Iberdomide Plus Daratumumab/Dexamethasone Yields Significant PFS Benefit in R/R Myeloma

Treatment with iberdomide (Zenbexus) plus daratumumab and hyaluronidase-fihj (Darzalex Faspro; subcutaneous daratumumab) and dexamethasone (IberDd) led to a statistically significant improvement in progression-free survival (PFS) compared with daratumumab, bortezomib (Velcade), and dexamethasone (DVd) in patients with relapsed/refractory multiple myeloma, meeting the PFS dual primary end point of the phase 3 EXCALIBER-RRMM trial (NCT04975997).¹

Findings announced by Bristol Myers Squibb showed that at a median follow-up of 23 months, patients treated with IberDd experienced a median PFS of 42 months vs 20 months for those given DVd (HR, 0.49; P < .000001), translating to a 51% reduction in the risk of disease progression or death with the iberdomide-based triplet.

The safety profile of iberdomide in combination with standard therapies remained consistent with previously reported safety findings from the study.

The readout builds on the previously reported improvement in minimal residual disease (MRD)–negative complete response (CR) with IberDd. Data presented at the 23rd International Myeloma Society Annual Meeting and Exposition and published in The Lancet showed that at a median follow-up of 15.7 months (interquartile range, 12.8-23.2), 41.1% of patients treated with IberDd (n = 207) achieved an MRD-negative CR vs 21% of patients given DVd (difference, 20.1%; 95% CI: 11.5%-28.6%; P < .0001; odds ratio 2.75; 95% CI, 1.77-4.30).^2,3

MRD-negative CR served as the trial's other dual primary end point, and these data supported the FDA's accelerated approval of the regimen in August 2026.⁴

The full PFS data will be presented at the 2026 ASH Annual Meeting and Exposition in December.

"These findings further underscore the value of [iberdomide] as an effective oral treatment option that can be easily used in diverse care settings, including community settings, where many patients receive their care," Cristian Massacesi, MD, chief medical officer and head of development at Bristol Myers Squibb, stated in a news release.¹

What was the design of EXCALIBER-RRMM?

EXCALIBER-RRMM is a 2-stage, randomized, open-label, multicenter phase 3 trial that enrolled 939 patients at least 18 years of age with multiple myeloma and measurable disease who had received 1 to 2 prior lines of therapy.⁵ Disease progression during or after the last line of therapy was required, as was an ECOG performance status of 0 to 2.

Patients with prior iberdomide exposure, plasma cell leukemia, Waldenström macroglobulinemia, POEMS syndrome, clinically significant amyloidosis, or known central nervous system involvement were excluded.

In stage 1 (n = 279), patients were randomly assigned to 1 of 3 iberdomide dose levels (1.0 mg, 1.3 mg, or 1.6 mg) plus daratumumab and dexamethasone or to DVd; the 1.0-mg dose was selected for further evaluation.⁴ In stage 2 (n = 660), patients were randomly assigned 1:1 to IberDd at the selected dose or DVd.

In the IberDd arm, patients received oral iberdomide at 1 mg once daily on days 1 through 21 of each 28-day cycle; subcutaneous daratumumab at 1800 mg on days 1, 8, 15, and 22 of cycles 1 and 2, on days 1 and 15 of cycles 3 through 6, and on day 1 of cycle 7 onward; and dexamethasone at 20 mg or 40 mg on days 1, 8, 15, and 22. Treatment continued until disease progression or unacceptable toxicity.^2,3

The dual primary end points were PFS and MRD-negative CR at any time. Secondary end points include overall survival (OS), sustained MRD negativity, overall response rate (ORR), time to response, duration of response, time to progression, time to next treatment, PFS2, safety, and quality of life as measured by the EORTC QLQ-C30 and QLQ-MY20 questionnaires.

What safety data have been reported for IberDd?

Regarding safety in that analysis, grade 3/4 treatment-emergent adverse effects (TEAEs) occurred in 91.7% of patients in the IberDd arm vs 70.1% of those in the DVd arm.³ Grade 3/4 neutropenia was more common with IberDd (84.3% vs 11.3%), whereas grade 3/4 thrombocytopenia was more common with DVd (12.7% vs 44.1%). Grade 3/4 infections occurred in 35.8% vs 21.1% of patients, respectively, and TEAEs led to discontinuation in 8.7% vs 3.3%.

References

1. Bristol Myers Squibb announces Zenbexus (iberdomide) in combination with daratumumab and dexamethasone (ZDd) demonstrates superior progression-free survival vs. standard of care in relapsed and refractory multiple myeloma in phase 3 EXCALIBER-RRMM study. News release. Bristol Myers Squibb. October 8, 2026. Accessed October 8, 2026. https://news.bms.com/news/corporate-financial/2026/Bristol-Myers-Squibb-Announces-ZENBEXUSTM-iberdomide-in-Combination-with-Daratumumab-and-Dexamethasone-ZDd-Demonstrates-Superior-Progression-Free-Survival-vs--Standard-of-Care-in-Relapsed-and-Refractory-Multiple-Myeloma-in-Phase-3---/default.aspx
2. 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 (IMS) Annual Meeting & Exposition; September 23-26, 2026; Glasgow, Scotland. Presentation LBA-12.
3. Lonial S, Dimopoulos 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. Published online September 25, 2026. doi:10.1016/S1470-2045(26)00450-X
4. FDA grants accelerated approval to iberdomide, daratumumab and hyaluronidase-fihj, and dexamethasone. FDA. August 13, 2026. Accessed October 8, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-iberdomide-daratumumab-and-hyaluronidase-fihj-and-dexamethasone
5. 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. Accessed October 8, 2026. https://clinicaltrials.gov/study/NCT04975997