Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma

Abstract

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.

Emerging Therapeutic Strategies to Overcome Drug Resistance in Multiple Myeloma

“…These mutations were not present in matched pre-treatment samples, suggesting these were acquired in response to treatment [ 11 ]. Similar studies have also showed acquired CRBN mutations in RRMM patients [ 10 , 42 ]. With lower frequencies, mutations in IKZF1, IRF4, and the CUL4B component of CRL4 CRBN have also been reported [ 10 , 11 ].…”

Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma

“…Studies have shown that MM usually shows substantial inter and intra-tumor heterogeneity, which is closely related to progression, resistance to therapy, and recurrences [8][9][10][11][12] . Loss of several other targets for different treatments, such as CRBN with immunomodulatory agents or BCL-2 with venetoclax, has been associated with resistance to these treatments 13,14 . A single antigen targeting CAR T-cell treatment may also be affected by the loss of target as a result of tumor evolution and selection.…”

Small-molecule HDAC and Akt inhibitors suppress tumor growth and enhance immunotherapy in multiple myeloma

“…Other reports have shown that most patients treated with lenalidomide have downregulated CRBN and upregulated IKZF1 gene expression [19]. CRBN mutations are also associated with pomalidomide resistance in MM [20]. A recent article on whole-genome sequencing (WGS) data from 455 patients and RNA sequencing (RNASeq) data from 655 patients, which included newly diagnosed, lenalidomide-refractory, and pomalidomiderefractory cohorts, reported an increase in the frequency of CRBN aberrations [20].…”

“…CRBN mutations are also associated with pomalidomide resistance in MM [20]. A recent article on whole-genome sequencing (WGS) data from 455 patients and RNA sequencing (RNASeq) data from 655 patients, which included newly diagnosed, lenalidomide-refractory, and pomalidomiderefractory cohorts, reported an increase in the frequency of CRBN aberrations [20]. These aberrations include point mutations, copy losses/structural variations, and a specific variant transcript (exon 10 spliced), with progressive IMiD exposure.…”