Male sex adversely impacts survival and myeloid malignancy risk in MGUS: a real-world population-based study

Monoclonal gammopathy of undetermined significance (MGUS) is a common plasma cell disorder with well described risks of progression to myeloma and lymphoplasmacytic lymphoma. Using data from an established UK population-based cohort of hematological malignancies and premalignancies, we investigated patient and disease characteristics, subsequent hematological malignancy, and survival in 4,651 people diagnosed with MGUS between 2005 and 2019. The 5-year net (relative) survival (disease-specific estimate of the probability of survival) for MGUS patients was 87.8% (95% confidence interval [CI]: 85.9-89.7), with males (83.8%; 95% CI: 81.0-86.6) more affected than females (92.2%; 95% CI: 89.7-94.7). The proportion of subsequent hematological malignancies was also higher in males than females (8.8% vs. 5.3%; P<0.00001); the average annual rates of transition being 1.81% (95% CI: 1.44-2.18) and 0.99% (95% CI: 0.72-1.27), respectively. Furthermore, whilst annual rates of transformation to myeloma (1.04%) and lymphoplasmacytic lymphoma (0.11%) were as expected, both were higher in males (1.23% and 0.18%) than females (0.87% and 0.06%). With a median time to diagnosis of 40 months, the incidence of myeloid malignancy was also raised in males (relative risk=3.6; 95% CI: 2.5-4.9), but not females (relative risk=1.0; 95% CI: 0.3-1.9). No associations between MGUS and subsequent development of chronic lymphocytic leukemia were observed. Providing new data on the nature of MGUS progression, our analyses revealed previously undescribed sex disparities; including worse survival and increased rates of myeloid malignancy in males with non-IgM MGUS. These findings have implications for future research, as well as risk stratification and monitoring of patients with this highly prevalent plasma cell dyscrasia.