Regulatory & Policy

BMS scores first CELMoD approval as FDA embraces MRD surrogate

Edited by Robert McTiernan··2 min read
BMS scores first CELMoD approval as FDA embraces MRD surrogate

Bristol Myers Squibb has received US FDA accelerated approval for Zenbexus (iberdomide), making it the first marketed CELMoD and establishing MRD-negative complete response as a surrogate endpoint for accelerated approval in relapsed or refractory multiple myeloma (r/r MM). The approval specifically covers Zenbexus in combination with daratumumab and hyaluronidase-fihj and dexamethasone (ZDd) in adults with r/r MM who have received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.

The approval is supported by data from the Phase III EXCALIBER-RRMM trial (NCT04975997), a randomized, open-label study comparing ZDd (n=207) against daratumumab, bortezomib, and dexamethasone (DVd; n=213) in patients with one to two prior lines of therapy. At a median follow-up of 16 months, ZDd produced an MRD-negative CR rate of 41% versus 21% with DVd (p < 0.0001). Full EXCALIBER-RRMM data, including PFS, are expected later in 2026.

As an accelerated approval, verification of clinical benefit in confirmatory trials is required, with progression-free survival (PFS) remaining a dual primary endpoint in the ongoing EXCALIBER-RRMM study. Zenbexus carries boxed warnings for embryo-fetal toxicity and serious venous and arterial thromboembolism, and is available only through a restricted distribution program (ZENBEXUS REMS).

Iberdomide acts as a molecular glue degrader, binding cereblon with higher affinity than earlier immunomodulatory drugs and redirecting the CRL4-CRBN E3 ubiquitin ligase to degrade the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are critical for myeloma cell survival. The deeper substrate degradation achieved by CELMoDs compared to conventional IMiDs is the mechanistic basis for activity in IMiD-exposed patients.

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Zenbexus enters a competitive second-line RRMM landscape that has expanded rapidly. Johnson & Johnson's Tecvayli plus Darzalex Faspro (teclistamab plus daratumumab and hyaluronidase-fihj), a BCMAxCD3 bispecific T-cell engager combination, received FDA approval in the same indication in March 2026 using an identical daratumumab backbone. Bristol Myers Squibb is also advancing a second CELMoD, mezigdomide, in combination with carfilzomib and dexamethasone; the FDA has accepted that NDA with a Prescription Drug User Fee Act target date of May 13, 2027, as previously reported.

The approval gives BMS the first commercial validation of its CELMoD platform, while mezigdomide could extend the approach into later-line disease if approved. More immediately, the use of MRD-negative CR to support accelerated approval creates a regulatory precedent that could influence development strategies across multiple myeloma.

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