FDA Grants Accelerated Approval to ZENBEXUS in Combination with Daratumumab and Hyaluronidase-fihj and Dexamethasone for Patients with Multiple Myeloma, as Early as First Relaps – BMSe

Bristol Myers Squibb announced that the FDA has approved ZENBEXUS (iberdomide) in combination with daratumumab and hyaluronidase-fihj and dexamethasone (ZDd) for the treatment of adult patients with multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.

Full approval for this indication will be contingent upon verification and description of clinical benefit in the confirmatory trial(s). ZENBEXUS is the first FDA-approved CELMoD, belonging to a new class called cereblon-modulating protein degraders for the treatment of multiple myeloma.

“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 programs,” said Cristian Massacesi, MD, chief medical officer and head of development at Bristol Myers Squibb. “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.”

Approval of ZENBEXUS is based on results from the Phase 3 EXCALIBER-RRMM trial evaluating ZENBEXUS, daratumumab and hyaluronidase-fihj and dexamethasone (ZDd; n=207) compared to daratumumab, bortezomib and dexamethasone (DVd; n=213) in patients with RRMM. At a median follow-up of 16 months, results showed treatment with ZDd demonstrated a statistically significant improvement in one of the dual primary endpoints of minimal residual disease (MRD)-negative complete response (CR) in 41% of patients (n=85; 95% CI: 34-48) vs. 21% of patients (n=44; 95% CI: 15-27) treated with DVd (p < 0.0001). MRD-negativity is among the deepest measures of response in multiple myeloma and is considered predictive of improved progression-free survival (PFS). This FDA decision marks the first approval in relapsed or refractory multiple myeloma based on MRD-negative CR.

“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 Sagar Lonial, MD, FACP, FASCO, EXCALIBER-RRMM lead investigator and chief medical officer of the Winship Cancer Institute of Emory University. “The strong results observed with the CELMoD-based combination within a familiar triplet approach creates the potential for a new treatment foundation in multiple myeloma.”

The combination of ZDd was observed to have a safety profile that is expected of the combination, with 7.8% of patients discontinuing ZDd due to adverse reactions. Among the key safety findings, ZDd can cause serious, life-threatening, or fatal infections and severe neutropenia. Neutropenia and infections in patients who received ZDd occurred at a rate of 90.2% and 78.9%, respectively, leading to few discontinuations (1% and 1.5%, respectively). The most common adverse reactions (≥20%) in the ZDd arm and DVd arm, respectively, were upper respiratory tract infection (54% and 52%), fatigue (36% and 33%), musculoskeletal pain (35% and 33%), pneumonia (34% and 17%), diarrhea (33% and 36%), motor dysfunction (26% and 17%), rash (26% and 15%), sleep disorder (25% and 28%), hypogammaglobulinemia (24% and 12%), COVID-19 (23% and 16%), and constipation (20% and 22%). Serious adverse reactions in ≥2% of patients included pneumonia (26%), upper respiratory tract infection (6.4%), second primary malignancy (5.9%), neutropenia (4.9%), febrile neutropenia (3.9%), COVID-19 (4.4%), and sepsis (2.9%). Fatal adverse reactions occurred in 10 patients (4.9%) who received ZENBEXUS. Sepsis (1.5%) was the only fatal drug reaction that occurred in more than 1 patient. The following fatal adverse reactions occurred in 1 patient each: listeria encephalitis, influenza, lung adenocarcinoma, cardiac arrest, large intestine perforation, metabolic acidosis, and respiratory failure.

“The goal for every person living with multiple myeloma is not simply to live longer, but to live well,” said Heather Cooper Ortner, president and chief executive officer of the International Myeloma Foundation. “That is why it is important to have access to effective therapeutic options, particularly in the community setting where the majority of myeloma care is delivered. This approval represents an important step forward by expanding treatment options for patients facing their first relapse. Every new option gives patients and their healthcare teams additional choices as treatment needs evolve, as well as renewed hope for the future.”

ZENBEXUS was granted Breakthrough Therapy designation and accelerated approval based on MRD-negative CR at any time in the EXCALIBER-RRMM study. This review was conducted under the FDA’s Project Orbis initiative, which enables concurrent review by the health authorities in several other countries.

While ZENBEXUS is the first FDA approved CELMoD therapy, a New Drug Application for mezigdomide, an investigational CELMoD, in combination with carfilzomib and dexamethasone is also currently under review with the FDA with a Prescription Drug User Fee Act target date of 13 May 2027.

About EXCALIBER-RRMM
EXCALIBER-RRMM (NCT04975997) is a Phase 3, multicenter, two-stage, randomized, open-label study evaluating the efficacy and safety of ZENBEXUS (iberdomide) in combination with daratumumab and hyaluronidase-fihj and dexamethasone (ZDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma (RRMM). The study included a dose optimization stage and was designed to assess dual-primary endpoints of minimal residual disease (MRD) negativity and progression-free survival (PFS), with additional secondary endpoints including overall survival (OS), overall response rate (ORR), safety and sustained MRD negativity. The study remains ongoing to assess the primary endpoint of PFS. Eligible participants included adults with 1 to 2 prior lines of anti-myeloma therapy and progressive disease. A total of 939 patients were randomized. The primary efficacy population for MRD negativity included the first 420 patients randomized to the ZENBEXUS (1 mg) + Dd arm (n=207) or the comparator daratumumab, bortezomib, and dexamethasone (DVd) arm (n=213). Treatment in both arms was administered until disease progression or unacceptable toxicity.

This approval, the first in RRMM based on MRD-negative complete response (CR), marks the first public disclosure of MRD-negative CR data from the EXCALIBER-RRMM trial. The MRD data were first disclosed at the time of approval to preserve the integrity of the study while additional endpoints mature. The study remains ongoing, with patients continuing to be evaluated for PFS, one of the trial’s dual primary endpoints. Full data from EXCALIBER-RRMM are expected this year.