Iberdomide – efficacy and safety in RRMM

Lonial begins by outlining how both iberdomide and mezigdomide are novel cereblon E3 ligase modulators (CELMoDs), which bind cereblon more potently than previous agents such as lenalidomide or pomalidomide. He describes how they have been engineered to ultimately induce cell death as well as arresting cell growth, leading to a more potent immune response.

Lonial recalls that in early phase I trials of iberdomide in combination with dexamethasone, an overall response rate (ORR) of over 30% was achieved in patients who had received ≥5 prior lines of therapy, with a similar response rate in patients who were resistant to BCMA-directed therapy. Clinical studies went on to suggest that iberdomide can improve overall responses, even in the context of relapsed and refractory disease, and without increasing the number of adverse events (AEs) – and Lonial notes that this represents a second important differentiation for novel CELMoDs vs previous agents developed for the treatment of multiple myeloma.

Lonial discusses that gastrointestinal, neurologic, and thrombotic toxicities, fatigue, and non-hematologic Grade 3/4 AEs are common with lenalidomide and pomalidomide, and that reductions in such toxicities with novel CELMoDs should enable patients to stay on a full dose of treatment and for potentially longer durations. He notes that this is being tested in a maintenance trial from the European Myeloma Network (EMN) group, where lenalidomide will be directly compared with iberdomide.

Lonial goes on to outline two ongoing trials that may ultimately lead to the FDA approval of iberdomide. The first is the EXCALIBER-RRMM trial (NCT04975997), a phase III study comparing the efficacy and safety of iberdomide in combination with dexamethasone and daratumumab (IberDd) vs daratumumab, bortezomib, and dexamethasone (DVd) in participants with RRMM. This trial is currently recruiting but is nearing completion of enrolment. The second trial is a randomized, phase III, maintenance trial of lenalidomide vs iberdomide in patients with RRMM post autologous stem cell transplant.

Lonial concludes that with these and other trials in progress, iberdomide will should soon be added to the armamentarium of new drugs that not only kill myeloma cells but also enhance the efficacy of other immune agents, including anti CD38 antibodies, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies.