FDA Grants Accelerated Approval to Zenbexus: First Multiple Myeloma Approval Based on MRD-Negative Complete Response

Although treatment options after multiple myeloma relapse are increasing, cancer cells often reappear after multiple rounds of therapy. The US Food and Drug Administration (FDA) granted accelerated approval to Bristol Myers Squibb’s iberdomide, marketed as Zenbexus, bringing not only a new combination regimen but also the first regulatory approval for a class of protein-degrading drugs known as CELMoDs.

The approval applies to adults who have received at least one prior line of therapy that included a proteasome inhibitor and an immunomodulatory drug. Zenbexus will be used with subcutaneous daratumumab and dexamethasone as the ZDd regimen. The pivotal phase 3 EXCALIBER-RRMM trial used the DVd regimen, comprising daratumumab, bortezomib, and dexamethasone, as the comparator.

The trial enrolled 939 patients, of whom 420 comprised the primary population used by the FDA to assess efficacy. At a median follow-up of 16 months, 41% of patients in the ZDd group achieved a “minimal residual disease-negative complete response,” compared with 21% in the control group. This endpoint combines a conventional complete response with results from highly sensitive testing, meaning that the disease was no longer detectable by standard methods and further testing also found no residual myeloma cells.

Zenbexus is a cereblon E3 ligase modulator (CELMoD) that uses the cell’s own protein-processing system to promote the elimination of proteins associated with myeloma survival. It is designed to both kill tumor cells directly and modulate immune responses. Early studies also provided a biological rationale for combining it with daratumumab and dexamethasone.

The efficacy came with toxicity that cannot be overlooked. Data released by the company showed that 84.3% of patients in the ZDd group developed grade 3 or 4 neutropenia, 40% experienced serious infections, and 4.9% had fatal adverse reactions. These figures mean that patients require close monitoring of blood cell counts, signs of infection, and overall tolerability during treatment; a deep response cannot be equated with low risk.

This is also the first time the FDA has used minimal residual disease-negative complete response as the basis for accelerated approval in relapsed or refractory multiple myeloma. It indicates that highly sensitive residual disease testing may provide an earlier efficacy signal, but it currently cannot prove that patients will necessarily live longer or that disease progression will inevitably be delayed.

EXCALIBER-RRMM is ongoing. Progression-free survival is another primary endpoint and will also be crucial to confirming clinical benefit. Whether Zenbexus can secure full approval, and whether this regulatory precedent will change the development pathway for other myeloma drugs, will depend on whether subsequent data can translate deep responses into durable and tangible benefits for patients.