Positive topline results from Phase 3 EXCALIBER-RRMM trial showed significant improvement in the dual-primary endpoint of progression-free survival (PFS) in ZDd combination vs standard of care (DVd).
On Thursday, October 8, Bristol Myers Squibb (BMS) announced positive topline results from the Phase 3 EXCALIBER-RRMM trial (NCT04975997) in a press release.
According to BMS, the combination of ZENBEXUSTM (iberdomide), daratumumab and dexamethasone (ZDd) significantly improved progression-free survival (PFS) compared to standard of care: daratumumab, bortezomib and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma in the Phase 3 EXCALIBER-RRMM study.
EXCALIBER-RRMM (NCT04975997) is a randomized, open-label, multicenter Phase 3 trial evaluating ZDd against DVd in adults with multiple myeloma who had received one to two prior lines of anti-myeloma therapy and had progressive disease.
Treatment continued until disease progression or unacceptable toxicity. The study also evaluates overall survival, overall response rate, safety and sustained MRD negativity.
Among 800 patients randomized equally to the two treatment groups, median PFS was 42 months with ZDd versus 20 months with DVd. The hazard ratio was 0.49 (p<0.000001), corresponding to a 51% reduction in the risk of disease progression or death with ZDd. The median follow-up was 23 months.
The results concern one of the study's two dual-primary endpoints. The other endpoint, minimal residual disease (MRD)-negative complete response, had previously shown a significant benefit for ZDd and supported the U.S. Food and Drug Administration's accelerated approval of Zenbexus for certain patients with relapsed or refractory multiple myeloma.
According to BMS, the safety profile of Zenbexus combined with standard therapies was consistent with previously reported findings.
The findings were presented at the 23rd International Myeloma Society annual meeting and published in The Lancet Oncology.
The company plans to present detailed results at the 68th Annual Meeting of the American Society of Hematology.
Safety remains an important consideration
The prescribing information carries boxed warnings for embryo-fetal toxicity and serious venous and arterial thromboembolic events, including deep vein thrombosis, pulmonary embolism, myocardial infarction and stroke.
Zenbexus is contraindicated during pregnancy and is available only through the restricted ZENBEXUS REMS program because of the risk of embryo-fetal harm.
In the EXCALIBER-RRMM study, among 204 patients receiving iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone, venous thromboembolic events occurred in 6.4% despite mandatory thromboprophylaxis. Arterial thromboembolic events occurred in 3.4%.
Neutropenia was also common. In the study, all-grade neutropenia occurred in 90.2% of patients receiving the iberdomide-containing regimen, including Grade 3 neutropenia in 30.9% and Grade 4 in 53.4%. Febrile neutropenia occurred in 5.4%.
Infections occurred in 78.9% of patients in the iberdomide-containing arm, including Grade 3 infections in 35.8%, Grade 4 infections in 3.4%, and fatal infections in 2%. Serious infections occurred in 40% of patients.
Serious adverse reactions occurred in 58.3% of patients receiving Zenbexus. The most common adverse reactions, occurring in at least 20% of patients, included upper respiratory tract infection, fatigue, musculoskeletal pain, pneumonia, diarrhea, motor dysfunction, rash, sleep disorders, hypogammaglobulinemia, COVID-19 and constipation.
Current U.S. indication
Zenbexus (iberdomide), in combination with daratumumab and hyaluronidase-fihj and dexamethasone, is indicated for adults with multiple myeloma who have received at least one prior line of therapy that included a proteasome inhibitor and an immunomodulatory agent.
The indication was granted under FDA accelerated approval, based on MRD-negative complete response at any time. Continued approval may depend on verification and description of clinical benefit in confirmatory trials.
Full prescribing information for Zenbexus, including boxed warnings, can be found online.
Bottom Line
The EXCALIBER-RRMM results show a substantial PFS advantage for the ZDd regimen, with median PFS more than twice as long as with DVd (42 vs. 20 months; HR 0.49).
However, the regimen has important and potentially serious risks, particularly embryo-fetal toxicity, blood clots, neutropenia and infections.
References:
Bristol Myers Squibb Announces ZENBEXUS (iberdomide) in Combination with Daratumumab and Dexamethasone (ZDd) Demonstrates Superior Progression-Free Survival vs. Standard of Care in Relapsed and Refractory Multiple Myeloma in Phase 3... BMS press release. October 8, 2026.
Lonial S, Dimopoulos MA, Gavriatopoulou M, Kim K, et.al. EXCALIBER-RRMM Investigators. 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. Lancet Oncol. 2026 Sep 25:S1470-2045(26)00450-X. doi: 10.1016/S1470-2045(26)00450-X.
FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma. U.S. Food and Drug Administration news release. August 13, 2026.
Zenbexus U.S Prescribing Information. BMS Package Inserts.