Belantamab mafodotin plus venetoclax in t(11;14)-positive relapsed or refractory multiple myeloma – the BELI(E)VE trial

Abstract Background Multiple myeloma (MM) is a widely incurable B-cell malignancy that predominantly affects older adults, representing 10% of hematologic cancers. Despite advancements in therapy that have significantly extended median overall survival (OS), MM remains a clinical challenge with poor prognosis for patients refractory to multiple drug classes. There is a critical need for innovative and personalized treatments, including for patients with translocation (11;14), a subgroup characterized by specific therapeutic vulnerabilities. Combined targeting of B-cell maturation antigen (BCMA) and BCL-2 presents a promising personalized treatment strategy for inducing deep remissions and improving outcomes in this specific subgroup. Methods The BELI(E)VE trial (NCT05853965) is a German investigator-initiated, prospective, multicenter, open-label phase I/IIa study designed to evaluate the combination of belantamab mafodotin and venetoclax, with or without dexamethasone, in patients with relapsed or refractory multiple myeloma (RRMM) with ≥1 prior treatment line and t(11;14) translocation. The study consists of a dose escalation phase (phase I) to determine the recommended phase 2 dose (RP2D), followed by a dose expansion phase (phase IIa) to assess clinical activity at the RP2D. The phase I portion employs a traditional 3+3 design across four dose levels, while the phase IIa expansion will include 25 additional patients treated at the RP2D. Safety, tolerability, and preliminary efficacy will be evaluated through comprehensive assessments, including assessment for minimal residual disease negativity and ocular exams. Discussion The BELI(E)VE trial aims to establish a novel personalized therapeutic approach for a specific subset of MM patients by combining belantamab mafodotin and venetoclax. This combination targets BCMA and BCL-2, potentially inducing deep and durable remissions. The study will provide critical data on the safety and efficacy of this combination, aiming to improve outcomes in t(11;14)-positive RRMM patients. The translational component, examining circulating tumor cells and mitochondrial activity, may identify mechanisms of resistance and response, guiding future personalized therapeutic strategies. Trial registration NCT05853965 (2023-04-22).