Most patients with MM die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, this study was done to perform whole-genome sequencing of 80 IGH-translocated tumor-normal newly diagnosed pairs and 24 matched relapsed tumors from the Myeloma XI trial. This was done to provide data to decrease the number of patients with MM die from progressive disease after relapse.

Multiple events were identified as potentially important for survival and therapy-resistance at relapse including driver point mutations, translocations, lengthened telomeres, and increased genomic instability. Despite heterogeneous mutational processes contributing to relapsed mutations across MM subtypes, increased AID/APOBEC activity is particularly associated with shorter progression time to relapse, and contributes to a higher mutational burden at relapse. In addition, we identify three enhanced major clonal evolution patterns of MM relapse, independent of treatment strategies and molecular karyotypes, questioning the viability of the “evolutionary herding” approach in treating drug-resistant MM.

The study provided data that shows that MM relapse is associated with the acquisition of new mutations and the clonal selection and suggest APOBEC enzymes among potential targets for therapy-resistant MM.