Sequential acquisition of 1p31.1-p12 LOH and 1q Gain is a common double-hit event in relapsed/refractory myeloma
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Therapy-driven genomic changes in multiple myeloma (MM) remain poorly defined. We analyzed whole-genome sequencing (WGS) data from relapsed/refractory MM (rrMM, N=386) and identified regional 1p31.1–p12 (hereafter 1pCEN, a region proximal to the centromere) loss-of-heterozygosity (LOH) as the only enriched aberration showing strong therapy-associated clonal selection (clonal timing rank fold-change = 3.7, P<2.2×10 -16 ). This event showed enriched co-occurrence with 1qGain (OR = 2.3 (1.5-3.8), P=2×10 -4 ) forming a recurrent “double-hit” in rrMM. To validate the clonal selection process, we examined three longitudinal cohorts (180 patients, 390 samples) and confirmed clonal expansion of 1pCEN and consistent prevalence of the 1pCEN+1q double-hit (20–24%). Survival analyses demonstrated significantly reduced progression-free survival in rrMM patients with this double-hit compared with those without. Comparison with a large newly diagnosed MM (ndMM) cohort confirmed previously-described 1p32 LOH is the prognostic locus at baseline, whereas 1pCEN is therapy-selected and largely independent of the 1p32 locus. Thus, 1pCEN+1q represents a recurrent double-hit event that clonally emerges in rrMM, conferring selective advantage under drug exposure and is distinct from the ndMM high-risk markers defined by current consensus guidelines. These findings nominate 1pCEN as a new genomic biomarker in rrMM and 1pCEN+1q may help patient stratification for therapeutic monitoring. Key Points A therapy-driven common genomic double-hit (1p31.1–p12 LOH with 1q gain) clonally emerges in relapsed/refractory myeloma.
Institutions: University of Oxford, Oxford University Hospitals NHS Trust, MRC Weatherall Institute of Molecular Medicine, MRC Molecular Haematology Unit, University College London, Icahn School of Medicine at Mount Sinai, Centre de Recherches en Cancérologie de Toulouse, Institut universitaire du cancer de Toulouse Oncopole, Université de Toulouse, Harvard University, Dana-Farber Cancer Institute
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7161954133