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High-Dose Melphalan Treatment Increases Mutational Burden at Relapse in Patients With Multiple Myeloma
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- The authors analyzed paired samples obtained from patients with multiple myeloma from the phase III IFM 2009 study (lenalidomide, bortezomib, and dexamethasone [RVD] versus RVD + high-dose melphalan [HDM] with autologous stem-cell transplantation) to evaluate the DNA-damaging effects associated with HDM. A similar number of mutations were observed at diagnosis among both groups, with a higher rate of mutation accumulation in the HDM-treated group, especially in those achieving complete response. The majority of the mutational load was at the subclonal level, with no significant changes in structural variants or copy number alterations. The mutational burden was not associated with worse outcomes.
- Clonal complexity appeared to increase after HDM exposure, with no apparent effect on clinical outcomes.
abstract
This abstract is available on the publisher's site.
Access this abstract nowHigh 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.
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High-Dose Melphalan Treatment Significantly Increases Mutational Burden at Relapse in Multiple Myeloma
Blood 2023 Jan 05;[EPub Ahead of Print], MK Samur, M Roncador, A Aktas Samur, M Fulciniti, AH Bazarbachi, RE Szalat, MA Shammas, AS Sperling, PG Richardson, F Magrangeas, S Minvielle, A Perrot, J Corre, P Moreau, A Thakurta, G Parmigiani, KC Anderson, H Avet-Loiseau, NC MunshiFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
In this study, Samur et al examined a large cohort of patients with newly diagnosed multiple myeloma who received a combination of lenalidomide, bortezomib, and dexamethasone (RVD) with or without high-dose melphalan and autologous stem-cell transplantation (HDM-ASCT). Using whole genome sequencing, they discovered that patients with myeloma who relapsed after HDM-ASCT harbored a higher number of mutations, primarily caused by a specific mutational signature (SBS-MM1) that has previously been linked to melphalan exposure. This further demonstrates melphalan's potent ability to cause mutations in tumor cells and strongly supports previous studies by Weinhold N et al, Rustad E et al, Landau HJ et al, and Rasche L et al. Recently, the mutagenic effect of melphalan has also been observed in relapsed diffuse large B-cell lymphomas1 and post–HDM-ASCT therapy–related myeloid neoplasms.2 However, the impact of these mutations is largely unknown, as most of them occur in noncoding regions of the genome and do not appear to affect clinical outcomes. Further research is needed to fully understand melphalan's mutagenic impact on both tumor and normal cells within and outside of the tumor microenvironment and how this may influence treatment strategies for patients with multiple myeloma.
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