From IMiDs to CELMoDs: The Evolving Landscape of Multiple Myeloma Treatment
By: Wendy LaGrego
Posted: Friday, September 25, 2026
Over the past 3 decades, immunomodulatory drugs (IMiDs) have evolved from the repurposing of thalidomide to become central components of multiple myeloma therapy, while next-generation cereblon E3 ligase modulators (CELMoDs) may offer new options for patients with IMiD-resistant disease. In a review published in the Journal of Clinical Oncology, Abdul-Hamid Bazarbachi, MD, of Columbia University Irving Medical Center/New York-Presbyterian Hospital, and colleagues, traced the clinical and mechanistic evolution of IMiDs and examined emerging evidence for the growing use of CELMoDs, particularly iberdomide and mezigdomide. The review incorporated evidence through May 2026.
Evolution of IMiD Therapy
The clinical development of IMiDs began with thalidomide, which produced rapid and durable responses in 32% of 84 heavily pretreated patients in a 1999 study. Lenalidomide subsequently emerged as a more broadly tolerable treatment platform and established lenalidomide/dexamethasone as a backbone for combination and continuous therapy. Its role expanded to maintenance after autologous stem cell transplantation; a meta-analysis of three trials (CALGB 100104, IFM 2005-02, and GIMEMA RV-MM-PI-209) demonstrated a median progression-free survival of 52.8 months with lenalidomide maintenance vs 23.5 months with placebo or observation, along with an overall survival benefit.
Pomalidomide/dexamethasone showed activity in lenalidomide- and bortezomib-refractory disease and became a platform for combinations with proteasome inhibitors and monoclonal antibodies. The authors characterized modern IMiD use as being “defined by setting-specific specialization rather than linear replacement,” with lenalidomide remaining prominent in front-line and maintenance therapy and pomalidomide occupying a principal post-lenalidomide role.
The discovery of cereblon as the target of thalidomide helped clarify the mechanism underlying this drug class. IMiDs act as molecular glues, reprogramming the CRL4CRBN E3 ubiquitin ligase to promote degradation of neosubstrates including Ikaros and Aiolos. Their depletion affects the IRF4-MYC survival pathway in myeloma cells while also promoting immune-mediated antitumor effects. CELMoDs were subsequently designed to enhance cereblon modulation and neosubstrate degradation.
Emerging CELMoDs
Iberdomide plus dexamethasone produced overall response rates of 26% to 36.8% in triple-class–refractory cohorts. In newly diagnosed, transplant-ineligible multiple myeloma, iberdomide plus daratumumab and dexamethasone yielded an overall response rate of 94.7%.
Mezigdomide plus dexamethasone produced a 41% overall response rate among 101 patients with triple-class–refractory disease who had received a median of six prior lines of therapy, with a median response duration of 7.6 months. Early mezigdomide combinations with daratumumab and proteasome inhibitors have produced response rates ranging from approximately 75% to 86%.
Across CELMoD studies, hematologic toxicity—particularly neutropenia—and infections have been important considerations.
Future Directions
The authors identified integration with immune-effector therapies as an important area for further investigation. Potential strategies include using CELMoDs before CAR T-cell therapy to improve T-cell fitness, concurrently with bispecific T-cell engagers, or as maintenance following T-cell–redirecting therapy. Iberdomide is also being evaluated as a potential alternative to lenalidomide for maintenance, whereas mezigdomide is being developed primarily for the post-IMiD setting.
Much of the CELMoD evidence comes from small, heterogeneous, open-label cohorts with immature follow-up, leading the authors to caution that “enthusiasm should be tempered when interpreting these early signals.” They emphasized the need for randomized phase III trials to establish long-term efficacy and safety. Cytopenias, infections, late toxicities, treatment sequencing, cost, and access will also need to be considered as the role of CELMoDs in multiple myeloma continues to evolve.
DISCLOSURE: For full disclosures of the study authors, visit ascopubs.org.
