Multiple myeloma often develops from the precursor condition monoclonal gammopathy of undetermined significance (MGUS), which is detectable in peripheral blood. Similarly, the light-chain subtype of multiple myeloma is preceded by light-chain MGUS. Clinical guidelines recommend annual peripheral blood monitoring of serum immune markers for patients with intermediate-risk and high-risk MGUS as determined by risk models that incorporate data from a single time-point. Longitudinal studies on serum immune markers in individuals with myeloma precursor disease to assess risk of disease progression have not been performed. In this prospective cross-sectional cohort study, 685 individuals with progressing or stable MGUS were studied to determine if longitudinal changes in serum immune markers are associated with progression from MGUS to multiple myeloma. The study was conducted from November 1993 through December 2011. Immune markers measured included serum protein and monoclonal immunoglobulin levels, serum free light chains, and serum light chains within each immunoglobulin class. During the 16-year follow-up period, 187 individuals progressed from MGUS to multiple myeloma or from light-chain MGUS to light-chain multiple myeloma. Researchers found that risk factors associated with progression of non-IgM MGUS to multiple myeloma were IgA isotype (OR 1.80, 95% CI 1.03 to 3.13, p=0.04), a monoclonal spike of 15 g/L or more (OR 23.5; 95% CI 8.9 to 61.9, p<0.001), a skewed (<0.1 or >10) serum free light chains ratio (OR 46.4, 95% CI 18.4 to 117.0, p<0.001), and severe immunoparesis (defined as two suppressed, uninvolved immunoglobulins; OR 19.1, 95% Cl 7.5 to 48.3; p<0.001). Risk factors associated with progression of light-chain MGUS to multiple myeloma were skewed serum free light chains ratio (OR 44.0, 95% CI 14.2 to 136.3 p<0.001) and severe immunoparesis (OR, 48.6, 95% CI, 9.5 to 248.2, p<0.001). Based on these identified risk factors, researchers calculated clinical risk scores and plotted them against longitudinal progression to multiple myeloma in individuals with at least one pre-diagnostic serum sample within two years of diagnosis and at least three serial samples. These analyses revealed that 53% of patients with MGUS that progressed to multiple myeloma had a high-risk score before progression, and 70% of these patients had preceding blood samples with low-risk and/or intermediate-risk scores. Similar results were found for light-chain MGUS. Overall, this study identified serum immune markers associated with progression from MGUS to multiple myeloma, and shows that low- or intermediate-risk MGUS can convert to high-risk MGUS, supporting the practice of annual serum immune marker testing in patients with MGUS or light-chain MGUS to determine clinical risk status.
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