From immunomodulators (IMiDs) to cereblon E3 ligase modulator (CELMoDs): the evolution of cereblon modulators in lymphoma therapy

Cereblon E3 ligase modulating drugs (CELMoDs) are next-generation immunomodulators (IMiDs) with a promising efficacy and safety profile. Early-phase clinical trials have shown clinical activity in heavily pretreated lymphomas, including those refractory to prior IMiD therapy or to cellular immunotherapies such as CAR-T. CELMoDs show potential as a fixed-duration, chemo-free option with durable responses in both relapsed/refractory (R/R) and treatment-naïve B-NHL. This review offers an exploration of cereblon (CRBN) as key for lymphomagenesis and highlights the mechanisms by which IMiDs and CELMoD target CRBN. Additionally, we discussed the key findings from early-phase clinical trials evaluating these newer agents as monotherapy and in combination regimens across first-line and R/R settings. Finally, we focused on ongoing clinical trials and discussed how CELMoDs may reshape the current treatment landscape and potentially redefine the standard of care in B-cell lymphomas.