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In a historic breakthrough for targeted protein degradation, Bristol Myers Squibb has secured the first FDA approval for a CELMoD therapy, with clearance of Zenbexus (iberdomide) as part of a combination regimen for previously treated multiple myeloma. In a regulatory milestone, Zenbexus also marks the first FDA nod for a new drug in multiple myeloma driven directly by minimal residual disease (MRD) as a surrogate endpoint rather than traditional longer-term metrics such as progression-free survival (PFS). The groundbreaking decision not only validates protein degradation—and BMS’ CELMoD specifically—as a viable modality, but also establishes a regulatory benchmark that serves as an example for future clinical trial designs. “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. And we believe this is only the beginning,” BMS’ chief medical officer and head of development, Cristian Massacesi, M.D., said in an Aug. 13 statement. Zenbexus is specifically approved in combination with Johnson & Johnson’s Darzalex and dexamethasone to treat adults with multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent. In the phase 3 Excaliber-RRMM trial, the novel combo topped the traditional cocktail of Darzalex, Takeda’s Velcade (bortezomib) and dexamethasone on one of the trial’s dual primary endpoints, with an MRD-negative complete response rate of 41% compared with 21% for the traditional regimen at any time during a median follow-up of 16 months. The data had not been disclosed before Thursday’s approval. The trial remains ongoing to assess PFS as its other primary endpoint, which is expected this year. As Zenbexus is cleared with an accelerated approval, BMS is on the hook to provide confirmatory evidence, such as PFS. MRD-negativity is a stringent measure of response in multiple myeloma. In Excaliber-RRMM, MRD-negativity is defined as the ability to detect one myeloma cell among 100,000 normal cells in patients who achieved a complete response or better. Before Zenbexus’ approval, the FDA issued a draft guidance in January on the potential use of MRD and complete response to support accelerated approval in myeloma, following unanimous endorsement of the endpoint from an external advisory committee in 2024. A few days after publishing the draft guidance, the FDA approved J&J’s Darzalex within a quadruplet combination to treat first-line, transplant-ineligible myeloma patients based on results from the phase 3 Cepheus trial, which used MRD-negativity as its primary endpoint. At that time, Darzalex had been marketed for over a decade, and the Cepheus trial had already read out its PFS data. Now, Zenbexus is the first new drug to win an accelerated approval based directly on MRD. Its Excaliber-RRMM trial design also follows the spirit of the FDA’s Project FrontRunner , which encourages drug companies to use a single phase 3 trial in earlier cancer treatment settings to support both an accelerated approval based on an earlier endpoint and its full nod. Zenbexus’ arrival brings an additional growth catalyst for BMS as its older blood cancer blockbuster Revlimid continues to see revenue decline after losing U.S. market exclusivity in 2022. In an Aug. 14 note, analysts at William Blair projected that Zenbexus’ U.S. sales could surpass $1 billion in early 2031. Despite the landmark approval, the drug’s market potential in its first indication may be limited. With only 4% of patients in Excaliber-RRMM having received a prior anti-CD38 antibody, there’s “limited data” for the combination in CD38-pretreated patients, as the FDA spells out in the drug’s label. As anti-CD38 antibodies such as Darzalex become the standard first-line treatment, the pool of patients without prior CD38 exposure is dwindling. Zenbexus’ label also includes a boxed warning for embryo-fetal toxicity and serious venous and arterial thromboembolism. BMS is running another phase 3, called Excaliber-Maintenance, testing Zenbexus as first-line maintenance therapy following stem cell transplant in patients with newly diagnosed multiple myeloma. In addition, the New Jersey pharma’s second CELMoD agent, mezigdomide, is also under FDA review in second-line-plus multiple myeloma, with a target decision date of May 13, 2027. Both meds will be compete with autologous CAR-T therapies such as Legend Biotech's and J&J’s Carvykti, as well as BMS’ own Abecma, as well as bispecific antibodies, including J&J’s Tecvayli . “[E]ach incremental contribution from the CELMoD franchise helps strengthen the transition from a company dependent on legacy products to one supported by a more diversified set of growth assets as LOE exposure grows,” Citi analysts said of BMS in an Aug. 13 note.

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 (BMS) Zenbexus (iberdomide), along with daratumumab and hyaluronidase-fihj and dexamethasone (ZDd), to treat adult multiple myeloma (MM) patients. The combination is intended for patients who have previously received at least one line of therapy that included both a proteasome inhibitor and an immunomodulatory agent. Zenbexus is said to be the first cereblon E3 ligase modulator (CELMoD) therapy approved by the FDA for MM treatment. Continued approval for this indication may depend on confirmation of clinical benefit in ongoing trials. In combination with ZDd, Zenbexus received the agency’s decision following results from the Phase III EXCALIBER-RRMM trial. The study compared Zenbexus, ZDd (n=207) with daratumumab, bortezomib and dexamethasone (n=213) in patients with relapsed or refractory MM. After a median follow-up of 16 months, 41% of patients treated with ZDd achieved minimal residual disease (MRD)-negative complete response compared to 21% receiving the comparator regimen. Safety data indicated that 7.8% of patients discontinued ZDd because of adverse reactions. Serious infections and severe neutropenia were observed, with neutropenia and infections occurring in 90.2% and 78.9% of patients, respectively. Fatal adverse reactions occurred in 4.9% of patients treated with Zenbexus, with sepsis as the only event affecting more than one individual. Other observed reactions included upper respiratory tract infection, pneumonia, diarrhoea and fatigue. Bristol Myers Squibb chief medical officer and development head Cristian Massacesi said: “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. “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. And we believe this is only the beginning. “This approval validates years of scientific research and strengthens our confidence in the potential of this approach as we continue to advance our innovative pipeline on behalf of patients with significant unmet needs.” This review was conducted under the FDA’s Project Orbis, enabling concurrent regulatory assessment in several other countries.