FDA Approves Novel Iberdomide Regimen in RRMM

The FDA has granted an accelerated approval to the regimen of iberdomide (Zenbexus; Bristol Myers Squibb) plus daratumumab/hyaluronidase-fihj and dexamethasone to treat patients with relapsed/refractory multiple myeloma who have received at least 1 line of therapy.^1,2 This regimen is a combination of a cereblon E3 ligase modulator (CELMoD), a CD-38–directed monoclonal antibody, and a corticosteroid.

“We are very excited to have a new treatment available, because especially with iberdomide, with dara and dex, it is a drug which actually works in patients who have even failed IMiDs [immunomodulatory drugs], who have failed lenalidomide and pomalidomide,” Prerna Mewawalla, MD, director of stem cell transplant and cellular therapy at Allegheny Health Network and associate professor of medicine at Drexel University College of Medicine, said in an interview about the approval.

When the NDA was accepted on February 17, 2026,³ its filing was supported by data on minimal residual disease (MRD) negativity rates from the phase 3 EXCALIBER-RRMM trial (NCT04975997), which compared IberDd against daratumumab, bortezomib (Velcade), and dexamethasone (DVd).⁴ It was also reviewed under the umbrella of the FDA’s Project Orbis initiative.³

“It was in 2024 that the FDA's ODAC [Oncologic Drugs Advisory Committee] voted to accept MRD at certain time points as an end point in myeloma trials,” Mewawalla explained.

The total enrollment was 939 patients for the ongoing EXCALIBER-RRMM trial.¹ The estimated primary completion date is November 16, 2027, and the study completion date is June 25, 2032.⁴ In stage 1, patients (n = 279) were randomly assigned to iberdomide plus daratumumab/hyaluronidase-fihj and dexamethasone (IberDd) at 1.0 mg, 1.3 mg, or 1.6 mg or to daratumumab and hyaluronidase-fihj, bortezomib (Velcade), and dexamethasone (DVd).^1,5 In stage 2, 660 patients were randomly assigned to 1.0 mg of IberDd or DVd.

The recommended oral dose of iberdomide is now 1.0 mg, with or without food, on days 1 through 21 of a 28-day cycle.

“The FDA’s acceptance of this application is a testament to the potential of iberdomide, in combination with anti-CD38 monoclonal antibodies, as a novel, potent, oral treatment option, with a manageable safety profile, for patients with multiple myeloma,” Cristian Massacesi, MD, executive vice president and chief medical officer, Bristol Myers Squibb, said in a statement upon submission of the NDA.³ “Furthermore, our filing for iberdomide based on the MRD end point underscores our commitment to pioneering new ways of advancing life-saving therapies for patients living with cancer.”

In EXCALIBER-RRMM, the coprimary end points are MRD-negative complete response (CR) at any point and progression-free survival (PFS) against which to evaluate treatment safety and efficacy.^1,5 Additional outcomes of interest are overall survival, overall response rate, duration of response, time to progression, time to next treatment, and health-related quality of life.

“I think what this does is it actually gets effective myeloma treatments to patients sooner,” Mewawalla noted, “because now we are not waiting for progression-free survival and overall survival, because we all know that in myeloma, that can take years to come."

The first 420 patients randomized to IberDd (n = 207) or DVd (n = 213) comprised the primary efficacy population for stages 1 and 2.¹ MRD-negative CR was close to twice as large with IberDd (41%; 95% CI, 34%-48%) vs DVd (21%; 95% CI, 15%-27%; P < .0001).

Iberdomide also received a breakthrough therapy designation and priority review from the FDA,³ and it is currently available only via restricted access due to the risk of embryo-fetal toxicity.¹ Project Orbis permits simultaneous review of new drug applications by the FDA and international health regulatory bodies.⁶

References

1. FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma. FDA. August 13, 2026. Accessed August 13, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-iberdomide-daratumumab-and-hyaluronidase-fihj-and-dexamethasone
2. Open-label study comparing iberdomide, daratumumab and dexamethasone (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in participants with relapsed or refractory multiple myeloma (RRMM) - CC-220-MM-002. Bristol Myers Squibb. Accessed August 10, 2026. https://www.bmsstudyconnect.com/mx/en/clinical-trials/NCT04975997.html
3. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s new drug application for iberdomide in patients with relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb. February 17, 2026. Accessed August 10, 2026. https://news.bms.com/news/corporate-financial/2026/U-S--Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-New-Drug-Application-for-Iberdomide-in-Patients-with-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx
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 August 10, 2026. https://clinicaltrials.gov/study/NCT04975997
5. FDA accepts new drug application for iberdomide as treatment for RRMM. News release. International Myeloma Foundation. February 17, 2026. Accessed August 10, 2026. https://www.myeloma.org/news-events/multiple-myeloma-news/fda-accepts-new-drug-application-iberdomide-rrmm
6. Project Orbis. FDA. Updated May 14, 2026. Accessed August 10, 2026. https://www.fda.gov/about-fda/oncology-center-excellence/project-orbis