Citations

Background The treatment of depression in children and adolescents is a substantial public health challenge. This study examined artificial intelligence tools for the prediction of early outcomes in depressed children and adolescents treated with fluoxetine, duloxetine, or placebo. Methods The study samples included training datasets ( N = 271) from patients with major depressive disorder (MDD) treated with fluoxetine and testing datasets from patients with MDD treated with duloxetine ( N = 255) or placebo ( N = 265). Treatment trajectories were generated using probabilistic graphical models (PGMs). Unsupervised machine learning identified specific depressive symptom profiles and related thresholds of improvement during acute treatment. Results Variation in six depressive symptoms (difficulty having fun, social withdrawal, excessive fatigue, irritability, low self‐esteem, and depressed feelings) assessed with the Children’s Depression Rating Scale‐Revised at 4–6 weeks predicted treatment outcomes with fluoxetine at 10–12 weeks with an average accuracy of 73% in the training dataset. The same six symptoms predicted 10–12 week outcomes at 4–6 weeks in (a) duloxetine testing datasets with an average accuracy of 76% and (b) placebo‐treated patients with accuracies of 67%. In placebo‐treated patients, the accuracies of predicting response and remission were similar to antidepressants. Accuracies for predicting nonresponse to placebo treatment were significantly lower than antidepressants. Conclusions PGMs provided clinically meaningful predictions in samples of depressed children and adolescents treated with fluoxetine or duloxetine. Future work should augment PGMs with biological data for refined predictions to guide the selection of pharmacological and psychotherapeutic treatment in children and adolescents with depression.

Age at depressive onset (AAO) corresponds to unique symptomatology and clinical outcomes. Integration of genome-wide association study (GWAS) results with additional “omic” measures to evaluate AAO has not been reported and may reveal novel markers of susceptibility and/or resistance to major depressive disorder (MDD). To address this gap, we integrated genomics with metabolomics using data-driven network analysis to characterize and differentiate MDD based on AAO. This study first performed two GWAS for AAO as a continuous trait in (a) 486 adults from the Pharmacogenomic Research Network-Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS), and (b) 295 adults from the Combining Medications to Enhance Depression Outcomes (CO-MED) study. Variants from top signals were integrated with 153 p180-assayed metabolites to establish multi-omics network characterizations of early (<age 18) and adult-onset depression. The most significant variant (p = 8.77 × 10−8) localized to an intron of SAMD3. In silico functional annotation of top signals (p < 1 × 10−5) demonstrated gene expression enrichment in the brain and during embryonic development. Network analysis identified differential associations between four variants (in/near INTU, FAT1, CNTN6, and TM9SF2) and plasma metabolites (phosphatidylcholines, carnitines, biogenic amines, and amino acids) in early- compared with adult-onset MDD. Multi-omics integration identified differential biosignatures of early- and adult-onset MDD. These biosignatures call for future studies to follow participants from childhood through adulthood and collect repeated -omics and neuroimaging measures to validate and deeply characterize the biomarkers of susceptibility and/or resistance to MDD development.

PURPOSE Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD). METHODS This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or severe) or relapse-free survival (CRFS). RESULTS Among 346 patients enrolled, 327 received HCT, 300 per protocol. Intent-to-treat rates of 2-year CRFS were 50.6% for CD34 selection (hazard ratio [HR] compared with control, 0.80; 95% CI, 0.56 to 1.15; P = .24), 48.1% for PTCy (HR, 0.86; 0.61 to 1.23; P = .41), and 41.0% for control. Corresponding rates of overall survival were 60.1% (HR, 1.74; 1.09 to 2.80; P = .02), 76.2% (HR, 1.02; 0.60 to 1.72; P = .95), and 76.1%. CD34 selection was associated with lower moderate to severe cGVHD (HR, 0.25; 0.12 to 0.52; P = .02) but higher transplant-related mortality (HR, 2.76; 1.26 to 6.06; P = .01). PTCy was associated with comparable cGVHD and survival outcomes to control, and a trend toward lower disease relapse (HR, 0.52; 0.28 to 0.96; P = .037). CONCLUSION CNI-free interventions as performed herein did not result in superior CRFS compared with tacrolimus and methotrexate with BM. Lower rates of moderate and severe cGVHD did not translate into improved survival.

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen (BCMA) targeting single-domain antibodies, demonstrated early, deep, and durable responses in the phase 1b/2 CARTITUDE-1 study in patients (pts) with relapsed/refractory multiple myeloma (RRMM) who had been heavily pretreated (Berdeja, Lancet, 2021). After a median follow-up of 12.4 months, the overall response rate (ORR; as assessed by independent review committee) was 97%, with 67% of pts achieving stringent complete response (sCR). The 12-month progression-free survival (PFS) and overall survival (OS) rates were 77% and 89%, respectively. Here, we report updated results from CARTITUDE-1 with longer duration of follow-up (median 18 months). Methods: Eligible pts had MM and received ≥3 prior therapies or were refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), and had received a PI, IMiD, and an anti-CD38 antibody. After apheresis, bridging therapy was permitted. Pts received a single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg; range 0.5-1.0×10 6) 5-7 days (d) after lymphodepletion (300 mg/m 2 cyclophosphamide, 30 mg/m 2 fludarabine daily for 3 d). Primary objectives were to characterize cilta-cel safety, confirm the recommended phase 2 dose (phase 1b), and evaluate cilta-cel efficacy (phase 2). Response was assessed per IMWG criteria by an independent review committee and minimal residual disease (MRD) negativity at 10 -5 by next-generation sequencing. In this combined phase 1b and phase 2 analysis, cytokine release syndrome (CRS; per Lee et al Blood 2014 grading criteria) and neurotoxicity (by CTCAE v5.0) were mapped to the ASTCT criteria for CRS and immune effector cell-associated neurotoxicity (ICANS), respectively. Results: As of Feb 11, 2021, 97 pts (58.8% male; median age 61.0 years [range 43-78]) received cilta-cel. Pts had received a median of 6 (range 3-18) prior lines of therapy; 83.5% were penta-drug exposed, 87.6% were triple-class refractory, 42.3% were penta-drug refractory, and 99.0% were refractory to last line of therapy. ORR was 97.9% (95% CI: 92.7-99.7); 80.4% of pts achieved sCR, and 94.8% achieved very good partial response or better (Figure). The median time to first response was 1 month (range 0.9-10.7), median time to best response was 2.6 months (range 0.9-15.2), and median time to complete response or better was 2.6 months (range 0.9-15.2). The median duration of response was 21.8 months (95% CI: 21.8-not estimable). Of 61 pts evaluable for MRD, 91.8% were MRD negative at the 10 -5 threshold; MRD 10 -5 negativity was sustained for ≥6 months in 44.3% (27/61) of pts and ≥12 months in 18% (11/61) of pts. The 18-month PFS and OS rates were 66.0% (95% CI: 54.9-75.0) and 80.9% (95% CI: 71.4-87.6), respectively. 18-month PFS rates in pts who achieved sustained MRD for ≥6 months and ≥12 months were 96.3% (95% CI: 76.5-99.5) and 100%, respectively. The most common grade 3/4 hematologic AEs in ≥25% of pts were neutropenia (94.8%), anemia (68.0%), leukopenia (60.8%), thrombocytopenia (59.8%), and lymphopenia (49.5%). There were no fatalities related to cytopenias, and no new safety signals with longer follow-up. CRS occurred in 94.8% of pts (mostly grade 1/2); median time to onset was 7 d (range 1-12), and CRS resolved within 14 d in 98.9% of pts. There was no new CAR T-cell neurotoxicity since the previous report. Post cilta-cel infusion, 21 deaths occurred during the study: 0 within first 30 d, 2 within 100 d, and 19 more than 100 d post infusion. Ten deaths were due to disease progression, 6 were treatment-related (as assessed by the investigator), and 5 were due to AEs unrelated to treatment. One patient was retreated with cilta-cel (for progressive disease) and had stable disease (per computerized algorithm) post-retreatment with no incidence of CAR T-cell neurotoxicity. Conclusions: At a longer median follow-up of 18 months, a single cilta-cel infusion led to early, deep, and durable responses in heavily pre-treated pts with MM. Follow-up is ongoing and updated data will be presented. Cilta-cel demonstrated a manageable safety profile with no new safety signals observed with longer follow-up. Further investigations of cilta-cel are ongoing in earlier lines of therapy (CARTITUDE-2 [NCT04133636], CARTITUDE-4 [NCT04181827], and CARTITUDE-5 [NCT04923893]) and in outpatient settings. Figure 1 Figure 1. Disclosures Martin: GlaxoSmithKline: Consultancy; Janssen: Research Funding; Sanofi: Research Funding; Amgen: Research Funding. Usmani: Takeda: Consultancy, Research Funding, Speakers Bureau; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; EdoPharma: Consultancy; Array BioPharma: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; GSK: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy. Berdeja: Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; Celularity, CRISPR Therapeutics: Research Funding; Abbvie, Acetylon, Amgen: Research Funding; EMD Sorono, Genentech: Research Funding. Jakubowiak: Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Cohen: Novartis: Research Funding; BMS/Celgene: Consultancy; Takeda: Consultancy; Genentech/Roche: Consultancy; Oncopeptides: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy, Research Funding. Hari: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Deol: Kite, a Gilead Company: Consultancy. Lesokhin: bristol myers squibb: Research Funding; Iteos: Consultancy; pfizer: Consultancy, Research Funding; Behringer Ingelheim: Honoraria; Trillium Therapeutics: Consultancy; Serametrix, Inc: Patents & Royalties; Genetech: Research Funding; Janssen: Honoraria, Research Funding. Munshi: Adaptive Biotechnology: Consultancy; Karyopharm: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Legend: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. O'Donnell: Onocopeptide: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Bristol Myer Squibb: Consultancy; Adaptive: Consultancy; Takeda: Consultancy. Stewart: Oncopeptides: Honoraria; Janssen: Honoraria; GSK: Honoraria; BMS: Honoraria; Amgen: Honoraria; Skyline diagnostics: Consultancy; Genomcs England: Membership on an entity's Board of Directors or advisory committees; Tempus Inc.: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; PikSci Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Sanofi Aventis: Honoraria. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Yeh: Janssen: Current Employment. Banerjee: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Allred: Janssen: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zudaire: Janssen: Current Employment. Deraedt: Janssen: Current Employment. Olyslager: Janssen: Current Employment. Pacaud: Legend Biotech: Current Employment. Lin: Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Gamida Cell: Consultancy; Sorrento: Consultancy; Legend: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding. Jagannath: Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. OffLabel Disclosure: At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved.

Abstract BACKGROUND: Our group recently reported on the results of Blood and Marrow Transplant (BMT) Clinical Trials Network (CTN) 1101 a randomized comparison between double umbilical cord blood (dUCB) and haploidentical bone marrow (haplo) with post-transplant cyclophosphamide (ptCy) in the nonmyeloablative setting that showed similar progression free survival (PFS) between the two treatment groups, but lower non-relapse mortality (NRM) and better of overall survival (OS) in the haplo arm. In this secondary analysis we sought to investigate if transplant center experience with haplo and or cord blood HCT had an impact on outcomes. PATIENTS AND METHODS: All patient randomized in BMT CTN 1101 were included. In order to determine the transplant center experience with either haplo or dUCB we queried the Center for International Blood and Marrow Transplant Research (CIBMTR) for number of transplants with each platform in the year prior to initiation of the study. Centers were then grouped as dUCB center (&gt; 10 dUCB, n=117, 10 centers), Haplo center (&gt;10 haplo and ≤10 dUCB, n=110, 2 centers), and ≤10 haplo and ≤10 dUCB HCTs (other center, n=140, 21 centers). Further analysis considered the alternative cut-off for haplo (&gt; 5 vs ≤ 5) experience, and considered the outcomes based on the donor experience vs. others (e.g. dUCB &gt; 10 vs. ≤ 10; haplo &gt; 5 vs. ≤ 5). RESULTS: The effect of center experience on HCT outcomes shown in Figure, below . After adjusting for age, Karnofsky performance score and, disease risk index we found that there was no difference in outcomes between haplo and dUCB for centers that were experienced with dUCB or had limited to no experience with either dUCB or haplo. In contrast, in centers that were primarily experienced with haplo had better outcomes with this donor type, as compared to dUCB. The higher risk of treatment failure (relapse or death) and overall mortality in dUCB in haplo experienced centers was driven by significantly higher risk of relapse. We then considered the transplant experience with each of the donor types separately. In transplant centers that had performed &gt; 10 dUCB, there were similar outcomes for recipients of both dUCB and haplo. Similarly, centers that had ≤ 5 haplo HCTs had no difference in outcomes between donor types suggesting an overlap with centers that had performed &gt; 10 dUCB HCTs. Overall mortality was higher among dUCB recipients in centers that had performed ≤ 10 dUCB. Notably, the hazard ratio of non-relapse mortality favored haplo in all four donor experience type of transplant center, albeit not statistically significant. CONCLUSION: Except for dUCB recipients in centers with &lt; 10 dUCB/year had worse overall mortality, primarily driven by relapse, the transplant center experience in the year prior to the initiation of BMT CTN 1101 had limited impact on the outcomes of this randomized clinical trial. Figure 1 Figure 1. Disclosures Brunstein: NANT: Research Funding; FATE: Research Funding; GamidaCell: Research Funding; BlueRock: Research Funding; AlloVir: Consultancy. Costa: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria. Cutler: Deciphera: Consultancy; Cimeio: Consultancy; Editas: Consultancy; Kadmon: Consultancy; Pfizer: Consultancy; Mallinckrodt: Consultancy; CareDx: Consultancy; Incyte: Consultancy; Omeros: Consultancy; Syndax: Consultancy; Mesoblast: Consultancy; Jazz: Consultancy. Horowitz: Sobi: Research Funding; Regeneron: Research Funding; Orca Biosystems: Research Funding; Tscan: Research Funding; Xenikos: Research Funding; Miltenyi Biotech: Research Funding; Stemcyte: Research Funding; Medac: Research Funding; Vor Biopharma: Research Funding; Kite/Gilead: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Kiadis: Research Funding; Seattle Genetics: Research Funding; Mesoblast: Research Funding; GlaxoSmithKline: Research Funding; Sanofi: Research Funding; Pfizer, Inc: Research Funding; Omeros: Research Funding; Magenta: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; Vertex: Research Funding; Genentech: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Shire: Research Funding; Gamida Cell: Research Funding; Daiicho Sankyo: Research Funding; CSL Behring: Research Funding; Chimerix: Research Funding; Bristol-Myers Squibb: Research Funding; bluebird bio: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Allovir: Consultancy; Actinium: Research Funding. Horwitz: Gamida Cell: Research Funding. McGuirk: Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Pluristem Therapeutics: Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astelllas Pharma: Research Funding; Gamida Cell: Research Funding; Fresenius Biotech: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau. Rezvani: US Department of Justice: Consultancy; Kaleido: Other: One-time scientific advisory board; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding. Rybka: Spark Therapeutics: Consultancy; Merck: Consultancy. Vasu: Kiadis, Inc.: Research Funding; Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Clinical data support the combination of an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). The combination of lenalidomide, bortezomib, and low-dose dexamethasone is a very active, well-tolerated standard of care in the transplant-ineligible NDMM population. Ixazomib, an oral proteasome inhibitor is approved by the US Food and Drug Administration in combination with lenalidomide and dexamethasone for the treatment of relapsed MM. Given that ixazomib has improved binding kinetics and pharmacologic profile compared with bortezomib, it is expected that these differences will translate into similar, if not improved, efficacy and safety profiles in the upfront setting. A phase l/ll study of lenalidomide, ixazomib, and dexamethasone in previously untreated patients with MM demonstrated that this combination was well-tolerated and active (NCT01217957). More recently, the GRIFFIN study evaluated the addition of the anti-CD38 monoclonal antibody, daratumumab to lenalidomide, bortezomib, and dexamethasone in transplant-eligible NDMM and demonstrated the ability of daratumumab to improve efficacy of the three-drug combination with an acceptable safety profile. Building upon these data, our study evaluates the addition of daratumumab to the all-oral regimen of lenalidomide, ixazomib, and dexamethasone in transplant-ineligible NDMM. The combination proposed in this study has been evaluated in NDMM irrespective of transplant eligibility and has demonstrated excellent efficacy and tolerability. Responses were rapid with 88% achieving a partial response (PR) or better after 2 cycles (33% very good partial response (VGPR) and 52% VGPR for 29 patients who had completed 4 cycles) with an overall response rate of 95%. 1 In our study, transplant-ineligible NDMM patients will be randomized to receive 12 cycles of induction with lenalidomide, ixazomib, dexamethasone, and daratumumab followed by lenalidomide alone versus lenalidomide, ixazomib, and daratumumab. Study Design and Methods: A randomized, phase II clinical trial (NCT04009109) is being conducted to assess the impact on progression-free survival (PFS) of the addition of ixazomib and daratumumab to lenalidomide as maintenance treatment following induction with lenalidomide, ixazomib, dexamethasone, and daratumumab. In this ongoing trial, eligible patients are randomized 1:1 to Arm A (12 cycles of lenalidomide, ixazomib, dexamethasone, and daratumumab followed by lenalidomide until disease progression or unacceptable toxicity or a maximum of 2 years of maintenance therapy) vs. Arm B (12 cycles of lenalidomide, ixazomib, dexamethasone, and daratumumab, followed by lenalidomide, ixazomib, and daratumumab until disease progression or unacceptable toxicity or a maximum of 2 years maintenance therapy). Eligible patients have NDMM requiring treatment, are ≥18 years, have ECOG PS of 0-2, and must have been deemed ineligible for stem cell transplantation. The primary endpoint is PFS. With a sample size of 188 patients (94 patients per arm) enrolled over a 36-month period and followed for a minimum of 24 months after the close of enrollment, a one-sided alpha=0.10 log rank test will have an 85% chance of detecting an increase in median PFS time from 30 months to 48 months (a hazard ratio of 0.625) with the addition of ixazomib and daratumumab to lenalidomide as a maintenance treatment following induction with ixazomib, lenalidomide, dexamethasone, and daratumumab. Secondary outcomes of interest include minimal residual disease, overall survival, changes in body composition, quality of life, psychosocial measures of functional status including social activity and support, psychological state, and nutrition using a geriatric assessment tool, and the association of these psychosocial measures with therapy-associated toxicities. 1Kapoor et al. Blood (2019) 134 (Supplement_1): 864. Support: Alliance Foundation Trials; Janssen, Takeda, Celgene; https://acknowledgments.alliancefound.org Figure 1 Figure 1. Disclosures O'Donnell: Bristol Myer Squibb: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Oncopeptide: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy. Nadeem: GSK: Consultancy; Karyopharm: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Bristol Myer Squibb: Consultancy. Dinner: Kite/Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Yee: Takeda: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Adaptive: Consultancy; GSK: Consultancy. Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy. Tuchman: Karyopharm: Research Funding; Shattuck Labs: Consultancy; Sanofi / Genzyme: Consultancy, Research Funding; Caelum: Consultancy, Research Funding; Oncopeptides: Consultancy. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Janssen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; Protocol Intelligence: Consultancy; Karyopharm: Consultancy, Research Funding; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding.