Iberdomide Combination Doubles PFS vs SOC Therapy in R/R Multiple Myeloma

Iberdomide (Zenbexus) in combination with daratumumab (Darzalex) and dexamethasone (ZDd) produced a statistically significant improvement in progression-free survival (PFS) vs daratumumab, bortezomib (Velcade), and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma as early as first relapse, meeting the second of 2 dual primary end points in the phase 3 EXCALIBER-RRMM trial (NCT04975997), according to topline results announced by the developer, Bristol Myers Squibb.¹

What did the progression-free survival analysis show?

At a median follow-up of 23 months, the median PFS was 42 months with ZDd vs 20 months with DVd (HR, 0.49; P <.000001), representing a 51% reduction in the risk of disease progression or death. The PFS confirmatory analysis population included all 800 patients randomly assigned to ZDd (n = 400) or DVd (n = 400).

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

“The results from EXCALIBER-RRMM reinforce the clinical value of [ZDd] as a treatment approach for relapsed or refractory multiple myeloma, demonstrating the strong benefit observed for minimal residual disease [MRD] negativity translated to a meaningful improvement in [PFS] for patients,” said Cristian Massacesi, MD, chief medical officer and head of development at Bristol Myers Squibb, in the news release.¹ “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. We look forward to sharing full results from the study

How does this result build on the earlier EXCALIBER-RRMM data?

EXCALIBER-RRMM was designed with the dual primary end points of MRD-negative complete response (CR) and PFS. The PFS result follows the previously reported MRD-negative CR data, which were presented at the 23rd International Myeloma Society (IMS) Annual Meeting & Exposition and simultaneously published in The Lancet Oncology.^2,3 In that analysis, ZDd 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. Those MRD-negative CR data supported the August 2026 FDA accelerated approval of iberdomide in combination with daratumumab and hyaluronidase-fihj (Darzalex Faspro) and dexamethasone for patients with multiple myeloma who have received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.⁴ Continued approval may be contingent on verification of clinical benefit in confirmatory trials.

What is the safety profile of the iberdomide combination?

In EXCALIBER-RRMM, serious adverse reactions occurred in 58.3% of patients receiving iberdomide, and fatal adverse reactions occurred in 4.9%, with sepsis (1.5%) as the only fatal drug reaction occurring in more than 1 patient.¹ All-grade neutropenia was reported in 90.2% of patients in the iberdomide arm, with grade 3 events in 30.9% and grade 4 events in 53.4%; febrile neutropenia occurred in 5.4%.

Infections were reported in 78.9% of patients receiving the iberdomide combination, including grade 3 events in 35.8% and serious infections in 40%. Venous thromboembolic events occurred in 6.4% of patients despite mandatory thromboprophylaxis, and arterial thromboembolic events occurred in 3.4%.

The iberdomide prescribing information carries a boxed warning for embryo-fetal toxicity and serious venous and arterial thromboembolism, and the agent is available only through a Risk Evaluation and Mitigation Strategy program.

What is the significance of iberdomide in multiple myeloma?

Iberdomide is a CELMoD and the first agent in its class to receive FDA approval. CELMoDs are more potent cereblon modulators than immunomodulatory drugs and are designed to retain activity even in the presence of low levels of functional cereblon, while offering the convenience of oral administration.

EXCALIBER-RRMM is a phase 3, multicenter, 2-stage, randomized, open-label study that included a dose-optimization stage and enrolled adults with 1 to 2 prior lines of anti-myeloma therapy and progressive disease; treatment in both arms continued until disease progression or unacceptable toxicity.

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/2s4m739a
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 Annual Meeting; September 23-26, 2026; Glasgow, Scotland. Abstract LBA-12.
3. 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
4. FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma. News release. August 13, 2026. Accessed August 13, 2026. https://tinyurl.com/38258auk