, with two M2 markers, CD163 and CD206. By following different TAM subpopulations during disease progression in the syngeneic murine 5T33MM model, we demonstrated a decrease in the number of inflammatory monocytes and an increase in the number of M2-oriented TAMs in BM. Co-culture experiments demonstrated that macrophages provide a survival benefit to myeloma cells that is maintained after treatment with several classes of anti-myeloma agent (melphalan and bortezomib); the greatest effect was observed with M2-polarized macrophages. The pro-survival effect was associated with activation of the STAT3 pathway in 5T33MM cells, less cleavage of caspase-3, and thus less apoptosis. AZD1480, an ATP-competitive JAK2 inhibitor, abrogated the observed TAM-mediated MM cell survival, and partially inhibited resistance to bortezomib. Despite having only a small quantitative impact on myeloid cells in vivo, AZD1480 treatment alone and in combination with bortezomib significantly reduced tumour load. In conclusion, M2 TAMs are present in the MM microenvironment, and contribute to MM cell survival and protection from drug-induced apoptosis. As a result of TAM-induced activation of the STAT3 pathway, 5T33MM cells are sensitized to AZD1480 treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.

Introduction Lenalidomide-based therapies are a standard of care for patients with newly diagnosed, transplant-ineligible MM. Daratumumab (DARA) is a human, CD38-targeted, IgG1κ monoclonal antibody which has single-agent activity in heavily pretreated MM patients. As previously reported in 3 phase 3 studies, the addition of DARA to standards of care in both relapsed refractory (D-Rd, DARA plus bortezomib and dexamethasone [D-Vd]) or transplant-ineligible NDMM (DARA plus bortezomib, melphalan, and prednisone [D-VMP]) resulted in a ≥50% reduction in the risk of disease progression or death (Palumbo A, et al. N Engl J Med 2016;375:754-766; Dimopoulos MA, et al. N Engl J Med 2016;375:1319-1331; Mateos MV, et al. N Engl J Med 2018;378:518-528). Of these, the POLLUX study with D-Rd showed the greatest benefit with a 63% reduction in risk of disease progression or death in patients with MM who had at least one prior line of therapy. Based on the efficacy and tolerable safety profile of D-Rd, we conducted a phase 3 study (MAIA) to evaluate D-Rd vs Rd in transplant-ineligible NDMM. Here we report the prespecified interim analysis of the MAIA study. Methods Patients ineligible for high-dose chemotherapy with autologous stem cell transplantation due to age ≥65 years or comorbidities were randomized 1:1 to Rd ± DARA. Stratification was based on International Staging System stage (ISS [I, II, III]), region (North America vs other), and age ( Results This international study randomized 737 patients (368 to D-Rd; 369 to Rd) from 14 countries. Key baseline characteristics were well balanced between the two arms. The median (range) age was 73 (45-90) years with 44% of patients ≥75 years, and 52% were male. Two thirds of patients had ECOG scores ≥1: ECOG score 0, 34%; 1, 50%; ≥2, 17%. Overall, 27%, 43%, and 29% were ISS stage I, II, and III, respectively. Of 642 patients evaluable for FISH/karyotyping analysis, 86% and 14% were standard and high cytogenetic risk, respectively. The prespecified interim analysis occurred after 239 PFS events on 24 September 2018 with a median follow up of 28 months. For the primary endpoint, the hazard ratio was 0.55 (95% CI, 0.43 to 0.72; P Conclusion The addition of DARA to Rd in patients with transplant-ineligible NDMM significantly reduced the risk of progression or death by 45%. There are no new safety signals using DARA plus Rd in NDMM. These data together with the phase 3 ALCYONE study (D-VMP vs VMP) support the addition of DARA to standard of care combinations in patients with NDMM ineligible for transplant. Disclosures Facon: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Plesner:Celgene: Other: Independent Response Assessment Comittee; Janssen: Consultancy. Orlowski:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioTheryX: Research Funding; Spectrum Pharma: Research Funding. Moreau:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bahlis:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hulin:Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Research Funding. Goldschmidt:Adaptive Biotechnology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; ArtTempi: Honoraria. O'Dwyer:Janssen: Consultancy. Perrot:Janssen: Consultancy, Equity Ownership, Honoraria. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Weisel:Celgene: Consultancy; Angeb: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding; Bristol Myers SquibbMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Ahmadi:Genmab: Employment, Equity Ownership. Chiu:Janssen Research & Development, LLC: Employment, Equity Ownership. Wang:Janssen Research & Development, LLC: Employment. Van Rampelbergh:Janssen: Employment. Uhlar:Janssen: Employment. Kobos:Janssen Research & Development: Employment. Qi:Janssen Research & Development, LLC: Employment. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding.