Copy number aberration profiling using shallow whole-genome sequencing-based LeukoPrint in multiple myeloma.

Abstract

7554 Background: Multiple myeloma (MM) is a clonal plasma cell malignancy in which cytogenetic abnormalities are central to prognosis and therapy. Karyotyping is limited by low plasma cell proliferation, and FISH provides only targeted, costly detection. LeukoPrint, a shallow whole-genome sequencing–based assay, enables genome-wide CNA profiling. Supported by prior validation, we launched a prospective multicenter trial (ChiCTR2300077768) to assess the clinical relevance of LeukoPrint-detected CNAs in MM, and report interim results from the first 102 patients. Methods: This multicenter, prospective trial aims to enroll 396 newly diagnosed active multiple myeloma patients per IMWG 2014 criteria. As of June 12, 2025, 102 patients from seven hospitals in China were enrolled. LeukoPrint was used to profile CNAs (>1 Mb) from paired bone marrow CD138⁺ plasma cell gDNA and peripheral blood cfDNA collected at diagnosis, post-induction, and relapse. Karyotyping and FISH were performed in parallel when available and compared with LeukoPrint. Risk stratification followed mSMART criteria. Results: LeukoPrint identified 863 CNAs (379 chromosomal and 484 sub-chromosomal) in 91 of 102 patients (89.2%). Hyperdiploidy was observed in 33 patients, non-hyperdiploidy in 58, and normal karyotype in 11. The most frequent alterations were 1q gain (53%) and chromosome 13 deletion (50%). Odd-numbered trisomies, often co-occurring, were detected in 51.0% of patients, predominantly in hyperdiploid cases, whereas del(13) was evenly distributed across ploidy groups. Subdiploidy was common (54%) and hyperdiploidy rare (13%) among IGH-translocated cases, suggesting mutual exclusivity of hyperdiploidy and IGH-translocation. LeukoPrint showed 88.4% concordance with FISH for four key prognostic CNAs (1p32-, 1q21+, 13q14-, 17p13-) but detected substantially more abnormalities, including in 80% of FISH-negative patients. It also markedly outperformed karyotyping (90.1% vs. 8.8%), consistent with the limited sensitivity of karyotyping due to the low proliferative activity of plasma cells in MM. Blood-based ctDNA analysis showed good concordance with bone marrow results (81.9%), and CNA dynamics tracked closely with clinical remission, supporting LeukoPrint as a robust tool for diagnosis and treatment monitoring in MM. Conclusions: LeukoPrint outperforms FISH and karyotyping, providing a cost-effective, genome-wide CNA platform in MM and demonstrating utility in ctDNA-based liquid biopsy. These results support LeukoPrint as a complementary, and potentially alternative approach to conventional cytogenetics. Clinical trial information: ChiCTR2300077768.