Iberdomide Triplet Improves MRD-Negative CRs in R/R Multiple Myeloma

Iberdomide (Zenbexus) plus daratumumab (Darzalex) and dexamethasone (IberDd) significantly increased the rate of measurable residual disease (MRD)–negative complete response (CR) vs daratumumab plus bortezomib (Velcade) and dexamethasone (DVd) in patients with relapsed/refractory multiple myeloma, meeting one of the dual primary end points of the phase 3 EXCALIBER-RRMM (NCT04975997) trial, according to findings presented at the 23rd Annual International Myeloma Society (IMS) Meeting & Exposition and published in The Lancet Oncology.^1,2

What were the MRD-negative CR and response outcomes?

At a median follow-up of 15.7 months, IberDd more than doubled the rate of MRD-negative CR at any time compared with DVd (41.1% vs 20.7%; OR, 2.75; 95% CI, 1.77-4.30), with MRD assessed by next-generation flow cytometry at a sensitivity of 10^–5. Among the 95 patients in the IberDd group who achieved a CR or better, 85 (89.5%) were MRD negative compared with 44 of 53 patients (83.0%) in the DVd group. The benefit was consistent across prespecified subgroups, including among patients with prior lenalidomide (Revlimid) exposure, lenalidomide-refractory disease, and lenalidomide use in the last prior line of therapy.

In secondary response analyses, the overall response rate (ORR) was 88.9% with IberDd vs 76.1% with DVd; the rate of CR or better was 45.9% vs 24.9%, and the rate of very good partial response or better was 74.4% vs 61.5%. Evaluation of the second dual primary end point, progression-free survival (PFS), is ongoing.

What was the safety profile of IberDd?

Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 91.7% of patients receiving IberDd vs 70.1% receiving DVd. Neutropenia was the most common grade 3/4 event with IberDd, occurring in 84.3% of patients vs 11.3% with DVd; 82.4% of patients in the IberDd arm received granulocyte colony-stimulating factor, and neutropenia was mostly managed with dose interruptions (51.5%) and dose reductions (13.2%), with iberdomide discontinuation due to neutropenia in 1.0%.

Rates of grade 3/4 thrombocytopenia (12.7% vs 44.1%) and any-grade peripheral sensory neuropathy (12.3% vs 42.6%) were lower with IberDd than DVd. Any-grade infections occurred in 78.9% of the IberDd arm vs 69.6% of the DVd arm, and most were grade 3 or lower; rates of fatal infections were similar between groups (2.0% vs 1.5%). Venous thromboembolism occurred in 5.9% vs 3.9% of patients, with no grade 3/4 events in the IberDd arm, for which thromboprophylaxis was mandatory. Deaths were reported in 11.1% of the IberDd group vs 15.5% of the DVd group, primarily due to progressive disease.

“In the EXCALIBER-RRMM trial, [IberDd] demonstrated significant improvement in MRD-negative CRs compared to the control arm. The benefit was seen across many pre-specified subgroups,” lead study investigator Sagar Lonial, MD, FACP, FASCO, chief medical officer of Winship Cancer Institute of Emory University and Anne and Bernard Gray Family Chair in Cancer of Emory University School of Medicine, stated in his presentation of the data. “Iberdomide [plus daratumumab/dexamethasone] does represent a new standard of care in the context of an early first relapse in a number of different clinical settings.”

What is the EXCALIBER-RRMM design and population?

EXCALIBER-RRMM is the first randomized phase 3 study in relapsed/refractory multiple myeloma to use dual primary end points of MRD-negative CR and PFS. The trial included a stage 1 dose-optimization phase, which selected the 1.0-mg iberdomide dose in line with the FDA’s Project Optimus principles, and a stage 2 efficacy and safety phase.

Eligible patients had received 1 to 2 prior lines of therapy with progressive disease and were not refractory to anti-CD38 monoclonal antibodies. In the IberDd arm, iberdomide was given orally once daily on days 1 to 21 of each 28-day cycle, with subcutaneous daratumumab and dexamethasone; the DVd arm followed the phase 2 CASTOR study (NCT02136134) schedule. The MRD-negative CR analysis included 207 patients assigned to IberDd and 213 assigned to DVd. The median age was 68 (range, 37-85) and 67 (range, 35-87) years, respectively; approximately two-thirds of patients had received 1 prior line of therapy, and roughly 90% had prior immunomodulatory drug exposure.

What is the significance of these findings?

MRD-negative CR strongly correlates with PFS and overall survival and is recognized by the FDA as an end point supporting accelerated approval. In August 2026, IberDd received FDA accelerated approval for patients with relapsed/refractory multiple myeloma based on the MRD-negative CR data from EXCALIBER-RRMM.³

The investigators noted that IberDd showed a safety profile consistent with the known effects of CELMoDs and daratumumab/dexamethasone. Iberdomide is also under investigation as maintenance therapy vs lenalidomide in the EXCALIBER-Maintenance trial (NCT05827016).

References

1. Lonial S, Dimopoulos MA, Gavriatopoulou M, et al. Iberdomide, daratumumab, dexamethasone versus daratumumab, bortezomib, dexamethasone in patients with relapsed/refractory multiple myeloma: results from EXCALIBER-RRMM phase 3 study. Presented at: 23rd International Myeloma Society Annual Meeting; September 23-26, 2026; Glasgow, Scotland. Abstract LBA-12.
2. Lonial S, Dimopoulos MA, Gavriatopoulou M, et al. Iberdomide, daratumumab, and dexamethasone versus daratumumab, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma (EXCALIBER-RRMM). Lancet Oncol. Published online September 25, 2026. 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. August 13, 2026. Accessed September 26, 2026. https://tinyurl.com/38258auk