IberDd Demonstrates Positive Topline Efficacy in Relapsed/Refractory Multiple Myeloma

The investigational cereblon E3 ligase modulator (CELMoD) iberdomide in combination with standard-of-care daratumumab (Darzalex) and dexamethasone (IberDd) led to a statistically significant improvement in minimal residual disease (MRD) negativity rates in patients with relapsed/refractory multiple myeloma compared with daratumumab, bortezomib (Velcade), and dexamethasone (DVd), according to data from a planned interim analysis of the phase 3 EXCALIBER-RRMM study (NCT04975997).1

According to the trial design and based on a recommendation from the Data Monitoring Committee, EXCALIBER-RRMM will continue without changes to examine the other dual-primary end point of progression-free survival (PFS), and the key secondary end point of overall survival (OS) as well as safety. The safety profile of IberDd has been generally consistent with prior studies. Bristol Myers Squibb plans to discuss the findings from EXCALIBER-RRMM with health authorities.

“This result builds on our significant experience in both targeted protein degradation and developing new treatment options for patients living with multiple myeloma,” Anne Kerber, Senior Vice President, Head of Development, Hematology, Oncology and Cell Therapy shared in a news release. “Iberdomide represents the first of a novel class of medicines, called CELMoDs, which has the potential to create a new foundation for multiple myeloma treatment that may be combined with other therapies.”

What Are the Key Design Characteristics of EXCALIBER-RRMM?

EXCALIBER-RRMMis an ongoing multicenter, 2-stage, randomized, open-label study that is examining IberDd in adult patients with relapsed/refractory multiple myeloma. Patients were required to have received 1 to 2 prior lines of anti-myeloma therapy, an ECOG performance status of 0 to 2, have achieved at least a partial response with at least 1 prior therapy, and have experienced disease progression during or after their last treatment regimen.2 Those who previously received iberdomide, had grade 2 (with pain), 3, or 4 peripheral neuropathy, or received prior treatment with bortezomib with a best response of less than a minimal response or disease progression less than 60 days from the last dose were excluded.

In the dose optimization portion of the trial (stage 1) patients were randomly assigned 1:1:1:1 to receive iberdomide at 1.0 mg, 1.3 mg, or 1.6 mg on days 1 through 21, all in combination with daratumumab and dexamethasone, or DVd. In the investigational arm, patients received subcutaneous daratumumab at 1800 mg on days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3 through 6, and day 1 of subsequent cycles, as well as oral dexamethasone at 40 mg on days 1, 8, 15, and 22. Treatment was given in 28-day cycles in the investigational arm.

In the DVd arm, patients received subcutaneous daratumumab at 1800 mg on days 1, 8, and 15 during cycles 1 through 3 and day 1 of subsequent cycles. Subcutaneous bortezomib was administered at 1.3 mg/m2 on days 1, 4, 8, and 11 during cycles 1 through 8; oral dexamethasone was given at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 1 through 8. Cycles 1 through 8 were 21 days and 28-day cycles were employed for cycle 9 and beyond.

Stage 1 of the study determined that the optimal dose of iberdomide in combination with daratumumab and dexamethasone is 1.0 mg based on safety, pharmacokinetics, and efficacy results.1 Stage 2 randomly assigned approximately 664 patients to receive either IberDd or DVd.

The dual primary end points are MRD negativity and PFS. Secondary end points include overall survival, overall response rate, duration of response, time to progression, time to next treatment, and health-related quality of life.

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 23, 2025. 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
2. 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