The approval of iberdomide is good news for people with myeloma that has returned. It also comes with trade-offs that deserve a plain look. In August, the US Food and Drug Administration granted accelerated approval to the drug, marketed as Zenbexus, for relapsed or refractory multiple myeloma.
What the trial numbers say
The decision rests on an interim analysis of EXCALIBER-RRMM, a phase 3 trial that compared iberdomide plus daratumumab and dexamethasone against daratumumab, bortezomib and dexamethasone. Patients had one or two earlier lines of therapy. Those whose disease was refractory to anti-CD38 treatment or bortezomib were excluded.
The complete response rate with no detectable minimal residual disease was 41% in the iberdomide arm and 21% in the comparison arm, CancerNetwork reported. Sagar Lonial of the Winship Cancer Institute of Emory University, the lead investigator, said in a news release that the approval brings an anticipated new therapeutic class and the potential for a new treatment foundation.
How the pill works
Iberdomide is the first CELMoD, or cereblon E3 ligase modulator, approved for myeloma. It is taken by mouth at 1.0 mg a day on days 1 to 21 of a 28-day cycle. Adam Cohen, director of Myeloma Immunotherapy at the Hospital of the University of Pennsylvania, told CancerNetwork that CELMoDs sit in the same family as older immunomodulatory drugs but are stronger cereblon modulators. They steer the cell’s protein-disposal machinery toward Ikaros and Aiolos, two transcription factors myeloma cells rely on. Early findings suggest this lets them keep working even when little functional cereblon remains.
Cohen also sees room to pair them with CAR T cells and bispecific antibodies to boost the immune effect. Oral dosing adds convenience, though the full regimen still includes injected daratumumab and oral dexamethasone.
What the headline number leaves out
Approval was accelerated because regulators accepted minimal residual disease negativity as a stand-in measure, which is meant to speed access in myeloma. It is not the same as longer survival. Progression-free survival is a co-primary end point of the trial and overall survival is a secondary one, and the study continues. A data monitoring committee reviewed the interim analysis and recommended it go ahead unchanged.
The safety picture is heavier than a single response rate suggests. Neutropenia occurred in 90.2% of patients and infections in 78.9%. Serious pneumonia struck 26%. The prescribing information carries boxed warnings for embryo-fetal toxicity and for serious venous and arterial blood clots, and it lists neutropenia, infections and second primary cancers as further warnings. Because of the pregnancy risk, the drug is sold only through the Zenbexus Risk Evaluation and Mitigation Strategy. Trial rules called for dose interruption and growth-factor support in grade 4 neutropenia.
Who was studied
EXCALIBER-RRMM ran in two stages. Stage 1, with 279 patients, settled on 1.0 mg daily over 1.3 and 1.6 mg. Stage 2 randomly assigned 660 patients 1:1 to the iberdomide or comparison regimen. Participants were 18 or older, had measurable disease and documented progression on or after their latest treatment, and had an ECOG performance status of 0 to 2.
Other studies are testing iberdomide as maintenance after stem cell transplant and as part of induction for newly diagnosed myeloma. The encouraging part is that people with relapsed disease have one more oral option. Anyone considering it should talk to their doctor about eligibility, the risks above, and how the safety program works.
Sources
- FDA Approves Iberdomide, the First CELMoD for Relapsed/Refractory Multiple Myeloma | Targeted Oncology – Immunotherapy, Biomarkers, and Cancer Pathways
- FDA Approves Iberdomide Combo in Relapsed/Refractory Multiple Myeloma | CancerNetwork
Photo: Shixart1985 (CC BY 2.0)
