The U.S. Food and Drug Administration (FDA) has granted accelerated approval to Zenbexus (iberdomide) in combination with daratumumab and hyaluronidase-fihj and dexamethasone (ZDd) for adults with multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.
The approval was announced by Bristol Myers Squibb (BMS) on August 13, 2026. According to the company, Zenbexus is the first FDA-approved CELMoD, a class of cereblon-modulating protein degraders, for multiple myeloma.
The accelerated approval was based on efficacy results from EXCALIBER-RRMM (NCT04975997), a two-stage, randomized, multicenter, open-label trial in adults with relapsed or refractory multiple myeloma who had received one or two prior lines of therapy. Patients whose disease was refractory to prior anti-CD38 monoclonal antibody therapy or prior bortezomib were excluded.
A total of 939 patients were randomized in the trial. Stage 1 included 279 patients assigned to one of three iberdomide dose levels in combination with daratumumab and hyaluronidase-fihj and dexamethasone or to daratumumab, bortezomib, and dexamethasone (DVd). Stage 2 included 660 patients assigned to iberdomide 1 mg plus daratumumab and hyaluronidase-fihj and dexamethasone or DVd.
The primary efficacy population for the minimal residual disease (MRD) analysis included the first 420 patients randomized to iberdomide 1 mg plus daratumumab and hyaluronidase-fihj and dexamethasone (n=207) or DVd (n=213).
At a median follow-up of 16 months, the MRD-negative complete response rate at any time was 41% with the iberdomide-based regimen, compared with 21% with DVd (p<0.0001). The respective 95% confidence intervals were 34%–48% and 15%–27%.
According to BMS, the FDA decision represents the first approval in relapsed or refractory multiple myeloma based on MRD-negative complete response. EXCALIBER-RRMM has dual primary endpoints of MRD negativity and progression-free survival (PFS), and the study remains ongoing to assess PFS. Additional endpoints include overall survival, overall response rate, safety, and sustained MRD negativity.
Sagar Lonial, MD, FACP, FASCO, lead investigator of EXCALIBER-RRMM and Chief Medical Officer of the Winship Cancer Institute of Emory University, said:
“The strong results observed with the CELMoD-based combination within a familiar triplet approach creates the potential for a new treatment foundation in multiple myeloma.”
The FDA-approved indication was granted under the accelerated approval pathway based on MRD-negative complete response at any time. Continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial or trials.
The prescribing information for Zenbexus includes boxed warnings for embryo-fetal toxicity and serious venous and arterial thromboembolism, as well as warnings and precautions for neutropenia, infections, and second primary malignancies. Because of the embryo-fetal toxicity risk, Zenbexus is available only through the restricted ZENBEXUS Risk Evaluation and Mitigation Strategy (REMS) program.
The recommended dose of iberdomide is 1 mg orally once daily on Days 1 through 21 of each 28-day cycle, with or without food, in combination with daratumumab, hyaluronidase-fihj, and dexamethasone. Treatment should continue until disease progression or unacceptable toxicity.
The FDA review was conducted under Project Orbis, in collaboration with Swissmedic in Switzerland. The application received Priority Review, and iberdomide had also received Breakthrough Therapy and Orphan Drug designations.
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