Next-Generation Sequencing for Clinically Viable Multiple Myeloma Genome Interrogation

Abstract

Multiple Myeloma (MM) is a severe and common malignancy which presents clinically with a highly aberrated genome, with mutations ranging in size from whole chromosome events to single nucleotide variants. The large chromosomal events, including translocations at the IgH locus and copy number variants, have well defined clinical correlates, whereas the clinical relevance of small-scale lesions is only recently coming to light. Accordingly, the current clinical standard for myeloma genome interrogation, fluorescent in situ hybridization (FISH), only reports on the large-scale lesions, leaving gaps in the prognostication of MM. Herein, we explore the use of next-generation sequencing (NGS) technologies for clinical assessment of the MM genome. We developed a targeted sequencing panel that, for the first time, robustly captures significant clinical associations with gene mutational status; it is an independent biomarker and outperforms FISH based prognostication. We also developed a whole genome sequencing (WGS) pipeline which outperforms FISH in the capture of structural variants down to 10X coverage. Taken together, we described a next generation sequencing approach for MM patients which is clinically viable and superior to FISH.