(PA-259) High Expression of NSD2 in Non t(4;14) Newly-diagnosed Multiple Myeloma Patients May Mimic t(4;14) Biology

In newly diagnosed multiple myeloma (ndMM) t(4;14) causes overexpression of the histone methyltransferase NSD2 (MMSET) which adds dimethyl groups on histone 3 lysine 36 residues leading to a gene expression program associated with poor prognosis. Interestingly, some patients without the translocation can have high NSD2 expression. Here,  we compared  genomic  and prognostic features between t(4;14) vs non-t(4;14) patients with high vs low NSD2 expression.  


Methods:

We analyzed multi-omics (DNA- & RNA-seq) data from three independent cohorts (CoMMpass, IFM2009, GAMER) with 1703 ndMM patients total.


Results:

In two datasets, most non-t(4;14) showed downregulated NSD2 vs normal PCs. However, ~25% of these non-t(4;14) had higher expression of NSD2 transcripts vs normal PCs. We compared clinical outcomes in t(4;14) patients, non-t(4;14) with high NSD2 (H-NSD2), and non-t(4;14) with low NSD2 (L-NSD2). H-NSD2 patients had similarly poor PFS and OS to the t(4;14) and significantly worse outcomes compared to L-NSD2 (H-NSD2: mPFS 22mo, mOS 63.5mo; t(4;14): mPFS 27.8mo, mOS 72.2mo; L-NSD2: mPFS 42.3mo, mOS NR). These findings were replicated on all datasets, confirming a prognostic role for high NSD2 on outcomes, independent of t(4;14).

H-NSD2 patients in CoMMpass had significantly higher prevalence of high risk features eg, P53 mutations (OR=3.42 [1.58-7.43]), del17p (OR=2.69 [1.48-4.83]), and t(14;16) (OR=2.50 [1.04-5.86]) and significantly lower prevenance of hyperdiploidy (OR=0.26 [0.17-0.39]) vs L-NSD2 patients. This enriched pattern of high risk features was replicated in IFM2009 and GAMER datasets.  

Transcriptomic analyses revealed that H-NSD2 patients exhibited significantly higher FGFR3 expression (log2FC=3.2, adj. p< 2.2e-16), resembling t(4;14) tumors. We found 367 genes with significant expression changes between L- and H-NSD2 groups (adj. p< 0.01 & abs(log2FC) > 1) after adjusting for cytogenetic imbalances. Increased genomic instability processes, including G2M checkpoint and mitotic spindle, were significantly upregulated (q-value< 0.0001) in H-NSD2 patients, while DNA repair and oxidative phosphorylation were downregulated (q-value< 0.001). Key upregulated genes in both H-NSD2 and t(4;14) groups included JAM3, CDC42BPA, FGFR3, and others. Analysis of master regulators  in the H-NSD2 group using RNA expression, ChIPseq, and single-cell ATAC-seq data identified E2F1/2/7/8, PHF19, and FOXM1 among the top transcriptional regulators.


Conclusions:

A subset of  ndMM may have high expression of NSD2 independent of t(4;14)  with poor clinical outcomes. The H-NSD2 group had significantly more high-risk genomic alterations with biology similar to t(4;14) group correlated with high NSD2 levels. Further ongoing analysis would elucidate the biology of high NSD2 and associated tumor genomic features and may support clinical investigation of NSD2 inhibition in the H-NSD2 MM patients.