FDA Approves Zenbexus as First CELMoD Therapy for Relapsed Multiple Myeloma
The FDA has granted accelerated approval to Zenbexus (iberdomide), the first approved CELMoD for multiple myeloma, based on promising MRD-negative complete response results.
The treatment landscape for multiple myeloma has reached an important milestone with the U.S. Food and Drug Administration's accelerated approval of Zenbexus (iberdomide). Bristol Myers Squibb announced the approval on August 13, 2026, for Zenbexus in combination with daratumumab and hyaluronidase-fihj and dexamethasone, known as ZDd. The therapy is indicated for adults with multiple myeloma who have received at least one prior line of treatment that included both a proteasome inhibitor and an immunomodulatory agent.
The decision is notable because Zenbexus is the first FDA-approved therapy from a new class called cereblon-modulating protein degraders, or CELMoDs. The approval represents a new development in targeted protein degradation and expands the treatment options available to people whose disease has returned or stopped responding to previous therapy.
What Is Zenbexus?
Zenbexus contains iberdomide, a cereblon E3 ligase modulator designed as part of Bristol Myers Squibb's targeted protein degradation research platform. Targeted protein degradation aims to address disease-related proteins by promoting their degradation rather than simply blocking their activity.
According to Bristol Myers Squibb, the company has built its targeted protein degradation platform over more than two decades of scientific research. The platform includes CELMoDs as well as other investigational approaches, including ligand-directed degraders and degrader antibody conjugates.
The arrival of an approved CELMoD is significant because it represents an evolution of the protein degradation approach already established through immunomodulatory drugs in multiple myeloma. While the new therapy offers another treatment option, its accelerated approval also means additional evidence is required to confirm its clinical benefit.
Clinical Trial Results Behind the Approval
The FDA's decision was based on results from the Phase 3 EXCALIBER-RRMM study. The trial evaluated Zenbexus combined with daratumumab, hyaluronidase-fihj and dexamethasone against a combination of daratumumab, bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma.
At a median follow-up of 16 months, 41% of patients receiving the Zenbexus combination achieved minimal residual disease-negative complete response, compared with 21% of patients receiving the comparator treatment. The difference was statistically significant, with a reported p-value of less than 0.0001.
The study included 207 patients in the Zenbexus combination arm and 213 patients in the comparator arm for the primary efficacy population used for the MRD-negative complete response analysis. The broader EXCALIBER-RRMM study randomized 939 patients and was designed to evaluate both minimal residual disease negativity and progression-free survival as dual primary endpoints.
Importantly, the progression-free survival analysis is still ongoing. The company stated that full data from the study are expected later in 2026. Therefore, while the MRD-negative complete response results were strong enough to support accelerated approval, the longer-term clinical benefit remains subject to further evaluation.
Why Minimal Residual Disease Matters
Minimal residual disease, commonly called MRD, refers to the small number of cancer cells that can remain after treatment and may not be detected through conventional diagnostic methods. In multiple myeloma, MRD testing has become an increasingly sensitive way of assessing how deeply a patient has responded to treatment.
Modern testing techniques, including next-generation sequencing and next-generation flow cytometry, can detect very small amounts of remaining malignant disease. These approaches can identify approximately one cancer cell among 100,000 to 1,000,000 normal cells, depending on the testing threshold.
However, MRD negativity should not be interpreted as proof that every cancer cell has been eliminated. It is instead a highly sensitive measure of disease burden and treatment response. The EXCALIBER-RRMM results are particularly notable because the FDA approval represents the first approval in relapsed or refractory multiple myeloma based on MRD-negative complete response.
Safety Considerations
Although the clinical results are encouraging, Zenbexus has important safety considerations. The prescribing information includes boxed warnings for embryo-fetal toxicity and serious venous and arterial thromboembolism. Zenbexus is contraindicated during pregnancy because it can cause fetal harm.
The treatment is also associated with an increased risk of serious blood clots, including deep vein thrombosis, pulmonary embolism, myocardial infarction and stroke. Thromboprophylaxis is recommended, with treatment decisions based on individual risk factors.
Blood-related complications are another important consideration. In the EXCALIBER-RRMM study, all-grade neutropenia occurred in 90.2% of patients receiving the Zenbexus combination, while Grade 3 and Grade 4 neutropenia occurred in 30.9% and 53.4% of patients, respectively. Febrile neutropenia occurred in 5.4% of patients.
Infections were also common. Infections, including opportunistic infections, were reported in 78.9% of patients receiving the Zenbexus combination, while serious infections occurred in 40% of patients.
These findings highlight why appropriate monitoring and supportive care remain important components of treatment.
What Accelerated Approval Means
Zenbexus received accelerated approval based on MRD-negative complete response. Under this pathway, continued approval can depend on confirmation and further description of clinical benefit through additional trials.
For patients and healthcare professionals, this means the approval provides access to a new treatment option while additional evidence is collected. The ongoing EXCALIBER-RRMM study will provide important information about progression-free survival and other outcomes that can help establish the longer-term value of the therapy.
The drug also received Breakthrough Therapy designation, and the FDA review was conducted under Project Orbis, an initiative that supports concurrent review by health authorities in multiple countries.
A New Chapter in Multiple Myeloma Treatment
The approval of Zenbexus marks an important development in the treatment of relapsed or refractory multiple myeloma. Its status as the first approved CELMoD introduces a new therapeutic class while building on the broader scientific field of targeted protein degradation.
The available clinical data show a meaningful difference in MRD-negative complete response compared with the study's comparator regimen. At the same time, the ongoing progression-free survival analysis and confirmatory requirements demonstrate the importance of continuing to evaluate the therapy over time.
For patients facing relapsed or refractory multiple myeloma, each additional treatment option can provide greater flexibility as treatment strategies evolve. Zenbexus therefore represents both a new therapy and a broader step forward in the development of protein degradation approaches for cancer treatment.
Sources
- Bristol Myers Squibb, “FDA Grants Accelerated Approval to Zenbexus,” August 13, 2026.
- Zenbexus U.S. Prescribing Information, August 2026.
- Lonial S, Dimopoulos MA, Berdeja JG, et al. “EXCALIBER-RRMM: a phase III trial of iberdomide, daratumumab, and dexamethasone in relapsed/refractory multiple myeloma.” Future Oncology. 2025;21(14):1761-1769.
- Szalat RE, Anderson KC, Munshi NC. “Role of minimal residual disease assessment in multiple myeloma.” Haematologica. 2024;109(7):2049-2059.