We hypothesized that the presence of monoclonal free light chains (FLC) in the serum of patients with monoclonal gammopathy of undetermined significance (MGUS) is a marker of clonal evolution and a risk factor for progression. Forty-seven patients with MGUS and documented progression to myeloma or related malignancy were compared with 50 age- and gender-matched patients with MGUS and no evidence of progression after 5 or more years of follow-up. The presence of an abnormal kappa/lambda FLC ratio in the serum was associated with a higher risk of MGUS progression (relative risk 2.5; 95% confidence interval: 1.6-4.0; P < 0.001).