The development of a multidrug-resistant condition is a significant factor in myeloma mortality. Widely used immunomodulatory drugs (IMiDs) and more recent CRBN E3 ligase modulator drugs (CELMoDs), which were now in clinical studies, were myeloma medications that target the cereblon (CRBN) protein. Resistance to IMiDs and negative results were brought on by CRBN genetic disruption. 

Using large whole-genome sequencing patient datasets (n = 522) at newly diagnosed, lenalidomide (LEN)-refractory, and lenalidomide-then-pomalidomide (LEN-then-POM)-refractory time points, researchers evaluated alternate genetic correlations of IMiD resistance in the study. They discovered no indication of genetic disruption by a mutation linked with IMiD resistance when they used gene targets reproducibly identified by published CRISPR/shRNA IMiD resistance screens. 

On the other hand, they discovered a chromosome region, 2q37, containing COP9 signalosome members COPS7B and COPS8, copy loss of which significantly enriched between newly diagnosed (incidence 5.5%), LEN-refractory (10.0%), and LEN-then-POM-refractory states (16.4%), and may have a negative impact on outcomes when clonal fraction was high. In addition, they found the acquisition of 2q37 deletion in 16% of instances with IMiD exposure but none in cases without IMiD exposure in a different dataset (50 patients) with sequential samples obtained during therapy. 

The CUL4-DDB1-CRBN E3 ubiquitin ligase must be maintained, and it was made possible by the COP9 signalosome. The area could be a brand-new, clinically useful indicator of IMiD resistance.

Reference: ashpublications.org/blood/article-abstract/140/16/1816/485954/Loss-of-COP9-signalosome-genes-at-2q37-is?redirectedFrom=fulltext