Kappa Free Light Chains Reflect Treatment Response and Progression Independent of Focal Inflammation in Multiple Sclerosis

ABSTRACT Background Cerebrospinal fluid (CSF) kappa free light chains (KFLC) is a sensitive marker of intrathecal immunoglobulin synthesis and is incorporated into the 2024 McDonald criteria for multiple sclerosis (MS). How disease‐modifying therapies (DMTs) influence KFLC dynamics and their association with treatment response remains unclear. Objective To determine whether intrathecal KFLC synthesis changes during DMT and whether these changes are associated with clinical outcomes. Methods Patients with treatment‐naïve relapsing–remitting MS were prospectively enrolled at the Sahlgrenska MS Center (Gothenburg, Sweden). Paired CSF and serum samples were collected at baseline and after 12 months of treatment with dimethyl fumarate (DMF) or natalizumab (NTZ). KFLC index was calculated as [(CSF KFLC/serum KFLC)/(CSF albumin/serum albumin)]. Treatment response was assessed using no evidence of disease activity‐3 (NEDA‐3) and progression independent of relapse and MRI activity (PIRMA + ). Results Forty‐eight patients were included (DMF n = 26, NTZ n = 22). NTZ reduced KFLC index from a median 117.4 (63.6–171.9) at baseline to 78.8 (39.4–104.0) at 12 months (adjusted p = 0.003), corresponding to a median decline of −51.0 (IQR −82.1 to −24.7), whereas DMF produced no meaningful change. In NTZ‐treated patients maintaining NEDA‐3 or without PIRMA + , KFLC index declined markedly (both p < 0.01). Change in KFLC index predicted outcomes, yielding an AUC of 1.0 for NEDA‐3 and 0.79 for non‐PIRMA + . Conclusions Natalizumab appears to reduce intrathecal KFLC synthesis, and a decline in KFLC index may reflect effective suppression of CNS humoral immunity. ΔKFLC index could serve as a sensitive biomarker of treatment response and disease stability in MS.