FDA Grants Accelerated Approval to Zenbexus Combination for Relapsed Multiple Myeloma | iPharmaCenter

The US Food and Drug Administration has granted accelerated approval to Zenbexus, also known as iberdomide, in combination with daratumumab and hyaluronidase plus dexamethasone for adults with multiple myeloma previously treated with at least one regimen containing both a proteasome inhibitor and an immunomodulatory medicine.

The approval is based on findings from the Phase 3 EXCALIBER-RRMM study, which evaluated the Zenbexus combination in patients with relapsed or refractory multiple myeloma.

Stronger Deep Response in Trial

In the study, 41% of patients receiving Zenbexus with daratumumab and hyaluronidase plus dexamethasone achieved a complete response with no detectable minimal residual disease. This compared with 21% of patients treated with daratumumab, bortezomib, and dexamethasone.

The difference was statistically significant, with the Zenbexus regimen nearly doubling the rate of MRD-negative complete responses.

Minimal residual disease negativity is considered one of the most sensitive indicators of treatment response in multiple myeloma. Although it does not confirm that every cancer cell has been eliminated, achieving this level of response has been associated with better progression-free outcomes.

The decision represents the first FDA approval in relapsed or refractory multiple myeloma supported by an MRD-negative complete response endpoint.

First FDA-Cleared CELMoD Therapy

Zenbexus is the first treatment in the cereblon E3 ligase modulator class to receive FDA approval. The therapy belongs to a newer group of targeted protein degraders being developed for multiple myeloma.

Bristol Myers Squibb said the approval marks an expansion of its targeted protein degradation research and introduces a new treatment class for patients whose disease has returned or stopped responding to previous therapy.

The medicine received Breakthrough Therapy designation and accelerated approval from the FDA. The regulatory review was also conducted under Project Orbis, a program that supports coordinated assessments among health authorities in multiple countries.

Details From EXCALIBER-RRMM

EXCALIBER-RRMM is an international, multicenter, randomized, open-label Phase 3 trial designed to compare the efficacy and safety of the Zenbexus combination with daratumumab, bortezomib, and dexamethasone.

The study includes two stages and was designed around two primary measures: MRD negativity and progression-free survival. Overall survival, overall response rate, safety, and durability of MRD negativity were included as additional outcomes.

The trial enrolled adults who had received one or two previous anti-myeloma treatment lines and whose disease had progressed. In total, 939 participants were randomized.

For the MRD analysis, researchers evaluated the first 420 randomized participants. The Zenbexus arm included 207 patients, while 213 patients received the comparator regimen. Treatment continued until the cancer progressed or side effects became unacceptable.

MRD Assessment in Multiple Myeloma

Minimal residual disease refers to the small population of cancer cells that may remain after treatment but cannot be detected through standard testing.

Newer testing methods, including next-generation sequencing and next-generation flow cytometry, can identify very small numbers of malignant cells among hundreds of thousands or even one million normal cells. These techniques allow researchers and clinicians to measure treatment response with greater precision.

MRD status is increasingly being assessed in multiple myeloma trials as a potential indicator of progression-free survival. Regulatory agencies are also giving greater attention to MRD outcomes when reviewing therapies for serious blood cancers.

However, MRD negativity should not be interpreted as proof that all cancer cells have disappeared.