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Background Lack of easy-to-interpret disease activity prediction methods in early MS can lead to worse patient prognosis. Objectives Using machine learning (multiple kernel learning – MKL) models, we assessed the prognostic value of various clinical and MRI measures for disease activity. Methods Early MS patients ( n = 148) with at least two associated clinical and MRI visits were investigated. T2-weighted MRIs were cropped to contain mainly the lateral ventricles (LV). High disease activity was defined as surpassing NEDA-3 Criteria more than once per year. Clinical demographic, MRI-extracted image-derived phenotypes (IDP), and MRI data were used as inputs for separate kernels to predict future disease activity with MKL. Model performance was compared using bootstrapped effect size analysis of mean differences. Results A total of 681 visits were included, where 81 (55%) patients had high disease activity in a combined end point measure using all follow-up visits. MKL model discrimination performance was moderate (AUC ≥ 0.62); however, modelling with combined clinical and cropped LV kernels gave the highest prediction performance (AUC = 0.70). Conclusions MRIs contain valuable information on future disease activity, especially in and around the LV. MKL techniques for combining different data types can be used for the prediction of disease activity in a relatively small MS cohort.