Men Face Double the Odds of Advanced Multiple Myeloma at Diagnosis

Men newly diagnosed with multiple myeloma are twice as likely to present with advanced stage III disease compared to women, according to research revealing sex differences at diagnosis.

Scientists at the University of Alabama at Birmingham analyzed 850 patients and found that 35% of men had reached stage III at diagnosis versus just 27% of women. Even after accounting for age, race, body mass index, lifestyle factors, and socioeconomic status, men faced more than double the odds of presenting with the most severe disease stage.

Multiple myeloma ranks as the second most common blood cancer in the United States, with incidence rates twice as high in men. An estimated 20,030 new male cases will be diagnosed in 2025 alone. Yet despite this pronounced sex difference in who develops the disease, researchers have struggled to explain why men also appear to have worse disease when first diagnosed.

What the Study Found at Diagnosis

The study, published in the journal Cancer, enrolled patients between 2009 and 2020 as part of the Integrative Molecular And Genetic Epidemiology (IMAGE) Study. Researchers collected detailed clinical measurements, laboratory results, and bone marrow samples from each participant.

Lead author Krystle L. Ong and colleagues found the stage III disparity persisted across statistical models that controlled for multiple confounding factors. Men also showed 72% higher odds of having elevated serum monoclonal protein levels (at least 3 grams per deciliter), a key marker of myeloma cell activity.

The International Staging System classifies myeloma into three stages based on blood levels of albumin and beta-2 microglobulin. Stage III represents the most advanced category, associated with lower survival rates and more aggressive disease requiring immediate treatment.

Kidney and Bone Damage Tell a Similar Story

Male patients had 71% increased odds of impaired kidney function and 97% higher odds of lytic bone lesions, the destructive holes myeloma creates in bones.

Laboratory measures showed men had significantly higher creatinine levels and lower estimated glomerular filtration rates, both red flags for declining kidney function. The authors note this pattern is consistent with sex differences seen in the general U.S. population, where men typically show worse kidney health markers.

Bone disease presented differently by sex. Lytic lesions appeared far more often in men, while women had higher rates of osteopenia (reduced bone density). Men had 41% lower odds of osteopenia, but when bone damage occurred in men, it tended toward the more destructive lytic pattern.

“Male patients with newly diagnosed multiple myeloma by comparison with females were more likely to have International Staging System stage III disease, high serum monoclonal protein, κ light chain disease, and more end-organ damage,” the researchers wrote.

Men were 60% more likely to have kappa light chain disease and 37% less likely to have light chain only disease. These immunoglobulin patterns represent different molecular subtypes of myeloma.

Why Age Seems to Matter

When researchers examined patients by age group, they found the stage III disparity remained significant across ages, with certain features more pronounced in younger men. Among patients aged 60 and under, males had 2.4 times the odds of stage III disease compared to women of the same age. In patients over 60, men still showed elevated odds at 2.05 times that of women.

Younger men showed significantly elevated rates of kappa light chain disease, an association not seen in older males. The relationship between male sex and certain chromosomal abnormalities also shifted with age.

Among younger patients, males had modestly higher rates of extremely elevated free light chain ratios (at least 100 times normal) and secondary copy number abnormalities compared to females. In older patients, this pattern reversed, with older males showing lower rates of these features than older females.

The authors noted that age may influence the prevalence of genomic alterations in male patients with newly diagnosed multiple myeloma, which may account for the excess tumor burden in men.

What Biological Mechanisms Might Explain These Differences

Multiple myeloma originates from plasma cells, the specialized immune cells that produce antibodies. The disease process begins with DNA damage during class switch recombination, a normal step in immune cell development.

Preliminary research suggests that estrogen and progesterone can modify activity of AID, an enzyme involved in this DNA rearrangement. Androgens may influence how B cells organize themselves and form germinal centers, the structures where immune responses develop.

The interplay between sex hormones and immune function may explain both why men develop myeloma more often and why their disease appears more advanced at diagnosis.

“It’s possible that sex-specific chronic immune activation and inflammation can lead to aberrant T-cell responses that allow multiple myeloma clones to escape immune surveillance,” the researchers explained. T-cells normally help control abnormal plasma cells, but hormones may alter this defense system differently in men and women.

Research suggests androgens may promote T-cell exhaustion, a state where immune cells lose their ability to fight cancer effectively. This could allow myeloma cells to grow unchecked in men.

The authors note the role of sex hormones in the underlying mechanism of normal class switch recombination and the support of transformed plasma cells remains unclear.

How This Compares to Previous Research

Earlier studies based on clinical trial data suggested that age at diagnosis is similar between men and women, and that men have more kidney problems while women have more anemia. The current findings confirm those patterns.

The doubled odds of stage III disease in men hasn’t been clearly documented before. The authors suggest this may reflect referral patterns or eligibility criteria in clinical trials, which can miss how diseases present across entire patient populations.

The research team enrolled 82% of eligible patients, an unusually high participation rate that reduces selection bias. Participants included 40% Black patients, reflecting the local population and providing better racial diversity than many myeloma studies.

What This Could Mean for Screening and Care

These sex disparities could eventually influence screening and monitoring strategies. If men tend to develop more aggressive disease earlier, they might benefit from closer surveillance during monoclonal gammopathy of undetermined significance, the precursor condition that sometimes progresses to myeloma.

The findings also raise questions about whether treatment intensity should be calibrated differently by sex, or whether clinical trial enrollment should be stratified by sex to better understand treatment response differences.

Current staging systems don’t incorporate biological sex, despite this research showing it associates with disease burden at diagnosis. Future risk stratification tools might improve accuracy by including sex as a variable.

Study Strengths and Limitations

Researchers systematically reviewed each case and collected data on health behaviors, socioeconomic factors, and comorbid conditions. This allowed them to rule out lifestyle and demographic explanations for the sex differences observed.

Chromosomal data was unavailable for about 25% of patients due to timing of when certain genetic probes were added and variations in how clinical laboratories processed bone marrow samples. While this data lapses didn’t differ significantly by sex (28% in females versus 23% in males), it could affect conclusions about genetic differences.

The study’s design captures only a snapshot at diagnosis, not how sex differences might influence disease progression or treatment response over time. Longitudinal studies following patients through treatment would help answer whether the initial staging disparity translates into different outcomes.

The relatively small sample size limited statistical power for detecting precise relationships, particularly for rare clinical features and chromosomal abnormalities. The small number of patients diagnosed at age 40 or younger prevented more granular age-group analyses.

The research team plans continued investigation into biological mechanisms driving these disparities, including detailed analysis of how sex hormones influence immune changes that enable myeloma to develop.

The increased odds of advanced disease in men points to a gap in cancer biology that has received limited attention. As researchers noted, male sex is an important risk factor for multiple myeloma, which may affect disease causes, development, and clinical presentation.

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