Bristol Myers Squibb’s Zenbexus (iberdomide), given with daratumumab, hyaluronidase-fihj and dexamethasone (ZDd), received FDA accelerated approval for adults with multiple myeloma previously treated with both a proteasome inhibitor and an immunomodulatory agent. The Phase III EXCALIBER-RRMM trial showed a 41% MRD-negative complete response rate with ZDd versus 21% for the comparator after 16 months. Safety concerns include high rates of neutropenia (90.2%), infections (78.9%), a 7.8% discontinuation rate for adverse reactions and a 4.9% fatal adverse event rate. Continued approval depends on confirmatory trials; the review was conducted under Project Orbis.
FDA Accelerates Approval of BMS’s Zenbexus (Iberdomide) for Multiple Myeloma — First-in-Class CELMoD
Zenbexus is said to be the first CELMoD therapy approved by the FDA for multiple myeloma treatment. Credit: Bristol-Myers Squibb / Business Wire.
The US Food and Drug Administration (FDA) has granted accelerated approval to Bristol Myers Squibb's Zenbexus (iberdomide) in combination with daratumumab, hyaluronidase-fihj and dexamethasone (ZDd) for the treatment of adults with multiple myeloma (MM) who previously received at least one regimen containing both a proteasome inhibitor and an immunomodulatory agent. Continued approval will depend on verification of clinical benefit from ongoing confirmatory trials.
Zenbexus is the first cereblon E3 ligase modulator (CELMoD) approved by the FDA for multiple myeloma, introducing a new therapeutic class that leverages targeted protein degradation to enhance anti-myeloma activity.
Phase III EXCALIBER-RRMM Results
The FDA’s decision was based on data from the randomized Phase III EXCALIBER-RRMM trial comparing ZDd (Zenbexus + daratumumab + hyaluronidase-fihj + dexamethasone; n=207) with a comparator regimen of daratumumab, bortezomib and dexamethasone (n=213) in patients with relapsed or refractory MM. After a median follow-up of 16 months, 41% of patients receiving ZDd achieved a minimal residual disease (MRD)-negative complete response versus 21% in the comparator arm.
Safety Profile
Safety findings showed substantial hematologic and infectious risks. Key safety outcomes included:
- Neutropenia: reported in 90.2% of patients
- Infections: reported in 78.9% of patients
- Discontinuations: 7.8% of patients stopped ZDd because of adverse reactions
- Fatal Adverse Reactions: occurred in 4.9% of patients treated with Zenbexus; sepsis was the only fatal event affecting more than one individual
Other commonly observed adverse events included upper respiratory tract infection, pneumonia, diarrhea and fatigue. Clinicians should consider these risks and monitor patients closely, especially for severe neutropenia and infections.
“Today's approval of Zenbexus represents meaningful progress for patients living with multiple myeloma and underscores the power of our targeted protein degradation platform, particularly our CELMoD programmes,” said Cristian Massacesi, Bristol Myers Squibb Chief Medical Officer and Head of Development. “As the first approved CELMoD, Zenbexus marks the arrival of a new treatment class and is an important milestone in our efforts to expand what is possible for patients with multiple myeloma.”
Regulatory Context
The approval was granted under the FDA’s accelerated approval pathway and was reviewed through Project Orbis, which facilitates concurrent regulatory assessment in multiple jurisdictions. As with other accelerated approvals, continued marketing authorization is contingent on confirmatory evidence of clinical benefit from ongoing trials.
Clinical Implication: Zenbexus offers a new treatment option for previously treated MM patients and demonstrates promising efficacy on MRD-negative complete response rates, but its use requires careful risk-benefit assessment due to high rates of neutropenia, infections and a non-negligible fatal adverse event rate.
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