High levels of CRBN isoform lacking IMiDs binding domain predicts for a worse response to IMiDs-based upfront therapy in newly diagnosed myeloma patients

Abstract

AbstractIn recent years, the immunoderivative (IMiD) agents have been extensively used for the treatment of multiple myeloma (MM). IMiDs and their newer derivatives CRBN E3 ligase modulator bind the E3 ligase substrate recognition adapter protein cereblon (CRBN), which has been recognized as one of the IMiDs’ direct target proteins, and it is essential for the therapeutic effect of these agents.High expression of CRBN was associated with improved clinical response in patients with MM treated with IMiDs, further confirming that the expression of IMiDs’ direct target protein CRBN is required for the anti-MM activity. CRBN’s central role as a target of IMiDs suggests potential utility as a predictive biomarker of response or resistance to IMiDs therapy. Additionally, the presence of alternatively spliced variants of CRBN in MM cells, especially those lacking the drug-binding domain for IMiDs, raise questions concerning their potential biological function, making difficult the transcript measurement, which leads to inaccurate overestimation of full-length CRBN transcripts. In sight of this, in the present study, we evaluated the CRBN expression, both full-length and spliced isoforms, by using real-time assay data from 87 patients and RNA sequencing data from 50 patients (n = 137 newly diagnosed MM patients), aiming at defining CRBN’s role as a predictive biomarker for response to IMiDs-based induction therapy. We found that the expression level of the spliced isoform tends to be higher in not-responding patients, confirming that the presence of a more CRBN spliced transcript predicts for lack of IMiDs response.