Iberdomide Holds Promise in Phase 3 R/R Myeloma Trial

Iberdomide plus standard therapy of daratumumab (Darzalex) and dexamethasone demonstrated a statistically significant improvement in minimal residual disease (MRD) negativity rates in patients with relapsed or refractory multiple myeloma, according to a planned interim analysis of the phase 3 EXCALIBER-RRMM study (NCT04975997).¹

“This result builds on our significant experience in both targeted protein degradation and developing new treatment options for patients living with multiple myeloma,” said Anne Kerber, senior vice president and head of Development, Hematology, Oncology and Cell Therapy, in a press release. “Iberdomide represents the first of a novel class of medicines, called [cereblon E3 ligase modulators (CELMoDs)], which has the potential to create a new foundation for multiple myeloma treatment that may be combined with other therapies.”

Bristol Myers Squibb, the sponsor, plans to discuss these data with health authorities.

What is the Phase 3 EXCALIBER-RRMM Study Investigating?

EXCALIBER-RRMM is a multicenter, randomized, controlled, open-label phase 3 study comparing the safety and efficacy of iberdomide plus daratumumab and dexamethasone vs daratumumab, bortezomib (Velcade), and dexamethasone (DVd) in patients with relapsed/refractory multiple myeloma.²

Stage 1 of the study identified 1.0 mg as the optimal dose of iberdomide. In stage 2,patients were randomized to receive iberdomide at 1.0 mg on days 1 to 21 of a 28-day cycle plus dexamethaonse and daratumumab or DVd.¹ Approximately 664 patients were randomized.

The primary end points are progression-free survival (PFS) and MRD-negative complete response.² Secondary end points include overall survival (OS), sustainability of MRD negativity, overall response rate (ORR), time to response, duration of response (DOR), time to progression, time to next treatment, safety, health-related quality of life, and pharmacokinetics.

To be eligible for study participation, patients must have documented diagnosis of multiple myeloma with measurable disease, received 1 to 2 prior lines of antimyeloma therapy, and have an ECOG performance status of 0 to 2. Those with known central nervous system involvement or who have plasma cell leukemia, Waldenström macroglobulinemia, or clinically significant amyloidosis are not eligible for enrollment.

What is Iberdomide?

Iberdomide is a member of a new drug class in myeloma known as CELMoD agents, which build on the established platform of immunomodulatory agents.³ CELMoDs like iberdomide are oral agents that can be used after disease relapse.

The first results of the phase 2 EMN26 trial (NCT04564703) demonstrated that iberdomide maintenance therapy prolonged remission following autologous stem cell transplant in patients with newly diagnosed myeloma and had a favorable safety profile compared with lenalidomide (Revlimid) maintenance.

Data from the phase 2 I2D study (NCT01383928) published in the Journal of Clinical Oncology in May 2024 investigated the all-oral trial of iberdomide, ixazomib (Ninlaro), and dexamethasone in older patients with myeloma at first relapse. Here, the ORR was 65%, with 36% of patients achieving a complete response or very good partial response. At a median follow-up of 14 months, the 12-month OS rate was 86%, 12-month DOR rate was 76%, and 12-month PFS rate was 52%.

REFERENCES:

1. 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 September 25, 2025. https://tinyurl.com/53tc84we

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) (EXCALIBER-RRMM). ClinicalTrials.gov. Updated July 10, 2025. Accessed September 25, 2025. https://clinicaltrials.gov/study/NCT04975997

3. Iberdomide - a CELMoD in clinical trials. International Myeloma Foundation. Accessed September 25, 2025. https://tinyurl.com/544eajk2