FDA Approves Iberdomide, the First CELMoD for Relapsed/Refractory Multiple Myeloma

The FDA granted accelerated approval to iberdomide (Zenbexus) in combination with daratumumab (Darzalex) and dexamethasone (IberDd) in patients with relapsed/refractory multiple myeloma who received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.¹

This marks the first approval of a cereblon E3 ligase modulator (CELMoD) for multiple myeloma. The approval was based on the minimal residual disease (MRD) negativity benefit compared with daratumumab, bortezomib (Velcade), and dexamethasone (DVd) in an interim analysis of the phase 3 EXCALIBER-RRMM trial (NCT04975997).²

The MRD-negative complete response (CR) rate at any time was 41% (95% CI, 34%-48%) in the IberDd arm and 21% (95% CI, 15%-27%) in the DVd arm (P <.0001). Approval based on MRD as a surrogate end point for regulatory purposes is meant to enable more rapid approvals in the multiple myeloma setting.

“The FDA approval of iberdomide marks the anticipated arrival of a new therapeutic class for relapsed or refractory multiple myeloma and has the potential to make a meaningful difference for patients,” Sagar Lonial, MD, FACP, FASCO, EXCALIBER-RRMM lead investigator and chief medical officer of the Winship Cancer Institute of Emory University, stated in a news release. “The strong results observed with the CELMoD-based combination within a familiar triplet approach creates the potential for a new treatment foundation in multiple myeloma.”

Mechanism of Action and Dose of Iberdomide

Iberdomide is an oral CELMoD given at 1.0 mg/day on days 1 to 21 of a 28-day cycle.^2,3 CELMods are intended to enhance degradation of Ikaros and Aiolos transcription factors more potently than immunomodulatory drugs such as lenalidomide (Revlimid).

EXCALIBER-RRMM Trial Design and Outcomes

The global, randomized, open-label, phase 3 trial has 2 stages: In stage 1, 1.0 mg daily was identified as the optimal dose of iberdomide compared with 1.3 and 1.6 mg in 279 patients. In stage 2, 660 patients were randomly assigned to receive IberDd vs DVd on a 1:1 basis.^2,3

Patients could have 1 or 2 prior lines of therapy. Patients were excluded from the trial if they had disease that was refractory to anti-CD38 therapy or bortezomib, and 10% of patients in each arm could have received prior anti-CD38 therapy.³ Stratification factors included number of prior lines of therapy, age of 70 or higher, and International Staging System status of 1, 2, or 3 at study entry. The co–primary end points were MRD-negative CR at any time and progression-free survival. Secondary end points include overall survival, overall response rate, quality of life, sustained MRD rate, and safety.

MRD-negative CR was defined as sensitivity at 10^–5 by next-generation flow cytometry in bone marrow aspirate in patients who achieve CR or better.

Safety Outcomes

There was specific guidance in the study for neutropenia as it is the most frequently reported toxicity with iberdomide, requiring dose interruption and use of granulocyte colony-stimulating factor for grade 4 neutropenia.³ Boxed warnings for embryo-fetal toxicity and serious venous and arterial thromboembolism are included in the prescribing information.¹

Neutropenia and infections were reported at a rate of 90.2% and 78.9% in the trial, but led to discontinuations in only 1% and 1.5%, respectively.² Among all patients treated with IberDd, 7.8% discontinued treatment because of adverse events (AEs), and 4.9% had fatal adverse events; the only fatal AE occurring in multiple patients was sepsis (1.5%). The most common AEs across the IberDd and DVd arms of the trial included upper respiratory tract infection (54% and 52%, respectively), fatigue (36% and 33%), musculoskeletal pain (35% and 33%), pneumonia (34% and 17%), diarrhea (33% and 36%), motor dysfunction (26% and 17%), rash (26% and 15%), sleep disorder (25% and 28%), hypogammaglobulinemia (24% and 12%), COVID-19 (23% and 16%), and constipation (20% and 22%).

Serious AEs included pneumonia in 26%, upper respiratory tract infection in 6.4%, second primary malignancy in 5.9%, neutropenia in 4.9%, febrile neutropenia in 3.9%, COVID-19 infection in 4.4%, and sepsis in 2.9%.

Iberdomide Under Further Investigation

Iberdomide is being investigated in other disease settings for multiple myeloma including multiple phase 3 trials. The EXCALIBER-Maintenance trial (NCT05827016) is comparing iberdomide maintenance after autologous stem cell transplant with lenalidomide maintenance, whereas the GMMG-HD9/DSMM XVIII (NCT06216158) trial is comparing iberdomide maintenance vs iberdomide plus isatuximab (Sarclisa) as dual maintenance. In the DETERMINATION-2 trial (NCT07624513), iberdomide will be given as part of quadruplet induction for newly diagnosed multiple myeloma, with MRD-adapted maintenance.

REFERENCES

1. FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma. News release. FDA. August 13, 2026. Accessed August 13, 2026. https://tinyurl.com/mxbm477f

2. U.S. FDA grants accelerated approval to Bristol Myers Squibb’s first CELMoD therapy Zenbexus, in combination with daratumumab and hyaluronidase-fihj and dexamethasone (ZDd) for patients with multiple myeloma, as early as first relapse. News release. Bristol Myers Squibb. August 14, 2026. Accessed August 14, 2026. https://tinyurl.com/6x4k5zfv

3. Lonial S, Dimopoulos MA, Berdeja JG, et al. EXCALIBER-RRMM: a phase III trial of iberdomide, daratumumab, and dexamethasone in relapsed/refractory multiple myeloma. Future Oncol. 2025;21(14):1761-1769. doi:10.1080/14796694.2025.2501920