Purpose: The goals of this study were to assess the performance of a novel lesion segmentation tool for longitudinal analyses, as well as to validate the generated lesion progression map between two time points using conventional and non-conventional MR sequences. Material and methods: The lesion segmentation approach was evaluated with (LeMan-PV) and without (LeMan) the partial volume framework using "conventional" and "non-conventional" MR imaging in a two-year follow-up prospective study of 32 early RAMS patients. Manual segmentations of new, enlarged, shrunken, and stable lesions were used to evaluate the performance of the method variants. The true positive rate was estimated for those lesion evolutions in both white matter and cortex. The number of false positives was compared with two strategies for longitudinal analyses. New lesion tissue volume estimation was evaluated using Bland-Altman plots. Wilcoxon signed-rank test was used to evaluate the different setups. Results: The best median of the true positive rate was obtained using LeMan-PV with non-conventional sequences (P < .05): 87%, 87%, 100%, 83%, for new, enlarged, shrunken, and stable WM lesions, and 50%, 60%, 50%, 80%, for new, enlarged, shrunken, and stable cortical lesions, respectively. Most of the missed lesions were below the mean lesion size in each category. Lesion progression maps presented a median of 0 false positives (range:0-9) and the partial volume framework improved the volume estimation of new lesion tissue. Conclusion: LeMan-PV exhibited the best performance in the detection of new, enlarged, shrunken and stable WM lesions. The method showed lower performance in the detection of cortical lesions, likely due to their low occurrence, small size and low contrast with respect to surrounding tissues. The proposed lesion progression map might be useful in clinical trials or clinical routine.