FDA Approves Iberdomide Combo in Relapsed/Refractory Multiple Myeloma

The FDA has approved the CELMoD iberdomide (Zenbexus) in combination with daratumumab (Darzalex) and hyaluronidase-fihj and dexamethasone for patients with relapsed/refractory multiple myeloma, according to a press release from the agency.¹

What data supported iberodmide’s approval?

The agency based its decision on findings from the multicenter, open-label phase 3 EXCALIBER-RRMM trial (NCT04975997) evaluating iberdomide plus daratumumab/dexamethasone vs daratumumab plus bortezomib (Velcade) and dexamethasone (DVd) among those with relapsed/refractory multiple myeloma.

Topline data showed that the minimal residual disease (MRD)-negative complete response (CR) rate was 41% (95% CI, 34%-48%) in the iberdomide combination arm vs 21% (95% CI, 15%-27%) in the DVd arm (P <.0001).

A boxed warning for the reatment includes embryo-fetal toxicity and serious venous arterial thromboembolism, plus neutropenia, infections, and secondary primary malignancies. Additionally, iberdomide is only available through the Zenbexus Risk Evaluation and Mitigation Strategy because of the embryo fetal toxicity warning.

Iberdomide is to be given at 1 mg orally once daily with or without food on days 1 to 21 of a 28-day cycle plus daratumumab and hyaluronidase-fihj and dexamethasone. Daratumumab and hyaluronidase-fihj is to be given subcutaneously on days 1, 8, 15, and 22 of cycles 1 to 2; days 1 and 15 of cycles 3 to 6; and day 1 of cycle 7 and onward. Dexamethasone is to be given orally at 20 mg or 40 mg on days 1, 8, and 15.

In September 2025, investigators announced that the iberdomide-based combination produced a statistically significant improvement in minimal residual disease (MRD) negativity rates compared with DVd in EXCALIBER-RRMM based on data from a planned interim analysis.² At the time of the analysis, a data monitoring committee recommended the continuation of the trial without any modifications to the dual primary end point of progression-free survival (PFS) and the secondary end points of overall survival (OS) and safety.

What does this approval mean for the multiple myeloma field?

This regulatory decision represents the first approval of an agent within the CELMoD class, a type of drug that treats cancer by leveraging the cell’s natural protein degradation machinery to mark specific target proteins for degradation by the proteasome.³ Although both immunomodulatory agents (IMiDs) and CELMoDs can bind cereblon, the mechanism of action for agents like iberdomide and mezigdomide allow them to remain effective even in the presence of low levels of functional cereblon. Additionally, CELMoDs may offer convenience through oral administration.

“[CELMoDs are] clearly active agents. They're essentially in the same class as the IMiDs, [but] they're more potent cereblon modulators, so they maybe have more direct effects on the myeloma cell as well as immune stimulatory effects,” Adam D. Cohen, MD, director of Myeloma Immunotherapy and professor of medicine at the Hospital of the University of Pennsylvania, stated in an interview with CancerNetwork® regarding the CELMoD class. “…There's a lot of potential with these agents as immune modulators to use them post CAR T cells with bispecifics to augment the immunologic effects of those other agents.”

How was EXCALIBER-RRMM designed?

As part of the 2-stage, multicenter, open-label EXCALIBER-RRMM trial, patients were randomly assigned to receive iberdomide plus daratumumab and dexamethasone across 3 dosing levels or DVd.⁴ Patients in the experimental arm received iberdomide at 1.0, 1.3, or 1.6 mg on days 1 to 21 of each 28-day cycle.

The trial’s primary end points were PFS and MRD-negative complete responses at any time. Secondary end points included OS, sustainability of MRD negativity, ORR, time to response, duration of response, time to progression, time to next treatment, PFS2, safety, quality of life per European Organization for Research and Treatment of Cancer - Quality of Life C30 Questionnaire, and time to maximum plasma concentration.

Patients 18 years and older who had multiple myeloma and measurable disease, 1 to 2 prior lines of treatment, and documented disease progression during or after the most recent line of treatment were eligible for enrollment on the trial. Having an ECOG performance status of 0 to 2 was another requirement for study entry.

What else is happening with CELMoDs in multiple myeloma?

In July 2026, the FDA accepted a new drug application (NDA) for the CeLMoD mezigdomide in combination with carfilzomib (Kyprolis) and dexamethasone for patients with relapsed/refractory multiple myeloma.⁵ The agency assigned a Prescription Drug User Fee Act date of May 13, 2027. Supporting data for the NDA came from the phase 3 SUCCESSOR-2 trial (NCT05552976).

References

1. FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma. News release. August 13, 2206. Accessed August 13, 2026. https://tinyurl.com/38258auk
2. Bristol Myers Squibb announces phase 3 EXCALIBER-RRMM study evaluating iberdomide in combination with standard therapies demonstrated a significant improvement in minimal residual disease negativity rates in relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb. September 23, 2025. Accessed July 30, 2026. https://tinyurl.com/5n9768k5
3. van de Donk NWCJ, Bahlis NJ, Pawlyn C, et al. The role of CELMoD agents in multiple myeloma. Onco Targets Ther. 2025;18:921-933. doi:10.2147/OTT.S398118
4. Open-label study comparing iberdomide, daratumumab and dexamethasone (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in participants with relapsed or refractory multiple myeloma (RRMM) (EXCALIBER-RRMM). ClinicalTrials.gov. Updated April 3, 2026. Accessed July 30, 2026. https://tinyurl.com/mstweynn
5. U.S. Food and Drug Administration accepts Bristol Myers Squibb's new drug application for mezigdomide in patients with relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb. July 13, 2026. Accessed July 30, 2026. https://tinyurl.com/5fp9dzmz