AbstractMost patients with multiple myeloma (MM) die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, we performed whole-genome sequencing of 80 IGH-translocated tumour-normal newly diagnosed pairs and 24 matched relapsed tumours from the Myeloma XI trial. We identify multiple events as potentially important for survival and therapy-resistance at relapse including driver point mutations (e.g., TET2), translocations (MAP3K14), lengthened telomeres, and increased genomic instability (e.g., 17p deletions). 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 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 “evolutionary herding” approach in treating drug-resistant MM. Our data show that MM relapse is associated with acquisition of new mutations and clonal selection, and suggest APOBEC enzymes among potential targets for therapy-resistant MM.