Background: Despite the introduction of new compounds to manage relapsed/refractory (R/R) multiple myeloma (MM) over the last decade, none are curative. Trials investigating novel agents or combinations are critical to advancing therapy. Overexpression of BCL-2 may contribute to the pathogenesis of t(11;14)-positive MM. Venetoclax (Ven) is a selective, potent, orally bioavailable BCL-2 inhibitor with activity in R/R t(11;14)-positive MM. Daratumumab, bortezomib, and dexamethasone is an FDA-approved triplet for MM. The addition of Ven to this regimen (± bortezomib) may result in additive antitumor effects via complementary mechanisms. Methods: This phase 1/2, multicenter study of Ven, daratumumab, and dexamethasone, with or without bortezomib, in R/R MM (NCT03314181) will have 2 parts, each with a dose-escalation and dose-expansion phase. Part 1 will evaluate Ven, daratumumab, dexamethasone (VenDd) in t(11;14)-positive patients who have had ≥ 3 prior therapies including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double refractory to both. The dose escalation phase will evaluate safety and tolerability; the randomized, blinded, expansion phase will assess the objective response rate of VenDd versus placebo-Dd. Part 2 will examine VenDd and bortezomib (VenDVd) in patients who have received 1 to 3 prior therapies and are not PI-refractory. The dose escalation phase will evaluate safety and tolerability; the single-arm, open-label expansion phase will assess efficacy per the International Myeloma Working Group (IMWG) criteria. A Bayesian Optimal Interval (BOIN) design will be used to guide dose escalation/de-escalation decisions in Parts 1 and 2. Secondary objectives will include progression free survival, duration of response, time-to-progression, minimal residual disease negativity, and pharmacokinetics and immunogenicity profiles of the Ven/daratumumab combinations. Exploratory objectives include evaluation of pharmacodynamic and predictive biomarkers associated with outcomes. Clinical trial information: NCT03314181