How might the clinical development of CELMoDs impact the treatment paradigm for MM?

The Multiple Myeloma Hub spoke with Paul Richardson, Dana-Farber Cancer Institute, Boston, US. We asked, How might the clinical development of cereblon E3 ligase modulators (CELMoDs) impact the treatment paradigm for multiple myeloma (MM)?

During this interview, Paul Richardson discussed the emerging role of CELMoDs in MM. Richardson reviewed the rationale for the development of these agents, what distinguishes them from traditional immunomodulatory agents (IMiDs), and the unmet needs they were designed to address in relapsed and refractory disease (RRMM). Richardson summarized clinical trial results with iberdomide and mezigdomide, highlighted their applications in high-risk and heavily pretreated patients, and emphasized their potential for use in earlier treatment settings and as maintenance therapy. Richardson also outlined ongoing phase III studies and novel combination strategies designed to optimize patient outcomes.

Key learnings

• Multiple myeloma is a continually evolving and heterogeneous disease, requiring a diverse range of treatment strategies based on both disease and patient characteristics.
• Treatment with IMiDs such as lenalidomide or pomalidomide are standard of care treatment in newly diagnosed MM (NDMM); however, the majority of patients will experience a relapse, and can become refractory to these IMiDs.
• CELMoDs are next-generation IMiDs, distinct from traditional IMiDs due to higher-affinity binding to cereblon, promoting enhanced degradation of transcription factors such as Ikaros and Aiolos. These features allow for retained efficacy in patients with prior exposure and refractoriness to IMiDs.
• CELMoDs exert both direct antimyeloma effects and potent immune-stimulatory activity, providing a rationale for combination with proteasome inhibitors, monoclonal antibodies, and corticosteroids.
• Preclinical studies demonstrate that CELMoDs enhance protein degradation, increase apoptosis, and improve immune cell function compared with lenalidomide and pomalidomide.
• Ongoing clinical studies with mezigdomide in combination with established agents, have shown efficacy in heavily pretreated patients, including in those with extramedullary disease and in patients previously treated with B-cell maturation antigen (BCMA)-directed therapies.
• Mezigdomide demonstrates particular promise in RRMM, including in patients with immune exhaustion and high-risk disease features.
• Iberdomide has also shown clinical efficacy in RRMM, including in patients previously exposed to BCMA-targeted therapies, and exhibits favorable tolerability in oral combination regimens.
• Iberdomide is additionally under investigation as a maintenance therapy following induction or transplant, with the potential to provide sustained efficacy and a lower risk of secondary malignancies compared with traditional IMiDs.
• Both investigational CELMoDs are being evaluated across multiple disease stages in ongoing phase III studies, including SUCCESSOR-1 and SUCCESSOR-2 for mezigdomide-based combinations, and EXCALIBER-RRMM for iberdomide-based combinations, to further define their role in the MM treatment landscape.
• Overall, CELMoDs represent a novel class of therapy with activity in high-risk and heavily pretreated patients, and emerging potential for integration into earlier lines of therapy and maintenance treatment.