Iberdomide Doubles MRD-Negative CR Rate in Phase 3 EXCALIBER-RRMM Trial

According to results from the phase 3 EXCALIBER-RRMM trial (NCT04975997), presented in a late-breaking oral session at the International Myeloma Society (IMS) 2026 Annual Meeting and simultaneously published in The Lancet Oncology, iberdomide (Zenbexus) plus daratumumab (Darzalex) and dexamethasone (IDd) more than doubled the rate of minimal residual disease (MRD)-negative complete response (CR) compared with daratumumab, bortezomib (Velcade), and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma (RRMM), according to data presented at the 23rd Annual International Myeloma Society (IMS) Meeting and published in The Lancet Oncology.^1,2 At a median follow-up of 15.7 months in the 420-patient primary efficacy population, 41.1% of patients receiving IDd achieved an MRD-negative CR compared with 20.7% of those receiving DVd (95% CI, 11.5%-28.6%; P < .0001; OR, 2.75; 95% CI, 1.77-4.30).

Study Design

EXCALIBER-RRMM is a phase 3, multicenter, 2-stage, randomized, open-label trial enrolling adults with RRMM who had received 1 to 2 prior lines of anti-myeloma therapy and had progressive disease. Stage 1 tested 4 dose-optimization arms across 280 patients to select an optimal iberdomide dose ahead of a seamless transition into stage 2. A total of 939 patients were ultimately randomized; the primary efficacy population for the MRD-negative CR end point comprised the first 420 patients randomized, with 207 assigned to IDd and 213 to DVd.1 The trial's dual primary end points are MRD-negative CR rate and progression-free survival (PFS); a confirmatory PFS analysis in the full 800-patient cohort remains ongoing.

Efficacy and Safety

Treatment benefit with IDd was consistent across prespecified subgroups, including patients with prior lenalidomide exposure and those refractory to lenalidomide. The overall response rate was 88.9% with IDd compared with 76.1% with DVd, and the rate of CR or better was nearly doubled at 45.9% vs 24.9%, respectively.

The safety profile of IDd was consistent with the known profiles of its individual components. Grade 3/4 neutropenia occurred in 84.3% of patients on ZDd vs 11.3% on DVd, concentrated mainly in the first 2 treatment cycles and generally managed with growth factor support and dose interruptions rather than dose reduction; iberdomide was discontinued for neutropenia in only 1.0% of patients. Grade 3/4 infections occurred in 39.2% of patients on ZDd vs 21.6% on DVd, with fatal infections remaining low in both arms (2.0% vs 1.5%). Peripheral sensory neuropathy, a hallmark toxicity of bortezomib, was markedly less frequent with ZDd than DVd at any grade (12.3% vs 42.6%) and grade 3/4 (2.9% vs 5.4%).

Clinical Context and Limitations

The findings build on an interim MRD analysis of EXCALIBER-RRMM that led the FDA to accept a new drug application for iberdomide, with breakthrough therapy designation and priority review, in February 2026. Based on the 420-patient MRD-negative CR data described here, the FDA granted accelerated approval in August 2026 to IDd for adults with multiple myeloma who have received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent, making iberdomide the first CELMoD to reach approval in multiple myeloma.³ Notably, this marked the first agent approved based on MRD negativity results. That approval remains contingent on verification of clinical benefit, which the ongoing PFS analysis in the 800-patient confirmatory cohort is designed to provide.¹

"We know that MRD activity does clearly correlate with progression-free survival and overall survival,” said Sagar Lonial, MD, FACP, professor and chair, Department of Hematology and Medical Oncology, Emory University School of Medicine, and Chief Medical Officer, Winship Cancer Institute of Emory University, during his presentation at IMS. "This really is a watershed moment for us in the field to be able to have an alternative end point that we're going to offer access to patients sooner."

Iberdomide is a CELMoD, a next-generation cereblon E3 ligase modulator engineered to more potently degrade the Ikaros and Aiolos transcription factors than earlier immunomodulatory drugs. Investigators noted that the 15.7-month median follow-up is short relative to other MRD analyses in myeloma, and that MRD-negative CR rates have continued to improve with longer follow-up in other trials, suggesting the current results may understate the durability of response.

REFERENCES

1. Lonial S et al. Iberdomide, Daratumumab, Dexamethasone (IberDd) Vs Daratumumab, Bortezomib, Dexamethasone (DVd) in Patients With Relapsed/Refractory Multiple Myeloma (RRMM): Results From EXCALIBER-RRMM Phase 3 Study. Presented at: 23rd Annual IMS Meeting; September 23-26, 2026; Glasgow, Scotland.

2. Lonial S, Dimopoulous MA, Gavriatopoulou M, et al. Iberdomide plus daratumumab and dexamethasone versus daratumumab, bortezomib, and dexamethasone in patients with relapsed or refractory multiple myeloma (EXCALIBER-RRMM): an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. doi: 10.1016/S1470-2045(26)00450-X

3. FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma. News release. FDA. August 13, 2026. Accessed September 25, 2026. https://tinyurl.com/mxbm477f