Iberdomide Triplet Improves PFS by 51% in Phase 3 Myeloma Trial

Iberdomide (Zenbexus) plus subcutaneous daratumumab (Darzalex Faspro) and dexamethasone (IDd) significantly prolonged progression-free survival (PFS) compared with daratumumab, bortezomib (Velcade), and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma (RRMM).

In the phase 3 EXCALIBER-RRMM trial (NCT04975997), median PFS reached 42 months with IDd vs 20 months with DVd (HR, 0.49; P < .000001) after a median follow-up of 23 months. The trial previously met its minimal residual disease (MRD) coprimary end point, leading to its FDA approval.

"The results from EXCALIBER-RRMM reinforce the clinical value of [iberdomide] in combination with daratumumab and dexamethasone as a treatment approach for relapsed or refractory multiple myeloma, demonstrating the strong benefit observed for [MRD] negativity translated to a meaningful improvement in [PFS] for patients," Cristian Massacesi, MD, chief medical officer and head of development at Bristol Myers Squibb in Princeton, New Jersey, stated in a news release.

Trial Design and MRD Results

EXCALIBER-RRMM is an open-label, multicenter study conducted in 2 stages, the first of which optimized the dose of iberdomide, an oral cereblon E3 ligase modulator (CELMoD). Adults were eligible if they had progressive disease after 1 or 2 prior lines of therapy. Treatment in both arms continued until progression or unacceptable toxicity. The coprimary end points were PFS and MRD-negative complete response (CR). Secondary end points include OS, overall response rate, safety, and sustained MRD negativity.

The findings presented at the 2026 International Myeloma Society (IMS) Annual Meeting in Glasgow, Scotland, and published simultaneously in The Lancet Oncology included the MRD findings from EXCALIBER-RRMM. Among the first 420 patients randomly assigned (IDd, n = 207; DVd, n = 213), 41.1% of those receiving IDd achieved MRD-negative CR vs 20.7% of those receiving DVd (OR, 2.75; 95% CI, 1.77-4.30; P < .0001) at a median follow-up of 15.7 months. Rates of CR or better were 45.9% vs 24.9%, and overall response rates were 88.9% vs 76.1%, respectively. Benefit was consistent across prespecified subgroups.

In terms of safety, grade 3/4 neutropenia occurred in 84.3% of patients in the IDd arm vs 11.3% in the DVd arm, and grade 3/4 infections in 39.2% vs 21.6%, whereas any-grade peripheral sensory neuropathy was less frequent with IDd (12.3% vs 42.6%).

Significance of PFS Outcomes

The PFS confirmatory analysis included all 800 patients randomized to IDd (n = 400) or DVd (n = 400). The full PFS results will be presented at the 68th American Society of Hematology Annual Meeting in New Orleans, Louisiana on December 12 to 15, 2026.

The FDA granted accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone on the basis of MRD-negative CR, the first approval to be based on this end point. The indication covers adults with multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent. Iberdomide is being investigated in other multiple myeloma settings including in the phase 3 EXCALIBER-Maintenance (NCT05827016) in comparison with lenalidomide (Revlimid) maintenance in the transplant-eligible newly diagnosed multiple myeloma setting.

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://tinyurl.com/3zv4y5nj

2. 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 International Myeloma Society Meeting; September 23-26, 2026; Glasgow, Scotland.

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