The mutagenic impact of melphalan in multiple myeloma

The introduction of whole genome and exome sequencing partnered with advanced bioinformatic pipelines has allowed the comprehensive characterization of mutational processes (i.e., mutational signatures) in individual cancer patients. Studies focusing on multiple myeloma have defined several mutational processes, including a recently identified mutational signature (called SBS-MM1) directly caused by exposure to high-dose melphalan (i.e., autologous stem cell transplant). High-dose melphalan exposure increases both the overall and nonsynonymous mutational burden detected between diagnosis and relapse by similar to 10-20%. Nevertheless, most of these mutations are acquired within the heterochromatin and late-replicating regions, rarely involving key myeloma driver genes. In this review, we summarize key studies that made this discovery possible, and we discuss potential clinical implications.

Automated summary

The identification of mutational processes in multiple myeloma, including a new mutational signature caused by exposure to high-dose melphalan, has been made possible through whole genome and exome sequencing. Exposure to high-dose melphalan increases mutational burden between diagnosis and relapse, with most mutations occurring in heterochromatin and late-replicating regions, rarely affecting key myeloma driver genes.