Recurrent loss of chromosome y in multiple myeloma is linked to disease progression and altered tumor immune microenvironment Free

Sex-based disparities in multiple myeloma (MM) are well established, with men being more commonly affected than women, however, the biological basis of this difference remains poorly understood. Although autosomal alterations have been extensively studied, abnormalities affecting the sex chromosomes have remained largely overlooked. Among them, loss of the Y chromosome (LOY), the most prevalent somatic mutation in older men and a defining feature of age-related clonal hematopoiesis, has long been disregarded as a biologically irrelevant byproduct of aging. However, emerging evidence in other malignancies challenges this view, suggesting that LOY may actively shape tumor behavior and modulate the immune microenvironment. This raises a critical question: could LOY help explain the male bias and clinical heterogeneity observed in MM? To answer this, we provide the first systematic characterization of LOY in MM, revealing its biological and clinical relevance and uncovering potential roles in disease progression and immune dysregulation.

We analyzed 944 newly diagnosed MM (NDMM) samples from the MMRF CoMMpass study using whole-exome and bulk RNA sequencing to assess the frequency, clonality, and transcriptional impact of LOY. Transcriptomic signatures were identified after adjusting for major genomic events, and pathway-level changes were explored using gene set enrichment analysis (GSEA). Additional transcriptomic datasets, including bulk and single-cell RNA-seq from public repositories, were integrated to evaluate LOY across disease stages, including premalignant conditions and relapsed MM. Single-cell data also enabled assessment of LOY prevalence at single-cell resolution.

We identify LOY as one of the most frequent somatic copy number alterations (CNA) in NDMM male patients (17.4% [99/569]). LOY is already detectable at precursor stages, including MGUS and SMM, with a rising frequency along disease progression. In MGUS, LOY is associated with a four-fold higher 10-year risk of progression to MM compared to males with wild-type Y (35% vs. 8%, P=0.001), supporting its potential role as an early event in tumorigenesis.

LOY is strongly enriched in MM patients with high-risk cytogenetic abnormalities such as t(4;14) (P<0.001), and gain(1q) (P=0.02), while being significantly underrepresented in hyperdiploid cases (P<0.01). No associations were found with TP53 alterations or increased genomic instability. Clonality analysis revealed that LOY is present in at least as many malignant cells as common MM drivers, including gain(1q), del(RB1), and recurrent trisomies, suggesting its early emergence and stable maintenance during tumor evolution. Supporting this, LOY was detected in 75-100% of malignant plasma cells in LOY tumors and was absent in non-malignant immune cells, underscoring its clonal and tumor-specific nature. Consistently, LOY was detected at relapse and in minimal residual disease in all patients in whom it was present at diagnosis, highlighting its persistence as a somatic CNA.

Clinically, LOY identifies a subgroup of male patients with significantly inferior outcomes. In multivariable models adjusting for age, R-ISS stage, and treatment type, LOY was independently associated with reduced progression-free survival (HR=1.44, 95% CI: 1.07-1.92, P=0.015) and overall survival (HR=1.70, 95% CI: 1.20-2.41, P=0.003).

Transcriptomic analyses revealed that LOY shapes a distinct transcriptional program characterized by pronounced immune suppression in MM. LOY tumors displayed significant downregulation of immune-related genes and reduced activity in key inflammatory signaling cascades, in conjunction with a suppression of tumor-adaptive programs that support invasion, angiogenesis, and oncogenic signaling, suggesting a general remodeling of the tumor and its microenvironment.

Our findings establish LOY as one of the most frequent CNA in male MM. Consistent with a candidate driver, LOY emerges early, persists through disease progression, and is preferentially associated with high-risk genomic features. Clinically, it defines a subgroup of patients with poorer outcomes, while functionally it may promote immune evasion and constrain tumor adaptability. Together, these findings highlight LOY as a previously unrecognized biologically and clinically significant alteration in MM, with potential implications for early detection, risk stratification, and targeted therapeutic approaches.