P-219: Longitudinal analysis of t(11;14) and t(4;14) genomes reveals distinct evolutionary trajectories in multiple myeloma.

Introduction: The t(4;14) and t(11;14) represent the most common translocated multiple myeloma (MM) subtypes and are associated with different clinical behaviours. Although differences in genomic aberrations and expression profiles have been shown at diagnosis, little is known about the genetic mechanisms underlying disease progression.

Methods: To gain insight, we analysed paired whole genome sequencing (median CD138+ tumour 46X; germline 23X) from longitudinal samples (n=34, median 3 per patient) derived from 8 t(11;14) and 5 t(4;14) MM patients with a median time between samples of 24.8 months. Additionally, we performed long-read RNA sequencing on the same patients for gene expression (n=18; median samples 2 per t(11;14) and 1 per t(4;14) patient).

Results: Canonical IGH translocations were observed at all timepoints. Regarding other structural variants (SV), there was no difference in breakpoint number and rate of acquisition between subtypes through progression. While copy number (CNA) remained stable in 2/3 evaluable t(4;14) patients, de novo changes were seen in 7/8 t(11;14) patients, with acquisition of gain1q (n=2), del6q (n=4), and del13q (n=1). This could suggest t(11;14) gain more de novo CNA at progression, including del6q associated with plasma cell leukaemia. There was no difference in mutational burden between subtypes but we identified subtype-specific mutational drivers such as PRKD2 in the t(4;14), and IRF4 in the t(11;14), consistent with the literature. Overlaps in driver mutations converged between subtypes to pathways of epigenetic regulation and DNA instability. Mutational signature analysis showed similar contribution of signatures, with clock-like SBS5 and hypermutation SBS9 active in all patients, melphalan-associated SBS-MM1 linked to ASCT rather than subtype, and APOBEC SBS13 remaining stable except one t(11;14) case (appeared at progression). Despite this, the rate of acquisition of both overall mutational burden and SBS9 signature contribution was higher in t(4;14) through progression (linear regression, p=0.04 and p=0.019 respectively).

Subtypes also displayed distinct transcriptomic profiles, with 206 differentially expressed genes reported between the subtypes (log2FC > ±2, p< 0.05). t(4;14) patients exhibited increased expression of genes on 1q whereas t(11;14) overexpressed genes on chromosome 11. As expected, t(11;14) was associated with a B cell phenotype, expressing a signature of B cell-associated genes, of which MS4A1 (CD20), CD79A, and RGS1 decreased in expression in 3/4 patients through progression.

Conclusions: Overall, we show marked differences in the mechanisms of progression between t(11;14) and t(4;14). Whilst SVs and mutational processes show similar patterns between subtypes, our data suggests t(4;14) have a higher rate of mutational acquisition whereas t(11;14) develop more high-risk copy number aberrations and lose B cell signature expression with progression. This could help inform subgroup-specific management through disease progression.