Iberdomide Regimen Cuts RRMM Progression Risk by 51%, Trial Finds

Iberdomide (Zenbexus; Bristol Myers Squibb) in combination with daratumumab and dexamethasone (ZDd) demonstrated a statistically significant improvement in the dual-primary end point of progression-free survival (PFS) among patients with relapsed or refractory multiple myeloma (RRMM), according to topline results from the phase 3 EXCALIBER-RRMM trial (NCT04975997) announced October 8.¹

ZDd Improves PFS in RRMM

After a median follow-up of 23 months, median PFS was 42 months with ZDd vs 20 months with daratumumab, bortezomib, and dexamethasone (DVd; HR, 0.49; P < .000001), representing a 51% reduction in the risk of disease progression or death. The data will be presented at the 2026 Annual Meeting of the American Society of Hematology, taking place from December 12 to 15, 2026, in New Orleans, Louisiana.

EXCALIBER-RRMM is a phase 3, multicenter, randomized, open-label study evaluating the efficacy and safety of ZDd vs DVd in patients with RRMM. It was designed to assess 2 primary end points: minimal residual disease (MRD) negativity and PFS. Secondary end points included overall survival, overall response rate (ORR), safety, and sustained MRD negativity. Eligible participants included adults with progressive disease who had received 1 or 2 prior lines of anti-myeloma therapy.

The PFS confirmatory analysis included all 800 patients, with 400 randomized to each treatment arm. Treatment in both arms continued until disease progression or unacceptable toxicity.

The PFS results build on earlier findings showing an improvement in MRD-negative complete response (CR) with ZDd vs DVd. These findings, which were presented at this year’s International Myeloma Society Annual Meeting, supported the FDA’s recent approval of the regimen.^2,3

At a median follow-up of 15.7 months among 420 patients, the trial showed a statistically significant and clinically meaningful improvement in the MRD-negative CR rate, with a higher rate in the ZDd arm than in the DVd arm (41.1% vs 20.7%; 95% CI, 11.5%-28.6%; P < .0001). The ORR was also higher with ZDd than with DVd (88.9% vs 76.1%), as was the CR rate (45.9% vs 24.9%).

ZDd’s safety profile was consistent with the known profile of the combination. Grade 3/4 neutropenia occurred in 84.3% of patients treated with ZDd vs 11.3% of those treated with DVd, predominantly occurring during the first 2 cycles. Grade 3/4 infections occurred in 39.2% vs 21.6% of patients, respectively, while fatal infections remained uncommon (2.0% vs 1.5%).

“These findings further underscore the value of Zenbexus 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, said in a news release.^{1 “}We look forward to sharing full results from the study.”

FDA Approval Expands RRMM Treatment Options

Based on the MRD-negative CR results, ZDd received accelerated approval on August 13, 2026.² The regimen is indicated for adult patients with multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent.¹ Continued approval, however, may be contingent upon verification and description of clinical benefit in a confirmatory trial.

“We are very excited to have a new treatment available, because especially with iberdomide, with dara and dex, it is a drug which actually works in patients who have even failed IMiDs [immunomodulatory drugs], who have failed lenalidomide and pomalidomide,” Prerna Mewawalla, MD, director of stem cell transplant and cellular therapy at Allegheny Health Network and associate professor of medicine at Drexel University College of Medicine, said in an interview with The American Journal of Managed Care^®.⁴

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… News release. Bristol Myers Squibb. October 8, 2026. Accessed October 14, 2026. https://news.bms.com/news/details/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. Shaw ML. FDA approves novel iberdomide regimen in RRMM. AJMC^®. August 13, 2026. Accessed October 14, 2026. https://www.ajmc.com/view/fda-approves-novel-iberdomide-regimen-in-rrmm
3. Bristol Myers Squibb announces first presentation of results for ZENBEXUS (iberdomide) in combination with daratumumab from phase 3 EXCALIBER-RRMM trial in relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb. September 25, 2026. Accessed October 14, 2026. https://news.bms.com/news/corporate-financial/2026/Bristol-Myers-Squibb-Announces-First-Presentation-of-Results-for-ZENBEXUS-iberdomide-in-Combination-with-Daratumumab-from-Phase-3-EXCALIBER-RRMM-Trial-in-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx
4. Mewawalla P, Shaw ML. Iberdomide approval elevates MRD’s role in myeloma: Prena Mewawalla, MD. AJMC. August 13, 2026. Accessed October 14, 2026. https://www.ajmc.com/view/iberdomide-approval-elevates-mrd-s-role-in-myeloma-prerna-mewawalla-md