Patients with RMS were treated with ozanimod 0.46 or 0.92mg/d or interferon β-1a 30μg/wk for 24 months in RADIANCE (NCT02047734) or ≥12 months in SUNBEAM (NCT02294058); completers could enroll in an open-label extension trial (DAYBREAK?NCT02576717) of ozanimod 0.92mg/d for up to ~6 years (database lock: 4/7/2023). Patients were pooled across studies and treatment arms. CDP-6 was defined as a ≥1-point increase from baseline in Expanded Disability Status Scale (EDSS) score, confirmed after 6 months. Predictors tested included demographics, disease duration, relapse history, prior treatment, EDSS, Kurtze Functional Systems Scores (FSS), Timed 25-Foot Walk Test (T25W), 9-Hole Peg Test (9HPT), low-contrast letter acuity (LCLA), MRI lesion counts and volumes, brain volumes, serum glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) at baseline. An Extreme Gradient Boosting (XGBoost)-based ML model was used. Model parameters were optimized using a stratified cross-validation strategy based on 80% (n=1804) of patients. Individualized risk scores for CDP-6 were derived for the remaining 20% (n=452) and categorized into risk tertiles (low, medium, high); incidence of CDP-6 was assessed for each tertile.