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.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 Approval based on MRD as a surrogate end point for regulatory purposes is meant to enable more rapid approvals in the multiple myeloma setting.

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 approximately 200 patients. In stage 2, approximately 664 patients were randomly assigned to receive IberDd vs DVd on a 1:1 basis.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.⁴ 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 coprimary end points were MRD-negative complete response (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.

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.

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.

The MRD-negative 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).

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. CELMods are intended to enhance degradation of Ikaros and Aiolos transcription factors more potently than immunomodulatory drugs such as lenalidomide (Revlimid).

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. US FDA. August 13, 2026. Accessed August 13, 2026. https://tinyurl.com/mxbm477f

2. Bristol Myers Squibb Announces Phase 3 EXCALIBER-RRMM Study Evaluating Iberdomide in Combination with Standard Therapies Demonstrated a Significant Improvement in Minimal Residual Disease Negativity Rates in Relapsed or Refractory Multiple Myeloma. News release. Bristol Myers Squibb. September 23, 2025. Accessed June 23, 2026. https://tinyurl.com/53tc84we

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