Blood: Multiple CRBN variants associated with amine/pomadamine access resistance!

The emergence of resistance to all available therapies is a major challenge in improving myeloma survival.
Cereblon (CRBN) is an important binding protein for a variety of drugs, including immunomodulation drugs (IMiDs) widely used in myeloma and new CRBN E3 connective enzyme regulators (CELMoDs), as well as certain protein hydrolysis (PROTAC) drugs that are being developed for the treatment of a range of diseases.
study used genome-wide sequencing (WGS) data from 455 patients and RNA sequencing (RNAseq) data from 655 patients from three different queues: a new confirmed queue (WGS, n=198; RNAseq, n=437) ), a len-difficult queue (WGS, n=203; RNAseq, n=176) and a Pomadamine (POM) - Resusced Queue (WGS, n=54; RNAseq, n=42).
Analysis of CRBN variation in different patients found that with the gradual exposure of IMiD, the frequency of three CRBN variants (i.e., point mutation, copy loss/structural variation, and a specific variant transcript (exon scissors no. 10) increased gradually until almost one-third of patients developed CBN mutations when they were resistant to POM.
CRBN mutations were associated with prognosis in patients with multiple myeloma Researchers found that all three CRBN variants were associated with poor prognosis when POM was used in patients who were already resistant to LEN, including those with lost gene replication and structural variation, a finding that had not been described before.
, this study is the first and largest comprehensive analysis of CBRN mutations in myeloma patients during treatment.
results of this study will help guide patients to choose CRBN targeted drugs for sequentia therapy.