Bristol Myers Squibb Reports Phase 3 EXCALIBER-RRMM Results Showing Higher MRD-Negative Responses With ZENBEXUS in Relapsed or Refractory Multiple Myeloma
Bristol Myers Squibb (NYSE: BMY) has announced the first presentation of detailed results from the prespecified analysis of its pivotal Phase 3 EXCALIBER-RRMM trial, evaluating ZENBEXUS™ (iberdomide) in combination with daratumumab and dexamethasone (ZDd) in patients with relapsed or refractory multiple myeloma (RRMM). The findings showed that the ZENBEXUS-based regimen produced a statistically significant and clinically meaningful improvement in minimal residual disease (MRD)-negative complete response (CR) compared with daratumumab, bortezomib and dexamethasone (DVd). (Bristol Myers Squibb)
The results were presented as a late-breaking oral presentation, Abstract #LBA12, at the 23rd Annual Meeting of the International Myeloma Society (IMS 2026), held September 23–26 in Glasgow, Scotland. The findings were also published simultaneously in The Lancet Oncology, providing additional peer-reviewed evidence from the Phase 3 study. (Bristol Myers Squibb)
At a median follow-up of 15.7 months, the prespecified efficacy analysis included 420 evaluable patients. The study reported an MRD-negative CR rate of 41.1% among patients receiving ZDd compared with 20.7% among those treated with DVd. The difference was statistically significant, with a 95% confidence interval of 11.5%–28.6%, a p-value below 0.0001 and an odds ratio of 2.75 (95% CI: 1.77–4.30). (Bristol Myers Squibb)
The results are particularly relevant because MRD negativity represents one of the deepest levels of response measured in multiple myeloma. Bristol Myers Squibb’s EXCALIBER-RRMM program is designed around two dual primary endpoints: MRD-negative complete response and progression-free survival (PFS). While the MRD-negative CR endpoint has now demonstrated a statistically significant treatment effect, the PFS evaluation in the confirmatory analysis cohort remains ongoing. (Bristol Myers Squibb)
Stronger Depth of Response With the ZENBEXUS-Based Regimen
Multiple myeloma is a blood cancer characterized by abnormal plasma cells accumulating in the bone marrow. Although treatment advances have improved disease control and survival, patients whose disease returns or becomes resistant to previous therapies continue to require additional treatment options.
The EXCALIBER-RRMM findings focus on patients whose disease had relapsed or become refractory after one or two previous lines of anti-myeloma treatment. The trial compares a regimen containing iberdomide, a cereblon E3 ligase modulator (CELMoD), with a commonly used combination based on daratumumab, bortezomib and dexamethasone.
In addition to the MRD-negative CR findings, the study demonstrated higher overall response rates with ZDd. The overall response rate was 88.9% with ZDd compared with 76.1% with DVd. The proportion of patients achieving a complete response or better was also substantially higher, at 45.9% versus 24.9%, respectively. (Bristol Myers Squibb)
The treatment effect was reported to remain consistent across prespecified patient subgroups. This included patients who had previously received lenalidomide as well as those whose disease was refractory to lenalidomide, including patients for whom lenalidomide had been part of their most recent prior treatment line. These findings are important because prior exposure and resistance to immunomodulatory therapy can influence treatment choices in relapsed multiple myeloma.
Sagar Lonial, MD, FACP, Professor and Chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine and Chief Medical Officer of Winship Cancer Institute of Emory University, said the detailed results demonstrated that adding oral iberdomide to the treatment regimen doubled the rate of MRD-negative complete responses across subgroups compared with DVd. He also highlighted the high overall and complete response rates and the potential for the regimen to be administered in different care settings, including community practices. (Bristol Myers Squibb)
EXCALIBER-RRMM Designed to Evaluate Efficacy and Safety
EXCALIBER-RRMM, identified on ClinicalTrials.gov as NCT04975997, is a Phase 3, multicenter, randomized, open-label, two-stage clinical study. It was designed to assess the efficacy and safety of ZENBEXUS combined with daratumumab and dexamethasone against daratumumab, bortezomib and dexamethasone in patients with RRMM.
The study enrolled adults with one to two prior lines of anti-myeloma therapy and progressive disease. Across the trial, 939 patients were randomized. For the primary MRD-negative CR efficacy analysis, the first 420 randomized patients were included, comprising 207 patients assigned to the ZENBEXUS-based regimen and 213 assigned to DVd. Patients in both treatment groups continued therapy until disease progression or unacceptable toxicity. (Bristol Myers Squibb)
Beyond MRD-negative CR and PFS, the study includes secondary measures such as overall survival, overall response rate, safety and sustained MRD negativity. The ongoing PFS analysis is expected to provide additional information about whether the deeper responses observed with ZDd translate into longer periods without disease progression.
Safety Findings and Neutropenia
The safety profile observed with ZDd was described as consistent with the known effects expected from the treatment combination. One of the most prominent adverse events was neutropenia.
Grade 3 or 4 neutropenia occurred in 84.3% of patients receiving ZDd compared with 11.3% of patients receiving DVd. The majority of these events occurred during the first two treatment cycles. According to Bristol Myers Squibb, neutropenia was generally managed through measures including granulocyte colony-stimulating factor (G-CSF) support and temporary treatment interruptions.
Dose reduction of ZENBEXUS because of neutropenia occurred in 13.2% of patients, while discontinuation of ZENBEXUS because of neutropenia occurred in 1.0%. (Bristol Myers Squibb)
Grade 3 or 4 infections were also reported more frequently in the ZDd group, occurring in 39.2% of patients compared with 21.6% in the DVd group. Fatal infections remained relatively uncommon, occurring in 2.0% of patients receiving ZDd and 1.5% of those receiving DVd. (Bristol Myers Squibb)
At the same time, the study showed lower rates of peripheral sensory neuropathy with ZDd. Any-grade peripheral sensory neuropathy occurred in 12.3% of patients receiving ZDd compared with 42.6% of patients receiving DVd. Grade 3 or 4 peripheral sensory neuropathy occurred in 2.9% and 5.4% of patients, respectively. (Bristol Myers Squibb)
These findings illustrate differences in the safety profiles of the two regimens, particularly the higher incidence of neutropenia and infections with ZDd and the substantially lower frequency of peripheral sensory neuropathy compared with the bortezomib-containing comparator.
FDA Accelerated Approval for ZENBEXUS
The latest EXCALIBER-RRMM data build on a regulatory milestone reached in August 2026. On August 13, the U.S. Food and Drug Administration granted accelerated approval to ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone for adults with multiple myeloma who have received at least one prior line of therapy that included a proteasome inhibitor and an immunomodulatory agent. (Bristol Myers Squibb)
The FDA decision was based on the MRD-negative CR findings from EXCALIBER-RRMM. At the time of the regulatory decision, MRD-negative CR occurred in approximately 41% of patients receiving the ZENBEXUS-based regimen compared with approximately 21% receiving DVd. Bristol Myers Squibb described the decision as the first approval in RRMM based on an MRD-negative complete response endpoint. (Bristol Myers Squibb)
Because the indication was granted under the accelerated approval pathway, continued approval may depend on verification and description of clinical benefit through confirmatory trial results. The ongoing PFS analysis from EXCALIBER-RRMM therefore remains an important component of the development program. (Bristol Myers Squibb)
Advancing CELMoD and Targeted Protein Degradation Research
ZENBEXUS represents Bristol Myers Squibb’s development of the CELMoD class within its broader targeted protein degradation research platform. CELMoD agents are designed to modify the activity of the cereblon E3 ubiquitin ligase complex, resulting in targeted degradation of specific proteins involved in disease biology.
Bristol Myers Squibb has built extensive expertise in protein degradation through the development of immunomodulatory drugs and is expanding this research into newer protein-degradation approaches. The company’s pipeline includes CELMoDs as well as other targeted protein degradation modalities, including ligand-directed degraders and degrader antibody conjugates. (Bristol Myers Squibb)
In multiple myeloma, the company is evaluating iberdomide alongside other next-generation CELMoD programs. Bristol Myers Squibb’s development strategy includes studying iberdomide in earlier lines of relapsed or refractory disease and exploring additional applications, including maintenance treatment following autologous stem cell transplantation. (Bristol Myers Squibb)
Cristian Massacesi, executive vice president, chief medical officer and head of development at Bristol Myers Squibb, said the Phase 3 findings reinforce the potential of ZENBEXUS in RRMM and described the MRD-negative CR result as an important validation of targeted protein degradation as a strategy for developing new treatment approaches in multiple myeloma. (Bristol Myers Squibb)
PFS Analysis Remains an Important Next Step
Although the MRD-negative CR endpoint produced a positive result, EXCALIBER-RRMM has not yet completed all of its planned analyses. The study’s other dual primary endpoint is PFS, which remains under evaluation in the confirmatory analysis cohort of approximately 800 patients. (Bristol Myers Squibb)
PFS will be particularly important in understanding the broader clinical impact of the regimen. MRD-negative status provides information about the depth of response, while PFS measures the length of time patients remain without disease progression or death. Together, these endpoints can provide complementary information about the effectiveness of treatment.
The ongoing analysis will therefore help establish whether the higher depth of response observed with ZDd is accompanied by a corresponding improvement in disease control over time.
Broader Implications for Relapsed Multiple Myeloma
The EXCALIBER-RRMM findings add to the continuing evolution of treatment strategies for relapsed or refractory multiple myeloma. Treatment decisions in RRMM can become increasingly complex as patients move through successive lines of therapy and develop resistance to previously used drug classes.
The higher MRD-negative CR rate observed with ZDd, together with its overall and complete response results, provides clinical evidence supporting the continued development of iberdomide-based combinations in this setting. At the same time, the safety findings highlight the importance of monitoring blood counts and infections and managing treatment-related adverse events appropriately.
The lower frequency of peripheral sensory neuropathy observed with ZDd compared with DVd is also a notable finding, particularly because neuropathy can be an important treatment-related concern with bortezomib-containing regimens. The trade-off between the increased incidence of neutropenia and infections with ZDd and the lower incidence of peripheral sensory neuropathy will remain relevant when clinicians consider treatment characteristics.
Bristol Myers Squibb continues to evaluate ZENBEXUS in additional clinical settings. The company is also conducting the EXCALIBER Maintenance study, which is investigating iberdomide as maintenance therapy following autologous stem cell transplantation. (Bristol Myers Squibb)
Overall, the Phase 3 EXCALIBER-RRMM results provide additional evidence for the activity of the ZENBEXUS-based triplet in relapsed or refractory multiple myeloma. The 41.1% MRD-negative CR rate with ZDd compared with 20.7% with DVd, combined with higher overall and complete response rates, represents the central finding from the prespecified analysis. The continuing PFS evaluation will provide further evidence regarding the durability and clinical impact of the regimen. (Bristol Myers Squibb)
With ZENBEXUS already having received accelerated FDA approval in combination with daratumumab and hyaluronidase-fihj and dexamethasone, the ongoing EXCALIBER-RRMM program now represents an important part of Bristol Myers Squibb’s effort to establish CELMoD-based treatment approaches in multiple myeloma. The company has said that it will continue to evaluate targeted protein degradation across hematologic malignancies and other diseases as it seeks to expand the therapeutic applications of the platform. (Bristol Myers Squibb)
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.