Real-World Experience of Using Next-Generation-Sequencing in Multiple Myeloma Diagnostics in the UK National Health Service.

Abstract

The IMS-IMWG 2025 updated definition of high-risk multiple myeloma (HRMM) introduced next-generation sequencing (NGS) based detection of TP53 single-nucleotide variants (SNV) as an independent high-risk factor. However, most published data on TP53 SNVs in MM derive from exploratory research studies using NGS interpretation pipelines outside of quality-controlled, clinically accredited laboratories, with limited information on co-occurring high-risk cytogenetic abnormalities (HRCA). To address this, we retrospectively reviewed all transplant-eligible newly diagnosed MM (NDMM) patients treated at the Royal Marsden Hospital in the UK between February 2021 and April 2026 who underwent standard-of-care parallel fluorescence in situ hybridization (FISH) testing for all IMS-IMWG consensus genomic staging (CGS) criteria and NGS-based TP53 SNV calling in the National Health Service diagnostically accredited Genomic Laboratory Hub (GLH). A total of 102 patients were included. Based on FISH, 24 patients (23.5%) fulfilled IMS-IMWG CGS criteria for HRMM, including 8 (7.8%) with del(17p) and 5 (4.9%) with biallelic del(1p32). All 24 patients had co-occurrence of 2+ HRCA, including all 5 patients with biallelic del(1p32). NGS identified 4 cases (3.9%) with TP53 mutations, of which 2 harbored del(17p), while 2 were classified as HRMM solely based on NGS results. However, both isolated TP53mut also carried additional HRCA. Thus, in this standard-of-care diagnostic setting, only 2% of NDMM were re-classified based on NGS findings and, notably, all 26 HRMM had 2+ high-risk lesions. Although limited by cohort size and lack of survival outcomes, these descriptive data demonstrate genomic co-occurrence rather than independent prognostic value and support a continued focus on reliable, quality-controlled detection of structural variants alongside NGS.