IMiD/CELMoD resistance in myeloma is associated with changes in lipid metabolism that may be targetable.

Immunomodulatory drugs (IMiDs) are a cornerstone of multiple myeloma treatment, and newer cereblon E3 ligase modulatory drugs (CELMoDs) are in clinical trials. However, a major barrier to improving patient outcomes is the inevitable development of resistance to these agents. To explore the mechanisms underlying IMiD/CELMoD resistance and identify novel targets for treatment, human cell line models of acquired IMiD/CELMoD resistance were generated. A quantitative proteome analysis of these models identified common changes in lipid synthesis proteins, and glucose-labeling experiments confirmed altered lipid flux. Proteomic analysis of paired patient samples at diagnosis and relapse on IMiD suggested similar changes in lipid pathways. A genome-wide CRISPR screen performed in a human multiple myeloma cell line with acquired CELMoD resistance identified dependencies in the lipid pathway genes stearoyl-CoA desaturase and membrane-bound transcription factor peptidase, site 1. This study has led to novel insights into lipid pathway changes in the IMiD/CELMoD-resistant state, which may represent targetable cancer cell vulnerabilities.