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Background Single-agent belamaf, a B-cell maturation antigen-targeting antibody-drug conjugate, induced durable responses with a manageable safety profile in patients with RRMM at 13 months of follow-up (DREAMM-2; NCT03525678). The unique multimodal mechanisms of action (MoAs) of belamaf, in combination with MoAs of selected agents, have the potential to achieve synergistic effects in RRMM to further enhance the benefit-risk profile. Belamaf is being evaluated in DREAMM-5 in various lines of treatment, as monotherapy or in combination with other agents. Methods DREAMM-5 (NCT04126200) is a phase 1/2 platform study that utilizes a master protocol with separate sub-studies comprised of sequential dose-exploration (DE) and cohort-expansion (CE) phases to identify effective belamaf combinations compared with a shared single-agent belamaf control arm (CE phase only). In the DE phase, patients will be assigned to one of the multiple belamaf dosing combination cohorts by a predetermined algorithm (N≤10 per cohort). A recommended phase 2 dose (RP2D) for each combination will be identified based on safety and preliminary efficacy in the DE phase. An interim analysis of safety, pharmacokinetic, biomarker, and efficacy data will be performed for each combination to determine if it should move forward to the CE phase. Patients in the CE phase (N≥35 per cohort) will be randomized to a sub-study, and within a sub-study, to either the combination arm or belamaf control arm. Patients will also be stratified by number of prior therapies; eligible patients will have received ≥3 prior lines, including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody. All patients will provide informed consent for participation. Primary objectives of the study are to identify the RP2D (DE phase), the overall response rate (≥partial response, CE phase), and safety and tolerability for each combination. Sub-study 1 (combination with GSK3174998, OX40 agonist antibody) is no longer open to enrollment. Sub-studies 2 (combination with GSK3359609, feladilimab, anti-ICOS agonist), 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics], gamma-secretase inhibitor), and 4 (combination with dostarlimab, PD-1 antagonist antibody) are currently open to enrollment. Sub-study 5 (combination with isatuximab [Sanofi], CD38 antagonist antibody) will be open to enrollment soon. Additional sub-studies will be explored based on scientific rationale and/or available preclinical combination data. Funding GSK (208887; NCT04126200). Belamaf drug linker technology licensed from Seagen Inc.; mAb produced using POTELLIGENT Technology licensed from BioWa. Nirogacestat and isatuximab produced by and used in collaboration with SpringWorks Therapeutics and Sanofi, respectively Encore Statement ©2021 European Hematology Association, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 EHA Annual Meeting. All rights reserved.