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Updated: Nov 5, 2025
Percutaneous Hepatic Perfusion PHP with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver
Published on: July 31, 2016
The mutagenic impact of melphalan in multiple myeloma
Francesco Maura1, Niels Weinhold2,3, Benjamin Diamond4
1Myeloma Program, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA. fxm557@med.miami.edu.
Abstract:
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 ~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.
Insights
High-dose melphalan, used in multiple myeloma treatment, causes a specific mutational signature (SBS-MM1). While increasing mutations, these rarely affect key cancer genes, suggesting limited impact on myeloma drivers.
Area of Science:
- Oncology
- Genetics
- Bioinformatics
Background:
- Whole genome and exome sequencing have enabled detailed analysis of cancer mutational processes.
- Multiple myeloma research has identified several mutational signatures, including SBS-MM1.
- SBS-MM1 is linked to high-dose melphalan therapy, a common treatment for multiple myeloma.
Purpose of the Study:
- To review studies characterizing mutational signatures in multiple myeloma.
- To discuss the origins and implications of the SBS-MM1 signature.
- To explore the clinical relevance of melphalan-induced mutations.
Main Methods:
- Comprehensive analysis of whole genome and exome sequencing data.
- Application of advanced bioinformatic pipelines for mutational signature identification.
- Review of key scientific literature on multiple myeloma genetics and treatment.
Main Results:
- High-dose melphalan exposure induces a distinct mutational signature (SBS-MM1).
- Melphalan increases overall and nonsynonymous mutational burden by approximately 10-20% between diagnosis and relapse.
- Acquired mutations are predominantly located in heterochromatin and late-replicating regions, sparing critical myeloma driver genes.
Conclusions:
- The SBS-MM1 signature provides a molecular marker for high-dose melphalan exposure in multiple myeloma.
- The limited involvement of driver genes in melphalan-induced mutations may have implications for treatment response and resistance.
- Further research is needed to fully understand the clinical impact of these findings.
