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

Although translocation events between chromosome 4 (NSD2 gene) and chromosome 14 (immunoglobulin heavy chain [IgH] locus) (t(4;14)) is considered high risk in newly diagnosed multiple myeloma (NDMM), only similar to 30% to 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 similar to 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 the 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 (median OS 28.6 late-disruption vs 59.2 early disruption vs 75.1 months 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 in t(4;14) MM patients.

Automated summary

Although t(4;14) translocation is considered high risk in NDMM, only a minority of patients with t(4;14) have poor outcomes. We conducted a large-scale WGS and RNA sequencing analysis on t(4;14) and non-t(4;14) NDMM patients, and identified biomarkers associated with poor outcome, including translocation breakpoints in the NSD2 gene and expression of IgH-NSD2 fusion transcripts. The location of DNA breakpoints also significantly impacts overall survival.