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ImportanceMost patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS.ObjectiveTo evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT.Design, setting, and participantsHematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled.InterventionsAutologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT.Main outcomes and measuresThe primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events.ResultsGrafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4% (90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9% (90% CI, 73.7%-97.1%) and 86.3% (90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores.Conclusions and relevanceAt 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.

Background: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing–remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. Objective: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. Methods: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. Results: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1–98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%; p < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13–0.20). Conclusion: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS. [ABSTRACT FROM AUTHOR]

Background: Diroximel fumarate (DRF) is a novel oral fumarate approved in the USA for relapsing forms of multiple sclerosis. DRF is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of monomethyl fumarate and are therefore expected to have similar efficacy/safety profiles; the distinct chemical structure of DRF may contribute to its tolerability profile.Objectives: The objective of this study was to compare the gastrointestinal tolerability of DRF and DMF over 5 weeks in patients with relapsing-remitting multiple sclerosis.Methods: EVOLVE-MS-2 was a phase III, randomized, double-blind, head-to-head, 5-week study evaluating the gastrointestinal tolerability of DRF 462 mg vs DMF 240 mg, administered twice daily in patients with relapsing-remitting multiple sclerosis, using two self-administered gastrointestinal symptom scales: Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and Global Gastrointestinal Symptom and Impact Scale (GGISIS). The primary endpoint was the number of days with an IGISIS intensity score ≥ 2 relative to exposure. Other endpoints included the degree of gastrointestinal symptom severity measured by IGISIS/GGISIS and assessment of safety/tolerability.Results: DRF-treated patients experienced a statistically significant reduction (46%) in the number of days with an IGISIS symptom intensity score ≥ 2 compared with DMF-treated patients (rate ratio [95% confidence interval]: 0.54 [0.39-0.75]; p = 0.0003). Lower rates of gastrointestinal adverse events (including diarrhea, nausea, vomiting, and abdominal pain) were observed with DRF than DMF (34.8% vs 49.0%). Fewer patients discontinued DRF than DMF because of adverse events (1.6% vs 5.6%) and gastrointestinal adverse events (0.8% vs 4.8%).Conclusions: DRF demonstrated an improved gastrointestinal tolerability profile compared with DMF, with less severe gastrointestinal events and fewer days of self-assessed gastrointestinal symptoms, fewer gastrointestinal adverse events, and lower discontinuation rates because of gastrointestinal adverse events.Clinical Trials Registration: ClinicalTrials.gov (NCT03093324). [ABSTRACT FROM AUTHOR]

Background: Low exposure to ultraviolet radiation (UVR) from sunlight may be a risk factor for developing multiple sclerosis (MS). Possible pathways may be related to effects on immune system function or vitamin D insufficiency, as UVR plays a role in the production of the active form of vitamin D in the body. Objective: This study examined whether lower levels of residential UVR exposure from sunlight were associated with increased MS risk in a cohort of radiologic technologists. Methods: Participants in the third and fourth surveys of the US Radiologic Technologists (USRT) Cohort Study eligible (N = 39,801) for analysis provided complete residential histories and reported MS diagnoses. MS-specialized neurologists conducted medical record reviews and confirmed 148 cases. Residential locations throughout life were matched to satellite data from NASA's Total Ozone Mapping Spectrometer (TOMS) project to estimate UVR dose. Results: Findings indicate that MS risk increased as average lifetime levels of UVR exposures in winter decreased. The effects were consistent across age groups <40 years. There was little indication that low exposures during summer or at older ages were related to MS risk. Conclusion: Our findings are consistent with the hypothesis that UVR exposure reduces MS risk and may ultimately suggest prevention strategies. [ABSTRACT FROM AUTHOR]