Monoclonal Gammopathies of Undetermined Significance (MGUS), Smoldering Multiple Myeloma (SMM), and asymptomatic Waldenström's Macroglobulinemia (WM) are precursor conditions with variable risk of progression to symptomatic malignancy. MGUS affects approximately 3–5% of adults over 50, while SMM and asymptomatic WM are less common and most often are detected incidentally. Their prevalence increases with age, reflecting cumulative genomic alterations and immune dysregulation. In younger patients, while less frequent, early onset may signal more aggressive biology and carry long-term implications, including psychosocial burden and prolonged surveillance. The aim of this analysis was to characterize asymptomatic monoclonal gammopathies in younger patients, including their characteristics and clinical course.

We analyzed consecutive patients diagnosed with asymptomatic monoclonal gammopathies between 2014 and 2024, at the Department of Clinical Therapeutics, Athens, Greece, according to IMWG 2014 criteria and for IgM MGUS and asymptomatic WM per IWWM-2/WHO criteria, prospectively entered in our database.

The analysis included 1240 patients with a median age of 65 years (range 28 to 100). Among them 150 (12.1%) were diagnosed before the age of 50 years, while 2% were younger than 40 years. Among patients younger than 50 years, the diagnoses were MGUS in 52% (IgG in 70%, IgA in 16%, IgM in 11%, light chain only in 2%), SMM in 45% and aWM in 3%. This distribution was not significantly different than in those 50 years or older. Among patients with SMM, the risk category distribution per IMWG 20/2/20 was similar with most patients in both age groups classified as low risk SMM (64% and 65% for ages below and 50 or above), 25% and 22% were intermediate and 9% and 13% high risk respectively.

There were significantly more female patients in the group below 50 (68% vs 57%, p=0.009). Although there were statistical differences in the level of total serum protein, serum albumin, serum creatinine and eGFR, hemoglobin and b2 microglobulin, these were not clinically significant (p<0.005 for all). Cytogenetics were available in 340 patients, and the distribution of cytogenetic aberrations was similar between age groups.

The median follow-up for the whole cohort is 3 years. In the whole cohort, 2, 3 and 5-year progression rate to symptomatic disease was 4%, 6% and 11%. More specifically was 0%, 2% and 4% for non-IgM MGUS, for SMM was 8%, 12% and 18%, it was 0%, 0% and 3% for IgM-MGUS and for aWM was 0%, 0% and 10%. No patient <50 progressed with symptomatic CRAB, but with either SLiM (n=4) or asymptomatic bone lesions detected in regular follow up imaging (n=3). For patients with SMM, progression rate to symptomatic MM at 2, 3 and 5-year was 4%, 6% and 12% for patients <50 years while for older patients was 9%, 13% and 20% respectively (p=0.049); however, after adjusting for risk (per 20/2/20) there was no significant difference (p=0.416). There was no significant difference in the progression rate among patients with non-IgM MGUS although there have been no progression events among patients diagnosed <50 years of age up (vs 5% at 5 years for those 50 or older, p=0.315). Among patients with IgM MGUS or with aWM there were no progression events among patients <50 years, but progression events were few also in the older age group (p=0.737). We also focused on patients below the age of 40 which may represent a unique population. Notably, in the iStopMM study the screening included only subjects 40 years or older. This was a small subgroup of patients (n=24), 71% of which were females, and 50% had SMM and 50% MGUS. Among those with SMM 75% had low and 25% intermediate risk SMM – no patient was at high risk per 20/2/20. No progression event has occurred in this group after a median follow up of 3 years.

In this contemporary cohort of patients with asymptomatic monoclonal gammopathies, those diagnosed under 50 years exhibited similar biological features compared to older patients, with generally low progression rates and low risk of complications, which may represent early detection in the disease course and close monitoring. Young patients with monoclonal asymptomatic monoclonal gammopathies, especially those with low-risk disease should be ensured about their good prognosis and be followed appropriately to reduce risk of complications and the anxiety associated with the diagnosis of an early malignancy.

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2025
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