FDA Approves Iberdomide Plus Daratumumab/Dexamethasone for R/R Myeloma

The FDA has granted accelerated approval to iberdomide (Zenbexus) plus daratumumab and hyaluronidase-fihj (Darzalex Faspro) and dexamethasone (IberDd) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.¹

The regulatory decision was supported by data from the phase 3 EXCALIBER-RRMM trial (NCT04975997), in which IberDd generated a statistically significant improvement in minimal residual disease (MRD) negativity rates vs daratumumab plus bortezomib (Velcade) and dexamethasone (DVd).^1-3

Findings supporting the approval showed that patients in the IberDd arm (n = 207) achieved an MRD-negative complete response rate at any time of 41% (95% CI, 34%-48%) compared with 21% (95% CI, 15%-27%) among patients treated with daratumumab plus bortezomib (Velcade) and dexamethasone (P < .0001).¹

“The goal for every person living with multiple myeloma is not simply to live longer, but to live well,” Heather Cooper Ortner, president and chief executive officer of the International Myeloma Foundation, stated in a news release.² “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.”

What was the design of the EXCALIBER-RRMM trial?

The open-label, multicenter, two-stage, randomized phase 3 EXCALIBER-RRMM trial is evaluating IberDd vs DVd in patients with relapsed or refractory multiple myeloma who have received 1 to 2 prior lines of antimyeloma therapy.⁴ Patients who are refractory to CD38-targeted antibody therapy or to bortezomib are excluded.

In stage 1, the dose-optimization phase, patients were randomly assigned 1:1:1:1 to receive iberdomide at 1.0 mg, 1.3 mg, or 1.6 mg plus daratumumab and dexamethasone, or to DVd; the 1.0-mg dose of iberdomide was selected for continued evaluation based on safety, pharmacokinetic, and efficacy data. In stage 2, approximately 664 patients were randomized 1:1 to IberDd in 28-day cycles or DVd in 21- or 28-day cycles. Stratification factors included number of prior lines of therapy (1 vs 2), age (≤ 70 years vs > 70 years), and International Staging System stage at study entry (I or II vs III).

The trial’s dual primary end points were MRD negativity and progression-free survival (PFS). Secondary end points included overall survival, overall response rate (ORR), duration of response, time to progression, time to next treatment, and health-related quality of life. The trial remains ongoing, with patients continuing to be evaluated for PFS following the MRD analysis that supported the NDA.^1,2

What safety data were reported for the combination?

Adverse effects (AEs) led to treatment discontinuation in 7.8% of patients treated with IberDd.²

For patients treated with the combination, neutropenia was reported at a rate of 90.2%, and infections occurred in 78.9% of patients. The rates of treatment discontinuations related to these AEs were 1% and 1.5%, respectively.

The most common AEs reported in at least 20% of patients treated with IberDd and DVd arms, respectively, were upper respiratory tract infection (54% vs 52%), fatigue (36% vs 33%), musculoskeletal pain (35% vs 33%), pneumonia (34% vs 17%), diarrhea (33% vs 36%), motor dysfunction (26% vs 17%), rash (26% vs 15%), sleep disorder (25% vs 28%), hypogammaglobulinemia (24% vs 12%), COVID-19 (23% vs 16%), and constipation (20% vs 22%).

Serious AEs that occurred in at least 2% of patients treated with IberDd 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%).

Ten patients (4.9%) treated with iberdomide-based therapy experienced fatal AES; sepsis (1.5%) was the only fatal reaction that occurred in more than 1 patient. Other fatal AEs that occurred in 1 patient each comprised listeria encephalitis, influenza, lung adenocarcinoma, cardiac arrest, large intestine perforation, metabolic acidosis, and respiratory failure.

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. U.S. FDA grants accelerated approval to Bristol Myers Squibb's first CELMoD therapy Zenbexus, in combination with daratumumab and hyaluronidase-fihj and dexamethasone (ZDd) for patients with multiple myeloma, as early as first relapse. News release. Bristol Myers Squibb. August 13, 2206. Accessed August 13, 2026. https://news.bms.com/news/corporate-financial/2026/U-S--FDA-Grants-Accelerated-Approval-to-Bristol-Myers-Squibbs-First-CELMoD-Therapy-ZENBEXUS-in-Combination-with-Daratumumab-and-Hyaluronidase-fihj-and-Dexamethasone-ZDd-for-Patients-with-Multiple-Myeloma-as-Early-as-First-Relapse/default.aspx
3. 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 7, 2026. https://news.bms.com/news/details/2025/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/default.aspx
4. Lonial S, Dimopoulos MA, Berdeja JG, et al. EXCALIBER-RRMM: a phase III trial of iberdomide, daratumumab, and dexamethasone in relapsed/refractory multiple myeloma. Future Oncol. 2025;21(14):1761-1769. doi:10.1080/14796694.2025.2501920