CELMoDs for the treatment of relapsed/refractory MM

The Multiple Myeloma Hub spoke with Paul Richardson, Dana-Farber Cancer Institute, Boston, US. We asked about cereblon E3 ligase modulators (CELMoDs) for the treatment of relapsed/refractory multiple myeloma (RRMM). 

During this interview, Richardson reviews clinical data on the activity of CELMoDs, including mezigdomide and iberdomide, in RRMM. Richardson highlights response rates observed in clinical studies, including activity in heavily pretreated and B-cell maturation antigen (BCMA)-exposed patients, as well as in extramedullary disease. Richardson also discusses safety findings, including hematologic toxicity and infection risk, and outlines emerging data on combination strategies and ongoing phase III trials. 

Key learnings 

• In the CC-92480-MM-001 study (NCT03374085), mezigdomide plus dexamethasone demonstrated clinical activity in heavily pretreated patients, including those with prior BCMA exposure and extramedullary disease.^1,2 
• Clinical activity with mezigdomide plus dexamethasone has also been observed in patients with high-risk cytogenetics and plasmacytomas.^1,2 
• Mezigdomide has been evaluated in combination regimens with proteasome inhibitors and monoclonal antibodies, with clinical activity observed in early-phase studies.^3,4 
• In the STOMP study (NCT02343042), mezigdomide combined with selinexor and dexamethasone demonstrated clinical activity in a heavily pretreated population with high rates of prior class exposure and refractory disease.⁵ 
• Pharmacodynamic analyses from mezigdomide-based combination studies have shown increased markers of T-cell activation and proliferation.⁵ 
• In the CC-220-MM-001 study (NCT02773030), iberdomide demonstrated clinical activity in RRMM, including in patients with prior BCMA exposure when combined with dexamethasone.⁶ 
• Iberdomide is also being evaluated in triplet and quadruplet combination regimens with monoclonal antibodies, proteasome inhibitors, and chemotherapy.^6–9 
• Early real-world data suggest that response rates and safety findings with mezigdomide plus dexamethasone are consistent with those observed in clinical studies.¹⁰ 
• CELMoDs are being evaluated in combination with T-cell-directed therapies, including bispecific antibodies and chimeric antigen receptor (CAR) T-cell approaches, with the aim of enhancing immune responses.^11–13  
• Hematologic toxicity, particularly neutropenia and thrombocytopenia, is commonly observed with CELMoD-based regimens, and infections require active monitoring in heavily pretreated populations.¹⁴ 
• Phase III studies, including SUCCESSOR-1 (NCT05519085), SUCCESSOR-2 (NCT05552976), and EXCALIBER-RRMM (NCT04975997), are ongoing to further define the role of CELMoDs in RRMM.^15–17

This educational resource is independently supported by BMS. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence.