Bristol Myers Squibb (BMS) announced that the US Food and Drug Administration (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.

Cristian Massacesi, MD, Chief Medical Officer and Head of Development, BMS, said, “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. 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 percent of patients (n=85; 95 percent CI: 34-48) vs. 21 percent of patients (n=44; 95 percent 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 combination of ZDd was observed to have a safety profile that is expected of the combination, with 7.8 percent 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 percent and 78.9 percent, respectively, leading to few discontinuations (1 percent and 1.5 percent, respectively). The most common adverse reactions (≥20 percent) in the ZDd arm and DVd arm, respectively, were upper respiratory tract infection (54 percent and 52 percent), fatigue (36 percent and 33 percent), musculoskeletal pain (35 percent and 33 percent), pneumonia (34 percent and 17 percent), diarrhea (33 percent and 36 percent), motor dysfunction (26 percent and 17 percent), rash (26 percent and 15 percent), sleep disorder (25 percent and 28 percent), hypogammaglobulinemia (24 percent and 12 percent), COVID-19 (23 percent and 16 percent), and constipation (20 percent and 22 percent).

Serious adverse reactions in ≥2 percent of patients included pneumonia (26 percent), upper respiratory tract infection (6.4 percent), second primary malignancy (5.9 percent), neutropenia (4.9 percent), febrile neutropenia (3.9 percent), COVID-19 (4.4 percent), and sepsis (2.9 percent). Fatal adverse reactions occurred in 10 patients (4.9 percent) who received ZENBEXUS. Sepsis (1.5 percent) 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.

ZENBEXUS was granted Breakthrough Therapy Designation (BTD) 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 (NDA) 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 (PDUFA) target date of May 13, 2027.