BELI(E)VE protocol evaluates belantamab mafodotin plus venetoclax in t(11;14)-positive relapsed or refractory multiple myeloma

The published BELI(E)VE protocol describes a prospective, multicenter, open-label phase I/IIa trial of belantamab mafodotin combined with venetoclax, with or without dexamethasone, in adults with relapsed or refractory multiple myeloma carrying the t(11;14) translocation. The investigator-initiated study is designed to establish a recommended phase 2 dose and assess the combination’s safety and preliminary clinical activity; it does not report patient outcomes.

The trial is registered as NCT05853965 and is planned to enroll as many as 49 patients at German hospitals. Phase I will evaluate four dose levels of belantamab mafodotin plus venetoclax, with or without dexamethasone, to determine the maximum tolerated dose and recommended phase 2 dose. A subsequent phase IIa expansion will treat 25 additional patients at the dose selected through phase I, based on safety, tolerability and preliminary efficacy. The first patient was enrolled in April 2024, and the total planned trial duration is 44 months, with survival follow-up continuing through the last patient’s final study visit.

Eligible patients must have relapsed or refractory multiple myeloma with documented t(11;14) translocation, progressive disease during or after the most recent treatment line, and sufficient organ function. The protocol was amended from its original requirement for at least four prior treatment lines. Under the revised criteria, enrollment can begin at first relapse after at least one treatment line, provided patients have previously received a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 monoclonal antibody. The selected population therefore has exposure to three major classes of myeloma therapy, although the protocol does not require all participants to be refractory to each class.

Phase I uses a traditional 3+3 dose-escalation design. Cohorts of three patients will receive successively assessed dose combinations, and an additional three patients may be enrolled at the same dose level if a dose-limiting toxicity occurs. The design anticipates 12 patients if 12 can be allocated across the four cohorts, but phase I may include between 12 and 24 patients depending on dose-limiting toxicities and the need to expand a cohort. Dexamethasone is included in the third and fourth cohorts to assess a triplet regimen. An independent data and safety monitoring board, comprising two multiple myeloma experts and a biostatistician, will review the accumulated safety data and recommend the dose for phase IIa.

Belantamab mafodotin is planned at 1.9 mg/kg intravenously every six weeks. The schedule was selected to reduce the potential burden and severity of corneal toxicity while preserving antitumour activity, and it differs from the more frequent schedules used in earlier and ongoing combination studies. Venetoclax will be tested orally at 400 mg or 800 mg once daily, beginning with 400 mg in the initial belantamab mafodotin combination cohort. The final phase I cohort is designed to assess belantamab mafodotin at 1.9 mg/kg every six weeks, venetoclax at 800 mg daily and dexamethasone at 40 mg weekly, with the steroid dose reduced to 20 mg weekly for patients aged 75 or older. These are investigational trial regimens rather than established approaches to treatment.

The phase I primary objectives are to establish the maximum tolerated and recommended phase 2 doses and to characterize the safety profile of the combination. Dose-limiting toxicities include specified prolonged grade 4 neutropenia or thrombocytopenia, any grade 4 nonhematological toxicity, and selected grade 3 nonhematological events judged possibly related to the study drugs by the monitoring board. Adverse events and changes in clinical signs and laboratory parameters will also be assessed using Common Terminology Criteria for Adverse Events version 5.0. The phase IIa primary objective is to assess safety and efficacy at the dose established in phase I.

Secondary efficacy endpoints include overall response rate, International Myeloma Working Group response categories, progression-free survival, duration of response, health-related quality of life and the proportion of patients achieving minimal residual disease negativity at a sensitivity of 10−5. Bone marrow testing is planned every four cycles, approximately every six months, and at progression, with minimal residual disease status assessed by a central laboratory. Quality-of-life questionnaires—EQ-5D, QLQ-C30 and QLQ-MY20—will be collected at baseline and additional follow-up points. Exploratory analyses will examine circulating tumor cells, mitochondrial activity and single-cell immunophenotyping to investigate possible response and resistance patterns.

Because corneal toxicity is a known concern with belantamab mafodotin, the protocol requires a baseline ophthalmologic examination and examinations before dosing during the first six cycles, followed by assessments every three months when no significant findings are present. Participants receive preservative-free artificial tears, are offered cooling eye masks during infusion, and may not wear contact lenses during treatment. Dose holds or reductions follow a scale integrating ophthalmologic findings, best-corrected visual acuity and patient-reported symptoms. The protocol also recommends anti-infective prophylaxis and follow-up for toxicity, remission status and subsequent antimyeloma treatment.

The principal limitation is that this is a protocol paper without efficacy, safety or tolerability results for BELI(E)VE, and no datasets were generated or analysed for the publication. The open-label, single-country design is intended primarily to establish a dose and provide preliminary evidence on safety and activity rather than a definitive comparison with another regimen. The planned analyses are descriptive and exploratory. Whether simultaneous targeting of BCMA and BCL-2 can benefit patients with t(11;14)-positive disease therefore remains unestablished and will require completion of both study phases and peer-reviewed reporting of the observed data.

Subject of Research: A phase I/IIa protocol testing dual BCMA and BCL-2 targeting in t(11;14)-positive relapsed or refractory multiple myeloma

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

Article References: Schaefers, C., Khandanpour, C., Hänel, M., Kull, M., Alsdorf, W., Kamili, A., Kosch, R., Krüger, W., Bohl, S., Mai, E. K., Scheid, C., Einsele, H., Brüggemann, M., Suling, A., Zapf, A., Bokemeyer, C., Weisel, K., & Leypoldt, L. (2026). Belantamab mafodotin plus venetoclax in t(11;14)-positive relapsed or refractory multiple myeloma – the BELI(E)VE trial. BMC Cancer, 26(1), Article 1141. https://doi.org/10.1186/s12885-026-16905-3

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16905-3

Keywords: BELI(E)VE trial, multiple myeloma, t(11;14) translocation, belantamab mafodotin, venetoclax, phase I/IIa, dose escalation, clinical trial protocol, BCMA, BCL-2, Belantamab, mafodotin