Currently, the most promising prognostic biomarkers for the prediction of conversion from CIS to clinically definite MS are CSF and serum levels of NfL (due to the large number of confirming studies), CSF levels of IgG-OCB, the kFLC kappa index and CHI3L1, and serum levels of vitamin D. Conversely, there are very few molecules that have been proposed to assess the disability accrual over time and to predict the conversion from RRMS to SPMS, thus this clinical step is still very tricky, and it still needs exploration. This evidence concerns the gene NEFL and in situ carcinoma.