Guidance on the interpretation of CRBN mutations in myeloma Free

In this issue of Blood, Chrisochoidou et al systematically evaluate the structural and functional consequences of cereblon (CRBN) missense mutations in immunomodulatory drug (IMiD)-resistant patients with myeloma, thereby discovering novel insights into therapeutic strategies to overcome drug resistance.¹ 

Fifteen years ago, Ito and colleagues were the first to identify CRBN as the molecular target of thalidomide, a drug initially developed in 1954 by Grünenthal as a sedative.² The compound’s teratogenic effects were unknown at the time, resulting in miscarriages and severe birth defects in more than 10 000 cases. Thalidomide was withdrawn from the market, but decades later thalidomide was repurposed for the treatment of erythema nodosum leprosum and, in 1999, for multiple myeloma.³ In 2010, Ito et al discovered that thalidomide binds to CRBN, a gene previously linked to mental retardation but not to cancer, thereby inhibiting its ubiquitin ligase activity.² Identification of this mechanism laid the groundwork for further studies, including the 2014 work by Krönke et al that demonstrated that lenalidomide induces the degradation of the key lymphoid transcription factors IKZF1 and IKZF3 via the CRBN-CRL4 E3 ligase complex, resulting in inhibition of myeloma cell proliferation and modulating immune responses.⁴ Subsequently the research group led by Stewart confirmed that CRBN is essential for the therapeutic effects of thalidomide and its derivatives and demonstrated that CRBN knockdown confers IMiD resistance.⁵ Shortly thereafter, in a heavily pretreated 37-year-old IgG-κ patient with multiple myeloma with progressive, multidrug refractory extramedullary disease, the first acquired truncating mutation of CRBN from a patient was described.⁶ Screening of patient cohorts revealed a 12% mutation rate of CRBN in drug-refractory multiple myeloma, which was significantly higher than the rate observed in newly diagnosed cases. Longitudinal studies indicated that these mutations emerge during the acquisition of IMiD resistance.⁷ Building on these findings, Gooding et al reported CRBN alterations, including point mutations, in 20.7% of patients with lenalidomide-refractory myeloma and 29.6% of patients with pomalidomide-refractory, correlating these aberrations with reduced therapeutic response.⁸ 

In their article, “Evaluating the impact of CRBN mutations on response to immunomodulatory drugs and novel CRBN-binding agents in myeloma,” Chrisochoidou et al categorize CRBN missense mutations into 3 main categories based on their functional impact: loss-of-function mutations that render IMiDs and cereblon E3 ligase modulatory drugs (CELMoDs) ineffective, neutral mutations with preserved responsiveness to therapy, and agent-dependent mutations that impair the activity of IMiDs but leave CELMoDs relatively unaffected. This classification is buttressed by structural modeling of CRBN’s interaction with neosubstrates and functional assays in a CRBN-knockout model. Notably, mezigdomide outperforms IMiDs in overcoming mutations that disrupt the drug binding.

The findings presented by Chrisochoidou et al raise important questions about the previously presumed clinical significance of CRBN missense mutations and reinforce the rationale for evaluating CELMoDs in patients harboring CRBN mutations after IMiD relapse. As emerging cell-based immunotherapies, such as chimeric antigen receptor T cells and bispecific antibodies, shift the clinical focus toward microenvironmental and immune modulation, the impact of tumor-specific CRBN mutations on IMiD-based treatments may become less clinically significant. Nevertheless, Chrisochoidou et al’s findings underscore the necessity for functional mutation profiling to optimize future therapeutic strategies, ensuring tailored interventions to circumvent CRBN-mediated resistance mechanisms.

Conflict-of-interest disclosure: The authors declare no competing financial interests.