Location of the t(4;14) translocation breakpoint within the NSD2 gene identifies a subset of high-risk NDMM patients.

Although translocation events between chromosome 4 (NSD2 gene) and chromosome 14 (IgH locus) (t(4;14)) is considered high-risk in newly diagnosed multiple myeloma (NDMM), only ~30-40% of t(4;14) patients are clinically high-risk. We generated and compared a large whole genome sequencing (WGS) and transcriptome (RNA-sequencing) from 258 t(4;14) (N=153 discovery, N=105 replication) and 183 non-t(4;14) NDMM patients with associated clinical data. A landmark survival analysis indicated only ~25% of t(4;14) patients had an overall survival (OS) <24 months, and a comparative analysis of the patient subgroups identified biomarkers associated with this poor outcome, including translocation breakpoints located in NSD2 gene and expression of IGH-NSD2 fusion transcripts. Three breakpoints were identified and are designated as: "no-disruption" (upstream of NSD2), "early-disruption" (in the 5' UTR) and "late-disruption" (within the NSD2 gene). Our results show a significant difference in OS based on the location of DNA breakpoints (mOS 28.6 "late-disruption" vs 59.2 "early disruption" vs 75.1 mo "no disruption"). These findings have been replicated in an independent replication dataset. Also, univariate and multivariate analysis suggest high-risk markers such as del17p, 1p independently contribute to poor outcome t(4;14) MM patients.