FDA clears first CELMoD therapy for multiple myeloma

Clinical takeaway: For patients with multiple myeloma at first relapse after prior exposure to both a proteasome inhibitor and an immunomodulatory agent, the newly approved iberdomide-based triplet (ZDd) offers a first-in-class CELMoD option that doubled MRD-negative complete response rates versus DVd, potentially providing a deeper response earlier in the treatment course.

On August 13, 2026, FDA granted accelerated approval to Zenbexus (iberdomide), in combination with daratumumab and hyaluronidase-fihj and dexamethasone (ZDd), for adults with multiple myeloma who have received at least one prior line of therapy that included both a proteasome inhibitor and an immunomodulatory agent. Continued approval may depend on confirmation of clinical benefit in ongoing studies.

Zenbexus is the first FDA-approved cereblon E3 ligase modulator (CELMoD), a novel class of targeted protein degraders that builds on the mechanism of immunomodulatory drugs such as lenalidomide and pomalidomide.

Approval was based on findings from the phase 3 EXCALIBER-RRMM trial, which enrolled patients with relapsed or refractory multiple myeloma who had received one or two prior lines of therapy. In the primary efficacy analysis, MRD-negative complete response was achieved in 41% of patients treated with ZDd (n = 207) versus 21% of those receiving the comparator regimen of daratumumab, bortezomib, and dexamethasone (DVd; n = 213), a statistically significant improvement (p<0.0001). MRD negativity is considered one of the deepest measures of response in multiple myeloma and is associated with improved outcomes.

At a median follow-up of 16 months, the iberdomide-based triplet doubled MRD-negative complete response rates compared with the standard regimen. Progression-free survival, a co-primary endpoint, remains under evaluation as the study continues. The approval is also the first in relapsed/refractory multiple myeloma to be based on MRD-negative complete response.

“The FDA approval of iberdomide marks the anticipated arrival of a new therapeutic class for relapsed or refractory multiple myeloma and has the potential to make a meaningful difference for patients,” said EXCALIBER-RRMM lead investigator Sagar Lonial, MD, chief medical officer of the Winship Cancer Institute of Emory University.

The prescribing information includes boxed warnings for embryo-fetal toxicity and serious venous and arterial thromboembolism, with neutropenia and infections among the key safety concerns.

Sources:

Bristol Myers Squibb. (2026 Aug 13). U.S. FDA Grants Accelerated Approval to Bristol Myers Squibb's First CELMoD Therapy ZENBEXUS™, in Combination with Daratumumab and Hyaluronidase-fihj and Dexamethasone (ZDd) for Patients with Multiple Myeloma, as Early as First Relapse

U.S. Food and Drug Administration. (2026 Aug 13). FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma