Genome-wide copy number profiling enhances risk stratification in multiple myeloma by shallow whole-genome sequencing Open Access

• LeukoPrint enables robust genome-wide CNA profiling via shallow WGS, outperforming karyotyping and matching FISH for key lesions.

• Combining LeukoPrint with FISH improves MM risk stratification, reclassifying 11.5% from standard-risk to high-risk for treatment guidance.

Comprehensive detection of copy number aberrations (CNAs) is critical for precise prognostic risk stratification in multiple myeloma (MM), but conventional cytogenetic methods remain limited. We developed LeukoPrint, a shallow whole-genome sequencing (sWGS) assay for genome-wide CNA profiling. Using this platform, we analyzed CNA profiles of 423 MM patients from three hospitals, comparing LeukoPrint with karyotyping and fluorescence in situ hybridization (FISH) to evaluate its diagnostic performance and clinical utility in prognostic assessment. Compared to karyotyping, LeukoPrint significantly increased abnormality detection rate (75.2% vs 11.2%) and identified CNAs in 73.3% of karyotyping-negative cases. Concordance with FISH for key prognostic CNAs (amp(1q), del(1p), del(13q), del(17p)) was 94.0%. Based on these findings, we propose replacing karyotyping with LeukoPrint combined with FISH for routine diagnostics. Integrating LeukoPrint + FISH results into the Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) risk model reclassified 11.5% of standard-risk patients as high-risk, identifying candidates for intensified therapy. Furthermore, LeukoPrint genome-wide profiling further revealed distinct CNA patterns between hyperdiploidy and non-hyperdiploidy, informing biological heterogeneity. In conclusion, LeukoPrint significantly outperforms conventional karyotyping and closely matches FISH for crucial CNA markers, offering an alternative for cytogenetic profiling and prognostic stratification in MM.