The newly-published Discontinuing Disease-modifying Therapies in Stable Relapsing-onset Multiple Sclerosis (DOT-MS) is the second important trial to examine the feasibility of discontinuing disease-modifying therapy (DMT) in patients with multiple sclerosis (Coerver et al. JAMA Neurol 2025;82:123-131).

The main inclusion criterion was no significant inflammatory disease activity in the previous five years during treatment with an injectable or oral platform therapy. ‘Significant’ was defined as no relapses, no Gd+ T1 lesions and <2 new T2 lesions (or <3 new T2 lesions in the past 10 years). For the primary outcome, significant inflammatory disease activity was differently defined as a relapse and/or >3 new T2 lesions or >2 Gd+ lesions. MRIs were scheduled at baseline and at months 3, 6, 12, 18 and 24.

An unusual aspect was that younger age was not an exclusion criterion. Median age was 54 years. The interquartile range in the discontinuation group was 47-58 years, so about one-quarter of patients were younger than age 47 years. Interestingly, 37% of eligible patients refused to participate in the study and 20 of 45 patients assigned to the discontinuation group did not discontinue or restarted treatment.

The two-year study was terminated early after a median of 15 months due to a recurrence of disease activity in the discontinue group. Overall, 8 of 45 patients (17.8%) in the discontinue group had significant inflammatory activity compared to 0 of 47 in the continue group; 11 of 45 (24.4%) had relapses or any MRI activity. In the discontinue group, the median age of patients with versus without inflammatory activity was substantially lower (46 vs. 54 years).

The results indicate that younger patients, including those treated with a modest-efficacy DMT, may experience a recurrence of inflammatory disease activity if treatment is stopped even if they have been stable for 5-10 years. However, it should be noted that >80% of patients in the discontinuation group had no significant inflammatory activity in the 15 months after discontinuation.

In comparison, in the DISCOMS trial, which limited enrolment to patients aged >55 years, the rate of new relapses/MRI lesions was 12.2% in the discontinue group versus 4.7% in the continue group (Corboy et al. Lancet Neurol 2023;22:568-577). The study was unable to conclude that discontinuation was non-inferior to continuation in older patients. However, during the 40-month extension, neither cohort experienced any relapses. New MRI lesions were uncommon in both the discontinuation (2 of 22 patients) and continuation groups (1 of 30 patients) (Corboy et al. Mult Scler 2025;31:159-173).