FDA Approves First CELMoD Drug for Multiple Myeloma

The FDA granted accelerated approval to the first cereblon E3 ligase modulation (CELMoD) therapy for relapsed or refractory multiple myeloma, the agency announced on Thursday. An oral drug, iberdomide (Zenbexus) is approved in combination with the anti-CD38 monoclonal antibody daratumumab and hyaluronidase (Darzalex Faspro) plus dexamethasone for adults who have received at least one line of therapy that included a proteasome inhibitor and immunomodulatory drug. Approval was based on results from EXCALIBER-RRMM, a phase III randomized trial that showed that iberdomide plus daratumumab-hyaluronidase and dexamethasone improved rates of minimal residual disease (MRD)-negative complete response versus daratumumab-hyaluronidase, bortezomib (Velcade), and dexamethasone (41% vs 21%, respectively, P<0.0001). "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," said investigator Sagar Lonial, MD, of the Winship Cancer Institute of Emory University in Atlanta, in a press release from drugmaker Bristol Myers Squibb. "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." Of note, EXCALIBER-RRMM excluded patients with disease refractory to prior anti-CD38 therapy or bortezomib. The most common adverse events with the regimen included upper respiratory tract infections, fatigue, musculoskeletal pain, pneumonia, diarrhea, motor dysfunction, rash, sleep disorders, hypogammaglobulinemia, COVID-19, and constipation. Common grade 3/4 laboratory abnormalities included decreases in neutrophil counts, white blood cell counts, and lymphocyte counts. Prescribing information for the CELMoD drug includes a boxed warning for embryo-fetal toxicity -- which warranted a risk evaluation and mitigation strategy (REMS) program -- along with serious venous and arterial thromboembolism. The warnings and precautions sections also flag possible risks for neutropenia, infections, and secondary primary malignancies.