High Dose Melphalan (HDM) improves progression free survival (PFS) in multiple myeloma (MM), yet melphalan is a DNA damaging alkylating agent, so we assessed its mutational effect on surviving myeloma cells by analyzing paired MM samples collected at diagnosis and relapse from the IFM 2009 study. We performed deep whole genome sequencing on 68 patients, 43 treated with RVD (lenalidomide, bortezomib, and dexamethasone combination) and 25 with RVD+HDM. Although the number of mutations was similar at diagnosis in both groups (7137 vs 7230; p=0.67), the HDM group had significantly more mutations at relapse (9242 vs. 13383, p=0.005). No changes in the frequency of copy number alterations or structural variants was observed. The newly acquired mutations were typically associated with DNA damage and double stranded breaks and were predominantly on the transcribed strand. A machine learning model using this unique pattern predicted patients who'd received HDM with high sensitivity, specificity, and positive prediction value. Clonal evolution analysis showed that all patients treated with HDM had clonal selection while a static progression was observed with RVD. A significantly higher percentage of mutations were subclonal in the HDM cohort. Intriguingly, HDM patients achieving CR had significantly more mutations at relapse yet had similar survival rates as RVD CR patients. This similarity could be due to HDM relapse samples having significantly more neoantigens. Overall, our study identifies increased genomic changes associated with HDM and provides rationale to further understand clonal complexity.