High-Dose Melphalan Significantly Increases Mutational Burden in Multiple Myeloma Cells at Relapse

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High-dose melphalan followed by autologous stem-cell transplant (ASCT) has been an important component of the first-line therapy in young patients (<70 years) with multiple myeloma (MM). The role of high-dose chemotherapy in the era of novel agents was recently investigated by the IFM/Dana-Farber 2009 study. This study reported that compared to lenalidomide, bortezomib, and dexamethasone (RVD) combination therapy, RVD with high-dose melphalan with ASCT showed 15 months improvement in progression-free survival. However, overall survival benefits were not observed in the study, possibly due to the fact that 80% of the patients in the non-transplant group received late transplants. However, the impact of melphalan, a DNA-damaging agent, on genomic integrity of the surviving myeloma cells at relapse remained unexplored. The IFM/Dana-Farber study provided a unique opportunity to investigate the role of melphalan on the myeloma genome at the time of relapse.

Mehmet Kemal Samur, PhD, led our group's investigation of this question, utilizing 68 patient samples (43 in the non-transplant and 25 patients in the transplant arm) from the IFM/Dana-Farber study, in which MM cells were collected at the time of diagnosis and a second sample was subsequently collected at the time of relapse. The purified myeloma cells were subjected to whole-genome sequencing. The analysis revealed that although the number of mutations at the time of diagnosis was similar in both the arms (a little over 7,000), patients undergoing high-dose melphalan had a significant increase in the number of mutations compared to the RVD alone group at the time of relapse (close to 13,383 vs. 9,242 respectively). This study showed that there are, on average, 2.43 times more mutations in the transplant group compared to the control group; however, no significant increase in structure changes including deletions, duplications, or copy-number alterations was observed after high-dose melphalan. Interestingly, MM cells in the high-dose melphalan group had more sub-clonal mutations at the time of relapse compared to the non-transplant group, suggesting more recent occurrence. Our study is also beginning to identify the DNA motifs where these mutations may be observed, and the types of genes affected (e.g. DNA-damaged repair pathway mutations) with high-dose melphalan.

In summary, our study identified a significantly increased number of mutations in myeloma cells following high-dose melphalan, raising important questions for clinical consideration. Currently, the clinical impact and significance of this increased number of mutations remains unclear; however, there is great interest in evaluating whether genomic instability following ASCT is associated with more aggressive myeloma and worse outcomes. This data does not suggest that high-dose melphalan should not be performed, but rather suggests the need for further research to identify cause and effect of this observation and to develop strategies which might help prevent occurrence of such genomic instability.

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