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Purpose: Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab., Methods: This phase I study (NCT03314181) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity., Results: Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd., Conclusion: VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14)., Competing Interests: Nizar J. BahlisHonoraria: Celgene, Janssen, AbbVie, Amgen, Sanofi, Takeda, Karyopharm Therapeutics, GlaxoSmithKline, Genentech/RocheConsulting or Advisory Role: Janssen, Celgene, Amgen, Sanofi, Takeda, Pfizer, Karyopharm TherapeuticsResearch Funding: Janssen, Celgene Rachid BazConsulting or Advisory Role: Karyopharm Therapeutics, BMS, AbbVie, Oncopeptides, Shattuck Labs, SanofiResearch Funding: Karyopharm Therapeutics, Celgene, Merck Sharp & Dohme, Takeda, Signal Genetics, AbbVie, Sanofi, Janssen, BMS Simon J. HarrisonHonoraria: AbbVie, Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen Cilag, Novartis, Roche/Genentech, Takeda, Haemalogix, SanofiConsulting or Advisory Role: AbbVie, Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen Cilag, Novartis, Roche/Genentech, Takeda, Haemalogix, SanofiSpeakers' Bureau: AbbVie, Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen Cilag, Novartis, Roche/Genentech, Takeda, TerumoResearch Funding: Haemalogix, Janssen CilagExpert Testimony: EUSA Pharma, Terumo Hang QuachConsulting or Advisory Role: GlaxoSmithKline, Celgene, Karyopharm Therapeutics, Janssen-Cilag, CSL Behring, Amgen, SanofiResearch Funding: Celgene, Amgen, Karopharm, GlaxoSmithKline, Sanofi Torben PlesnerConsulting or Advisory Role: Janssen, Celgene, Takeda, AbbVie, Genmab, Oncopeptides, GenentechSpeakers' Bureau: Janssen, TakedaResearch Funding: Janssen, Genmab, Celgene, Takeda, Oncopeptides, Genentech, AbbVie, Roche Philippe MoreauHonoraria: Celgene, Janssen-Cilag, Amgen, GlaxoSmithKline, AbbVie, SanofiConsulting or Advisory Role: Celgene, Janssen, Amgen, GlaxoSmithKline, Sanofi, AbbVie Simon D. GibbsHonoraria: Janssen Oncology, Pfizer, AbbVie, Celgene/Bristol Myers Squibb, AmgenConsulting or Advisory Role: AbbVie Abdullah Al MasudEmployment: AbbVieStock and Other Ownership Interests: AbbVie Jeremy A. RossEmployment: AbbVieStock and Other Ownership Interests: AbbVie Orlando BuenoEmployment: AbbVieStock and Other Ownership Interests: AbbVieResearch Funding: AbbVieTravel, Accommodations, Expenses: AbbVie Jonathan L. KaufmanHonoraria: TecnofarmaConsulting or Advisory Role: Janssen, Celgene, TG Therapeutics, Sanofi, Tecnofarma, GenentechResearch Funding: Merck, Celgene, Janssen, Sutro Biopharma, Fortis, Amgen, AbbVie/Genentech, Bristol Myers SquibbTravel, Accommodations, Expenses: Janssen, Celgene, Bristol Myers Squibb, Sanofi, Amgen, TakedaNo other potential conflicts of interest were reported.