Newly Approved Treatment Option for Multiple Myeloma Patients
- The FDA has granted accelerated approval to iberdomide (ZENBEXUS)—the first drug in a new class called CELMoDs as part of the ZDd regimen (iberdomide, daratumumab hyaluronidase-fihj, plus dexamethasone) for adults with multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent.
- Approval is based on the Phase 3 EXCALIBER-RRMM trial, where the ZDd combination produced MRD-negative CRs at roughly twice the rate of the standard regimen. Per the FDA announcement and manufacturer press release, the ZDd combination produced MRD-negative CRs at roughly twice the rate of the comparator regimen. Continued approval is contingent on confirmatory studies.
- Dr. Paul Richardson explains that CELMoDs work by “targeting the cereblon E3 ligase complex—essentially the cell’s protein‑disposal system,” helping break down key survival proteins in myeloma cells while boosting the immune system’s ability to finish the job.
The FDA has granted accelerated approval for iberdomide (ZENBEXUS) in combination with daratumumab hyaluronidase-fihj plus dexamethasone (ZDd) for adults with multiple myeloma who have received at least one prior line of therapy, including both a proteasome inhibitor and an immunomodulatory agent.
Since this is an accelerated approval, full approval will depend on confirmatory trial(s) that verify and further characterize the clinical benefit of the regimen. Iberdomide represents the first FDA-approved agent in the CELMoD class, a next-generation group of oral cereblon protein degraders developed to treat multiple myeloma.
How CELMoDs Work (many community doctors are not familiar with this new class)
“These are orally bioavailable agents that target the cerebral E3 ligase complex – essentially the cell’s protein disposal system. This is a central sort of switchboard inside the myeloma cell. It’s absolutely vital to its pathobiology,” Dr. Paul Richardson, one of the world’s leading myeloma experts and a principal investigator for CELMoD trials, who serves as director of clinical research at the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, tells SurvivorNet.
“By blocking the cerebral E3 ligase complex and closing it, there’s targeted degradation of key survival factors in myeloma: Ikaros and Aiolos (zinc-finger transcription factors essential for plasma cell/myeloma cell survival),” Dr. Richardson added.
“By obliterating these transcription factors, which is essentially what mezigdomide does, and also its close cousin iberdomide, although mezigdomide does it the most, it triggers not only the death of the myeloma cell, but most importantly it brings together the immune system within the patient to finish off what is left behind,” Dr. Richardson explained further.
Iberdomide and the investigational agent mezigdomide are related CELMoDs that share this mechanism; mezigdomide is generally the more potent degrader but is not FDA-approved. The approved agent discussed here is iberdomide (ZENBEXUS).
“This is such an important advance. I mean, an oral therapy can be given in community practices in the Midwest, in suburban settings, and in urban settings. This is very, very important. So, I think FDA will be looking to move this very quickly to full approval, and I certainly hope so,” Dr. Richardson said.
What the Trial Data Revealed
The Phase 3 EXCALIBER-RRMM trial (NCT04975997) compared the ZDd combination against daratumumab, bortezomib, and dexamethasone (DVd) in patients with R/R multiple myeloma who received one or two prior lines of therapy. Patients were followed for a median of approximately 16 months, and the trial evaluated MRD-negative complete response.
The researchers looked closely at minimal residual disease (MRD) in patients.
The trial evaluated MRD-negative CR as its primary endpoint.
The trial results:
- The MRD-negative complete response rate at any time was 41% (95% CI, 34%–48%) in the IberDd (ZDd) arm.
- The MRD-negative complete response rate was 21% (95% CI, 15%–27%) in the DVd arm (P < .0001).
Patients on ZDd were about twice as likely to reach MRD-negative CR as those on the standard regimen. This is the first FDA approval in relapsed or refractory multiple myeloma based on an MRD-negative complete response endpoint.
This marks the first FDA approval in relapsed or refractory multiple myeloma based on an MRD-negative complete response, the drug manufacturer, Bristol Myers Squibb, said in a news release.
What Does the Safety Profile Look Like
The safety profile of iberdomide is predominantly hematologic. In the ZDd cohort, the most frequent grade 3 and 4 treatment events were neutropenia (63%), anemia (28%), while grade 3/4 non-hematologic toxicity was low. The prescribing information carries a boxed warning for embryo-fetal toxicity and serious venous and arterial thromboembolism, along with warnings for neutropenia, infections, and second primary malignancies. Because of the embryo-fetal risk, iberdomide is available only through the restricted ZENBEXUS REMS program.
What the approval means
IMiD resistance is occurring earlier in myeloma, with many patients relapsing on lenalidomide and quickly becoming resistant to multiple drug classes. Iberdomide offers a new way to reactivate the cereblon pathway after IMiD failure, with an all-oral, community-deliverable regimen that is particularly practical for early relapse.
Iberdomide may also strengthen the immune response by increasing T/NK-cell activity and reducing T-cell exhaustion. This could enhance the effectiveness of newer immunotherapies, including bispecific antibodies and CAR T-cell therapy. Ongoing studies are evaluating iberdomide in maintenance and in combination with other major myeloma therapies, potentially expanding its role beyond treatment of relapsed disease.
