Objective To explore the early warning value of combined detection of serum β2-microglobulin (β2- MG), interleukin-6 (IL-6), and free light chain (FLC) in identifying renal injury associated with multiple myeloma (MM). Methods A total of 60 patients with MM admitted to the Department of Hematology at Zhengzhou Central Hospital Affiliated to Zhengzhou University between January 2021 and December 2024 were enrolled. Patients were divided into two groups based on renal function status: a normal renal function group and an abnormal renal function group, with 30 cases in each group. Serum levels of β2-MG, IL-6, and the FLC-iFLC/uFLC ratio were measured and compared between the two groups. Multivariate Logistic regression analysis was used to identify independent risk factors for renal dysfunction. The diagnostic performance of individual and combined indicators was evaluated using receiver operating characteristic (ROC) curves. Results The levels of serum β2-MG, IL-6, and FLC-iFLC/uFLC ratio were significantly higher in the abnormal renal function group than those in the normal group (P<0.001). Multivariate Logistic regression analysis revealed that β2-MG (OR=2.527), IL-6 (OR=1.790), and the FLC-iFLC/uFLC ratio (OR=3.472) were independent risk factors for renal dysfunction in MM patients (P<0.01). ROC curve analysis showed that the area under the curve (AUC) for β2-MG, IL-6, and FLC-iFLC/uFLC ratio were 0.876, 0.842, and 0.897, respectively, with sensitivities of 83.3%, 80.0%, and 86.7%, and specificities of 76.7%, 73.3%, and 80.0%. The combined detection of the three indicators yielded an AUC of 0.945, with sensitivity and specificity improved to 93.3% and 90.0%, respectively. Conclusion Serum β2- MG, IL-6, and FLC-iFLC/uFLC ratio are independent risk factors for renal injury in patients with MM. Combined detection of these indicators demonstrates superior diagnostic performance compared to individual testing and can serve as a valuable clinical tool for early warning of MM-associated renal injury.