Rapid Progress in the Use of Immunomodulatory Drugs and Cereblon E3 Ligase Modulators in the Treatment of Multiple Myeloma

SIMPLE SUMMARY: Due to the complex mechanism of actions, immunomodulatory drugs (IMiDs) are one of the primary drug classes used to treat multiple myeloma (MM). IMiDs are the backbone of treatment for both newly diagnosed, post-transplant maintenance, and relapsed/refractory MM. The standard of care is a combination of IMiDs, corticosteroids (e.g., dexamethasone) with either a proteasome inhibitor or a monoclonal antibody. Future management will include a quadruplet of all four drug classes. Recent clinical trials have shown that another class of cereblon inhibitors in development, Cereblon E3 ligase modulators (CELMoDs), have significant activity in MM even when refractory to approved IMiDs. ABSTRACT: Over the past two decades, the improvement in our understanding of the biology of MM and the introduction of new drug classes, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PI), and monoclonal antibodies (MoAb), have significantly improved outcomes. The first IMiD introduced to treat MM was thalidomide. The side effects observed during treatment with thalidomide initiated work on the synthesis of IMiD analogs. Subsequently, lenalidomide and pomalidomide were developed, both with different safety profiles, and they have better tolerability than thalidomide. In 2010, the cereblon (CRBN) protein was discovered as a direct target of IMiDs. By binding to CRBN, IMiDs change the substrate specificity of the CRBN E3 ubiquitin ligase complex, which results in the breakdown of internal Ikaros and Aiolos proteins. Most clinical trials conducted, both in newly diagnosed, post-transplant maintenance and relapsed/refractory MM, report a beneficial effect of IMiDs on the extension of progression-free survival and overall survival in patients with MM. Due to side effects, thalidomide is used less frequently. Currently, lenalidomide is used at every phase of MM treatment. Lenalidomide is used in conjunction with other agents such as PIs and MoAb as induction and relapsed therapy. Pomalidomide is currently used to treat relapsed/refractory MM, also with PIs and monoclonal antibodies. Current clinical trials are evaluating the efficacy of IMiD derivatives, the CRBN E3 ligase modulators (CELMoDs). This review focuses on the impact of IMiDs for the treatment of MM.