FDA Grants Accelerated Approval to Iberdomide (Zenbexus) for Pretreated Multiple Myeloma

On August 13, the U.S. Food and Drug Administration (FDA) granted accelerated approval to iberdomide (Zenbexus), a cereblon-modulating protein degrader (CELMoD), in combination with daratumumab and hyaluronidase-fihj plus dexamethasone for adults with multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.

Efficacy was evaluated in EXCALIBER-RRMM (ClinicalTrials.gov identifier NCT04975997), a two-stage, randomized, multicenter, open-label trial in adults with relapsed or refractory multiple myeloma who had previously received one or two prior lines of therapy. Patients who had disease refractory to prior anti-CD38 monoclonal antibody therapy or to prior bortezomib were excluded. In stage I, patients (n = 279) were randomly assigned to one of three dose levels of iberdomide (1, 1.3, or 1.6 mg) in combination with daratumumab and hyaluronidase-fihj plus dexamethasone (Dd) or to the comparator arm of daratumumab and hyaluronidase-fihj plus bortezomib and dexamethasone (DVd). In stage II an additional 660 patients were randomly assigned to iberdomide at 1 mg in combination with Dd vs the comparator arm of DVd. The major efficacy outcome measure was measurable residual disease (MRD)-negative complete response at any time. The primary efficacy population included the first 420 patients assigned to receive 1 mg of iberdomide in combination with Dd (n = 207) or the comparator arm of DVd (n = 213) across stages I and stage II. The MRD-negative complete response rate at any time was 41% (95% confidence interval [CI] = 34%–48%) in the iberdomide/Dd arm and 21% (95% CI = 15%–27%) in the DVd arm ( P < .0001).

“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 the lead investigator of EXCALIBER-RRMM. “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 prescribing information for iberdomide includes a boxed warning for embryo-fetal toxicity and serious venous and arterial thromboembolism, as well as warnings and precautions for neutropenia, infections, and secondary primary malignancies. Because of the risk of embryo-fetal toxicity, iberdomide is available only through a restricted distribution program called ZENBEXUS Risk Evaluation and Mitigation Strategy (REMS). The recommended iberdomide dosage is 1 mg orally once daily, with or without food, on days 1 through 21 of a 28-day cycle, in combination with Dd. Daratumumab and hyaluronidase-fihj is administered subcutaneously at 1,800 mg on days 1, 8, 15, and 22 of cycles 1–2; days 1 and 15 of cycles 3–6; and day 1 of cycles 7 and beyond. Dexamethasone is administered orally at 20 mg or 40 mg on days 1, 8, 15, and 22. Treatment should continue until disease progression or unacceptable toxicity.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence which provides a framework for the concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with Switzerland’s Swissmedic. The application was granted Priority Review, and iberdomide also received Breakthrough Therapy and Orphan Drug designations. The FDA had previously accepted the New Drug Application for iberdomide in combination with daratumumab and dexamethasone (IberDd) for relapsed or refractory multiple myeloma, with a Prescription Drug User Fee Act target date of August 17, 2026. Iberdomide is a first-in-class cereblon E3 ligase modulator, representing a transition from the immunomodulatory drugs (IMiDs) like lenalidomide and pomalidomide to the next generation of “protein degraders.” Unlike IMiDs, which really just arrest cell growth, CELMoDs actually kill the cells; they are engineered to be more effective at targeting the immune system and have tighter binding affinity. “The FDA’s acceptance of this application is a testament to the potential of iberdomide,” said Bristol Myers Squibb’s chief medical officer. “Furthermore, our filing for iberdomide based on the MRD endpoint, underscores our commitment to pioneering new ways of advancing life-saving therapies for patients living with cancer.”