First EXCALIBER-RRMM results presented for Zenbexus plus daratumumab in relapsed or refractory multiple myeloma – BMS

Bristol Myers Squibb announced first time presentation of results from the prespecified analysis of the pivotal Phase 3 EXCALIBER-RRMM trial (NCT04975997) evaluating ZENBEXUS (iberdomide) in combination with daratumumab and dexamethasone (ZDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma (RRMM).

At a median follow-up of 15.7 months in 420 evaluable patients, the study showed a statistically significant and clinically meaningful improvement in minimal residual disease (MRD)-negative complete response (CR) rate, with significantly more patients achieving an MRD-negative CR with ZDd compared to DVd (41.1% vs. 20.7% [95% CI: 11.5%–28.6%]; p<0.0001; odds ratio 2.75 [95% CI: 1.77–4.30]). The dual primary endpoints of the study are MRD-negative CR rate and progression-free survival (PFS).

These data were presented [Abstract #LBA12] at the 23rd Annual Meeting of the International Myeloma Society (IMS 2026) taking place in Glasgow, Scotland. These data were also simultaneously published in The Lancet Oncology.

Treatment benefit with ZDd was consistent across prespecified subgroups, including patients with prior lenalidomide exposure, and refractoriness to lenalidomide (including in the last prior line of treatment). The overall response rate (ORR) was 88.9% with ZDd compared to 76.1% with DVd, and the rate of complete response or better was also nearly doubled at 45.9% vs. 24.9%, respectively.

“Achieving deep, MRD-negative complete responses early in relapse is strongly associated with long-term clinical benefit and overall disease control for patients with multiple myeloma,” said Sagar Lonial, MD, FACP, Professor and Chair of the Department of Hematology and Medical Oncology, Emory University School of Medicine, and Chief Medical Officer, Winship Cancer Institute of Emory University. “These detailed EXCALIBER-RRMM results demonstrate that adding oral iberdomide to this regimen doubled the rate of MRD-negative complete responses or better across subgroups compared to standard DVd, and delivered high rates of overall and complete responses, reinforcing the triplet as a highly effective and manageable regimen that can be easily administered across diverse care settings, including community practices.”

The safety profile of ZDd was consistent with what is expected of the combination. Grade 3/4 neutropenia occurred in 84.3% of patients treated with ZDd vs. 11.3% treated with DVd, occurring predominantly during the first two cycles. Neutropenia was mostly manageable with G-CSF support and temporary dose interruptions (dose reduction of ZENBEXUS due to neutropenia was 13.2%; discontinuation of ZENBEXUS due to neutropenia was 1.0%). Grade 3/4 infections occurred in 39.2% of patients treated with ZDd vs. 21.6% with DVd, with fatal infections remaining low (2.0% vs. 1.5%). Notably, rates of peripheral sensory neuropathy were markedly lower with ZDd compared with DVd (any grade: 12.3% vs. 42.6%; Grade 3/4: 2.9% vs. 5.4%).

“These Phase 3 results reinforce the potential of ZENBEXUS to advance treatment for patients with relapsed or refractory multiple myeloma,” said Cristian Massacesi, executive vice president, chief medical officer and head of development, Bristol Myers Squibb. “As the first therapy in multiple myeloma to demonstrate superiority on an MRD-negative complete response primary endpoint, ZENBEXUS marks an important advance for patients and further validates the potential of targeted protein degradation to expand what is possible in multiple myeloma.”

Based on these results from EXCALIBER-RRMM, ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone received accelerated approval from the FDA for the treatment of adult patients with multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent, marking the arrival of a new treatment class. Evaluation of the dual primary endpoint of PFS in the confirmatory analysis cohort (n=800) is ongoing.

About EXCALIBER-RRMM
EXCALIBER-RRMM (NCT04975997) is a Phase 3, multicenter, two-stage, randomized, open-label study evaluating the efficacy and safety of ZENBEXUS (iberdomide) in combination with daratumumab and dexamethasone (ZDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma (RRMM). The study included a dose optimization stage and was designed to assess dual-primary endpoints of minimal residual disease (MRD)-negative complete response (CR) rate and progression-free survival (PFS), with additional secondary endpoints including overall survival (OS), overall response rate (ORR), safety and sustained MRD negativity. Eligible participants included adults with 1 to 2 prior lines of anti-myeloma therapy with progressive disease. A total of 939 patients were randomized. The primary efficacy population for MRD-negative CR included the first 420 patients randomized to the ZENBEXUS (1 mg) + Dd arm (n=207) or the comparator daratumumab, bortezomib, and dexamethasone (DVd) arm (n=213). Treatment in both arms was administered until disease progression or unacceptable toxicity.

Citation: Iberdomide plus daratumumab and dexamethasone versus daratumumab, bortezomib, and dexamethasone in patients with relapsed or refractory multiple myeloma (EXCALIBER-RRMM): an open-label, randomised, controlled, phase 3 trial. Authors: Sagar Lonial, Meletios A Dimopoulos, Maria Gavriatopoulou et al. Lancet Oncol. 2026 Sep 25:S1470-2045(26)00450-X. doi: 10.1016/S1470-2045(26)00450-X. Epub ahead of print. PMID: 42790445.