A first for the CELMoD class
In August, the US Food and Drug Administration granted accelerated approval to iberdomide, sold as Zenbexus. It is the first cereblon E3 ligase modulator, or CELMoD, cleared for multiple myeloma. Bristol Myers Squibb developed the pill, which is a thalidomide analog. It is meant for adults whose disease has come back or stopped responding, and who have already tried at least one earlier line of treatment that included a proteasome inhibitor and an immunomodulatory drug. Patients take it alongside daratumumab with hyaluronidase-fihj and dexamethasone.
How it differs from lenalidomide
Older immunomodulatory drugs such as lenalidomide and pomalidomide also work through cereblon. CELMoDs are built to do it harder. Dr. Jesús Berdeja of the Sarah Cannon Research Institute and Tennessee Oncology told OncLive that the newer agents grip cereblon more tightly and push the immune system further than their predecessors. Bristol Myers Squibb data show iberdomide binds with higher affinity than either older drug, and the class is designed to break down the Ikaros and Aiolos proteins more effectively. Dr. Adam Cohen of the Hospital of the University of Pennsylvania added in an interview with CancerNetwork that these drugs may keep working even when only a little functional cereblon is left.
Berdeja also pointed to mezigdomide, a second oral CELMoD. In the phase 3 SUCCESSOR-2 trial, mezigdomide with carfilzomib and dexamethasone gave a median progression-free survival of 18.0 months, against 8.3 months for carfilzomib and dexamethasone alone (hazard ratio 0.48). Those patients had already been treated with lenalidomide and an anti-CD38 antibody. Berdeja said CELMoD combinations have beaten standard regimens in prospective studies and could replace some current options.
What the EXCALIBER-RRMM trial showed
The approval rests on an interim look at EXCALIBER-RRMM, a randomized, open-label phase 3 study of 939 adults with relapsed or refractory myeloma. All had received one or two earlier lines of therapy. People whose disease was refractory to an anti-CD38 antibody or to bortezomib were left out. Stage 1, with 279 patients, tested three iberdomide doses; stage 2 randomized 660 patients to the 1 mg dose or to the comparison regimen of daratumumab, bortezomib and dexamethasone.
The early signal was clear. The rate of complete response with no detectable minimal residual disease was 41% on the iberdomide combination and 21% on the comparison regimen (P below .0001). Sagar Lonial of the Winship Cancer Institute of Emory University, the lead investigator, said in a news release that the results create the potential for a new treatment foundation. Survival data are not in yet, and the trial goes on.
Dosing and safety
Iberdomide is taken at 1.0 mg by mouth once daily on days 1 to 21 of each 28-day cycle, with or without food. Dexamethasone is 20 mg or 40 mg on days 1, 8 and 15, and daratumumab with hyaluronidase is given by injection under the skin on a schedule that thins out after the first cycles.
The label carries boxed warnings for embryo-fetal toxicity and for serious venous and arterial blood clots. It also warns about low neutrophil counts, infections and second primary cancers. In the trial, neutropenia occurred in 90.2% of patients and infections in 78.9%, though they led to stopping treatment in only 1% and 1.5%. Because of the pregnancy risk, the drug is available only through the Zenbexus Risk Evaluation and Mitigation Strategy program.
The encouraging part is a new kind of oral option for people running short of choices. Patients should talk to their doctor about whether this regimen fits their treatment history, and about how the safety program and blood-count monitoring would work for them.
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
- Iberdomide
- Five Under 5: Top Oncology Videos for the Week of 10/12 | OncLive
Photo: Coolcaesar at English Wikipedia (CC BY-SA 3.0)
