Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder, with a 1% yearly risk of progression to Multiple Myeloma (MM). Evolution of M-spike and serum Free Light Chain (sFLC) during follow-up could identify patients at high risk of progression. In this region-wide study, including 4756 individuals, 987 patients with MGUS were identified and baseline factors as well as evolving involved FLC (iFLC) were evaluated as potential markers for risk of progression from MGUS to MM. Furthermore, evolving iFLC and M-spike were assessed quarterly for a median of five years. At baseline, patients that progressed had significantly higher iFLC compared to non-progressors. The risk factors of M-spike >1.5g/dl, age >65 years and iFLC >100mg/L were all independently associated with increased risk of MGUS to MM progression. For patients that had any two-three risk factors, the five-year cumulative probability of progression was significantly higher (31%) compared to no risk factors (2%). Evolving iFLC >100mg/L during follow-up was consistently associated with increased risk of progression. Based on our observations, we propose to include iFLC as a monitoring tool for all MGUS patients. Furthermore, we recommend a quarterly monitoring in all high-risk patients. Finally, we suggest that the risk of MGUS progression should be stratified with age, M-spike, and iFLC at baseline. This article is protected by copyright. All rights reserved.