OBJECTIVES: Patients with RRMS can benefit from disease modifying treatments (DMT) through delayed disease progression and reductions in relapse frequency. For patients who continue to experience disease activity despite DMT, therapeutic options have been limited. Understanding the relative prognosis of these sub-optimally treated (SOT) patients is of considerable interest given the availability of new treatment options. The aim of our study was to evaluate disease progression of SOT and non-SOT patients enrolled to the placebo arm of the FREEDOMS® trial. METHODS: SOT patients were identified as patients who experienced either an unchanged relapse rate, or at least one relapse with additional disease activity observed on MRI, despite treatment with a DMT in the prior year. For each patient group (SOT and non-SOT), Markov state transition matrices were derived. Each matrix evaluated the annual probability of patients transitioning between stages of the Expanded Disability Status Scale (EDSS). Comparisons between patient groups included time to disability greater or equal to (≥) EDSS 4 and EDSS 6, time from EDSS 4 to disability ≥EDSS 6 and mean EDSS score over time. RESULTS: Median time to EDSS ≥4 and EDSS ≥6 was 5.5 [4.5, 7.5] and 9.0 [7.0, 12.0] years in SOT patients, compared with 10 [8.5, 12.0] and 18.5 [16.0, 22.5] years in non-SOT patients. Median time from EDSS 4 to disability greater than EDSS 6 was 3.4 [1.8, 5.4] years in SOT compared to 5.3 [3.5, 8.0] years in non-SOT patients. Mean EDSS scores at 2, 5 and 10 years post-onset were estimated at 1.05, 2.55 and 3.21 for SOT and 0.95, 2.13 and 3.07 for non-SOT, respectively. CONCLUSIONS: The analysis suggests that RRMS patients who experience relapse and MRI activity despite previous treatment with a DMT face faster progression to severe disability states. The analysis highlights the importance of effective treatment options for these patients.