Biomarker Synergy in Relapsing Multiple Sclerosis: Neurofilament Light Chain and B Cells in Relation to Disease Outcomes

Background and Objectives Anti-CD20 B-cell–depleting therapies demonstrate robust efficacy in people with multiple sclerosis (pwMS). This study addressed the limited understanding of relationships between B-cell populations before and after treatment with ocrelizumab and outcomes in people with relapsing MS (pwRMS) or primary progressive MS (pwPPMS). Methods Total circulating blood B cells and B-cell subsets were examined at baseline and longitudinally in pwRMS and pwPPMS enrolled in the pivotal Phase 3 trials (OPERA I, OPERA II, and ORATORIO). Relationships to disease outcomes before and after treatment with ocrelizumab or comparators were evaluated using generalized linear models and time-to-event analyses. Results Ocrelizumab rapidly depleted total B cells in pwRMS. Blood samples (n = 15,025) were assessed from 3 Phase 3 trials from 2,370 pwMS, demonstrating depletion in all B-cell subsets. Greater depletion was observed with higher ocrelizumab exposure and longer treatment duration. In limited pwMS with detectable B cells, the majority were mature-naive B cells. Findings from the double-blind treatment period considered robust were that pwRMS with detectable mature-naive, memory, or total B cells had greater risk of developing new/enlarging T2 lesions (odds ratio: 3.8–4.9; p < 0.001), while pwPPMS with higher circulating plasmablasts had greater thalamic volume loss (β: −1.4; p < 0.001). Above-median baseline memory B-cell levels identified interferon beta-1a–treated pwRMS at greater risk of disability progression (hazard ratio: 2.0; p < 0.01), with larger numbers of slowly expanding lesions ( p < 0.01). When interferon beta-1a–treated pwRMS presented both high baseline B cells and high serum neurofilament light (NfL; B cells/NfL high), they showed an even higher risk of disability progression (HR: 3.10; p < 0.001). Treatment with ocrelizumab in this subgroup of pwRMS with B cells/NfL high resulted in a near 4-fold reduction in risk of disability progression (HR: 0.25, p < 0.001). Discussion Ocrelizumab treatment depleted total B cells and all B-cell subsets in an exposure-dependent and duration-dependent manner. PwRMS with detectable on-treatment B cells had greater risk of new/enlarging T2 lesions, suggesting that sustained deep B-cell depletion may be important for preventing disability worsening. High baseline B cells when present with high NfL identified a population at increased risk of disease worsening who could benefit from ocrelizumab treatment.