Concepts of IMiD resistance. IMiD resistance can be divided into myeloma cell–intrinsic factors and myeloma cell–extrinsic factors. Myeloma cell–intrinsic factors include genetic alteration of CRBN (including mutations, copy number changes and differential splicing), alterations to the E2 ubiquitin conjugating enzymes and the COP9 signalosome, and transcriptional plasticity. There are also changes in the tumor microenvironment, for example, immune cell exhaustion. To target IMiD resistance we can consider reversing resistance or exploiting potential vulnerabilities that may develop alongside the generation of resistance. Image created using biorender.com.