RCT: Discontinuing First-Line DMT in Long-Term Stable Relapsing MS Leads to Recurrence of Disease Activity

Background: Increasing numbers of patients with relapsing-onset multiple sclerosis (MS) are receiving first-line disease-modifying therapies (DMTs) to control inflammatory lesions and reduce disability progression. Yet, extended therapy raises questions regarding overtreatment, adverse effects, and costs, especially in older or clinically stable individuals.

Objective: This randomized, multicenter, rater-blinded clinical trial (DOT-MS) assessed whether discontinuing first-line DMT in adults with MS who had at least five years of clinical and radiological stability is safe in terms of recurrence of significant inflammatory disease activity.

Methods: Eighty-nine participants (median age 54 years, 67% female) were randomly assigned 1:1 to either continue or discontinue their first-line DMT. Inclusion required relapse-onset MS without new, sizeable brain MRI lesions (≤1 new T2 lesion in the previous five years or ≤3 new T2 lesions in the past ten years). Follow-up included clinical evaluations, gadolinium-enhanced brain MRI at baseline and months 3, 6, 12, 18, and 24, and optional unscheduled visits. The primary endpoint was significant inflammatory disease activity, defined as clinical relapse and/or ≥3 new T2 lesions or ≥2 contrast-enhancing lesions. The trial was prematurely terminated by the data safety monitoring board due to higher-than-expected disease activity in the discontinue arm.

Results: After a median follow-up of 15.3 months, none of the 44 participants in the continue group had significant disease activity, versus 8 of 45 (17.8%) in the discontinue group (95% CI for difference, 0.09–0.32). Nearly all events were MRI-detected new or enhancing lesions, though two participants experienced clinical relapses. Most individuals with reactivation were able to regain stability upon DMT reintroduction. Serum neurofilament light levels rose during episodes of inflammatory activity, but neither NfL nor GFAP levels reliably predicted disease recurrence at baseline. No difference in serious adverse events emerged between groups.

Conclusions: In this trial, discontinuation of first-line DMT in long-term stable MS was associated with a significant risk (about 20%) of inflammatory reactivation, particularly noted in participants under 55 years old. As a result, close clinical and MRI monitoring should be mandatory if discontinuation is attempted, with early DMT reinitiation if necessary.

Implications for Practice: Clinicians may consider stopping first-line DMT in select patients who exhibit prolonged stability, especially in older adults, but must remain vigilant. Rapid detection of any radiological or clinical sign of reactivation is crucial, as reintroducing therapy may reestablish disease control.

Study Strengths and Limitations: Strengths include its randomized design, systematic imaging schedule, and thorough biomarker sampling. Limitations involve early trial termination, restricting subgroup analyses and definitive noninferiority testing. Routine spinal cord imaging was not performed, potentially underestimating subclinical disease activity.

Future Research: Longer-term observational follow-up is ongoing to clarify how these participants fare over time and to identify biomarkers that may better predict risk of rebound activity. Evaluating cost-effectiveness and long-term clinical outcomes will guide future decisions about DMT discontinuation.

Reference: Coerver EME, et al. Discontinuation of First-Line Disease-Modifying Therapy in Patients With Stable Multiple Sclerosis: The DOT-MS Randomized Clinical Trial. JAMA Neurology. 2024. DOI: http://doi.org/10.1001/jamaneurol.2024.4164