BIRMINGHAM, AL — Multiple myeloma (MM) occurs about twice as often in men as in women, but until recently the biologic and clinical drivers of that disparity have been poorly understood. New data from the Integrative Molecular and Genetic Epidemiology (IMAGE) study suggest that men not only develop MM more frequently but also present with features consistent with a greater tumor burden at diagnosis.1
The IMAGE analysis evaluated 850 patients with newly diagnosed MM and compared clinical features and chromosomal abnormalities between men and women, adjusting for race, age, body mass index, education, income, smoking and alcohol use. Even after accounting for these factors, male sex remained strongly associated with more advanced disease at presentation.
Men were twice as likely as women to present with International Staging System (ISS) Stage III disease and were significantly more likely to have high serum monoclonal protein levels (≥3 g/dL). They also had higher odds of κ light chain disease and greater evidence of end-organ damage, particularly impaired renal function and lytic bone lesions. Collectively, these findings point to a higher disease burden at diagnosis in men.
In contrast, women were more likely to present with osteopenia and light chain–only disease, suggesting meaningful sex-based differences in disease phenotype rather than simple diagnostic delay.
Age appeared to modify several of these associations. The strength of the relationship between male sex and greater tumor burden was most pronounced in older men, although certain features, such as κ light chain disease and advanced stage, were more evident in younger men. The study also identified age-dependent interactions between sex and specific genomic features, including abnormalities in free light chain ratios and copy number alterations, raising the possibility that biologic drivers of MM may differ by both sex and age.
Investigators emphasized that these differences were not explained by socioeconomic or behavioral factors alone. While men are more likely to have exposures associated with cancer risk, such as smoking or occupational hazards, the persistence of these associations after adjustment suggests that biologic sex plays an independent role in MM pathogenesis.
Several mechanisms may help explain this excess risk. Sex hormones are known to influence immune regulation, inflammation, DNA repair, and cell-cycle control, all of which are central to myeloma development. Early evidence suggests that estrogen and progesterone can modulate activation-induced cytidine deaminase (AID), an enzyme involved in class-switch recombination and somatic hypermutation and that those processes play a role in myeloma-initiating mutations. Androgens, meanwhile, appear to shape B-cell positioning, germinal center formation, and T-cell function in ways that may favor immune exhaustion and tumor progression in males.
Emerging data also suggest that sex-specific differences in anti-tumor immunity may influence how precursor plasma cell clones escape immune surveillance. Because immune dysfunction is increasingly recognized as a driver of progression from early plasma cell disorders to overt MM, these sex-based immune effects may be particularly relevant.
Taken together, the IMAGE findings suggest that the higher incidence of MM in men may reflect not only increased risk of developing disease, but also biologic mechanisms that promote more aggressive tumor biology at diagnosis. Understanding these differences could inform future strategies for risk stratification, early detection and tailored treatment approaches in both men and women with MM or its precursor conditions.
Clinical Takeaways for VA Clinicians
Given the higher likelihood of advanced stage, renal impairment and greater tumor burden at diagnosis in men, clinicians should maintain a low threshold for evaluating male veterans with unexplained anemia, kidney dysfunction, bone pain or monoclonal protein abnormalities for plasma cell disorders, according to the research.
In addition, because male veterans are more likely to present with biologically aggressive disease, earlier evaluation and close monitoring of MGUS and other precursor conditions in male veterans, particularly those 65 and older, may help reduce delays in diagnosis and end-organ damage.
- Ong KL, Arnold KD, Wessel MC, et al. Sex differences in the clinical presentation of patients with newly diagnosed multiple myeloma. Cancer. 2026 Jan 15;132(2):e70192. doi: 10.1002/cncr.70192. PMID: 41521749; PMCID: PMC12793818.