With the introduction of both immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide, and the use of these in combination with drugs from other classes, IMiDs have made a dramatic progress in the treatment of multiple myeloma (MM). However, despite improvement in outcomes, patients with MM ultimately relapse and must undergo further treatment. Early studies show that Cereblon E3 Ligase Modulators (CELMoDs®) iberdomide and CC-92480 show similar trends in activity in patients refractory to IMiDs. This new next generation of IMIDs have shown enhanced tumoricidal and immune-stimulatory effects compared with first-generation IMiDs and have the potential to replace the current standard of care in both frontline and RRMM. This program covers the benefits as well as current challenges with the use of first-generation IMiDs while exploring the MOA, clinical, and safety activity to date of selective CELMoD® therapy in MM.