BMY Zenbexus: First CELMoD Approval in Myeloma

The FDA granted accelerated approval on August 13 to Bristol Myers Squibb’s (BMY) Zenbexus (iberdomide), the first CELMoD (cereblon E3 ligase modulator) to reach the market. Zenbexus is approved in combination with daratumumab, hyaluronidase-fihj, and dexamethasone, a triplet BMS calls ZDd, for adults with relapsed or refractory multiple myeloma who have had at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent. The decision landed four days ahead of the August 17 PDUFA date.

The approval rests on EXCALIBER-RRMM, which randomized 939 patients overall. The MRD analysis covered the first 420 randomized to ZDd (n=207) or daratumumab, bortezomib, and dexamethasone (DVd, n=213). At a median follow-up of 16 months, ZDd produced a minimal residual disease (MRD)-negative complete response in 41% of patients versus 21% for DVd (p<0.0001). MRD negativity means no detectable cancer cells at the most sensitive level of testing, the strictest measure of response in myeloma. This is the first myeloma approval based on MRD-negative complete response rather than progression-free survival.

The mechanism is why this matters beyond one drug. Revlimid and Pomalyst, BMS’s older immunomodulatory drugs, bind cereblon but degrade it imprecisely. CELMoDs like iberdomide are engineered to degrade disease-driving proteins more potently, and BMS is positioning the class as the successor to a franchise that has anchored its oncology business for a decade. Multiple myeloma accounts for roughly 35,000 new US diagnoses a year, and nearly every patient eventually relapses, so each new line of therapy matters. A second CELMoD, mezigdomide, is under FDA review with a May 13, 2027 PDUFA date, as covered in the mezigdomide PDUFA analysis.

The boxed warnings are not cosmetic. Neutropenia hit 90.2% of patients on ZDd and infections 78.9%, with warnings for embryo-fetal toxicity and venous and arterial thromboembolism. Fatal adverse reactions occurred in 4.9% of patients. Because this is an accelerated approval, BMS must confirm clinical benefit in follow-up trials, with the progression-free survival endpoint still outstanding.

BMS shares closed at $65.47 on August 20. The company is fighting the Eliquis and Opdivo patent cliff, and its rumored $400 billion AstraZeneca tie-up was reported denied. A de-risked next-generation oncology franchise is the counterweight to that standalone thesis. For the broader competitive picture in myeloma, see the CAR-T versus bispecifics breakdown.

What to watch next: full EXCALIBER-RRMM data expected this year, including whether the MRD benefit translates into a progression-free survival win that converts this accelerated approval into full approval.

Source: EXCALIBER-RRMM on ClinicalTrials.gov (NCT04975997); BMS Phase 3 EXCALIBER-RRMM announcement