Emergence of drug resistance to all available therapies is the major challenge to improving survival in myeloma. Cereblon (CRBN) is the essential binding protein of the widely-used IMiD and novel CelMOD drugs in myeloma, as well as certain PROTACs in development for a range of diseases. Using whole genome sequencing data from 455 patients and RNASeq data from 655 patients, including a newly-diagnosed cohort (n=198 WGS, n=437 RNASeq), a lenalidomide (LEN)-refractory cohort (n=203 WGS, n=176 RNASeq) and a pomalidomide (POM)-refractory cohort (n=54 WGS, n=42 RNASeq), we find incremental increase in the frequency of three CRBN aberrations, namely point mutations, copy loss/structural variation and a specific variant transcript (exon 10-spliced), with progressive IMiD exposure, until almost one third of patients have CBRN alterations by the time they are POM-refractory. We find all 3 CRBN aberrations are associated with an inferior outcome to POM in those already refractory to LEN, including those with gene copy loss and structural variation, which has not previously been described. This is the first comprehensive analysis of CBRN alterations in myeloma patients as they progress through therapy, and the largest dataset. It will help inform patient selection for sequential therapies with CRBN-targeting drugs.