Can Older MS Patients Stop Their Treatment?

Non-inferiority for discontinuing multiple sclerosis (MS) therapy in patients over 55 with stable disease was not established by a randomized phase IV DISCOMS trial. "Discontinuation of disease-modifying therapy might be a reasonable option in patients older than 55 years who have stable multiple sclerosis, but might be associated with a small increased risk of new MRI activity," John Corboy, MD, MS, of the University of Colorado School of Medicine in Aurora, and co-authors wrote in Lancet Neurology.

The 2-year primary outcome was the percentage of patients with a new disease event—either a relapse, or any new or expanding T2 brain MRI lesion.

"Our study addresses important concerns about the risks and benefits of disease-modifying therapies as people age," Corboy said in a prepared statement. "The primary objective of our study was to identify whether discontinuation is safe to consider for older patients with multiple sclerosis and no recent relapse or new MRI activity, and our goal was to provide an estimate of disease recurrence in this context. This study will aid decision-making when health care providers and people with multiple sclerosis discuss potential disease-modifying therapy discontinuation as patients age."

DISCOMS was a multicenter non-inferiority trial that studied 259 MS patients 55 or older enrolled at a U.S. MS center between May 2017 and February 2020. Median age of the study population was 63, 83% were women, and 89% were White.

All had no relapse in the last 5 years and no new MRI lesion in the past 3 years. Most had relapsing MS (83%), and the last relapse was 13.9 years ago on average.

All participants had been continuously taking an approved MS therapy for 5 or more years. Participants were randomized to continue (n=128) or discontinue (n=131) therapy.

In 73% of the overall cohort, the therapy used was an injectable treatment (glatiramer acetate or interferon beta). Other treatments included teriflunomide (n=8), dimethyl fumarate (n=38), fingolimod (n=18), natalizumab (n=4), and ocrelizumab (n=2).

Baseline Expanded Disability Status Scale (EDSS; range 0-10, higher scores indicate greater disability) scores were 3.3 in the continuation and 3.4 in the discontinuation group.

Relapse assessors and MRI readers were masked to patient assignment. Patients and treating investigators were not masked. Relapse was defined in patients seen within 7 days of onset as a change in the assessed EDSS by the examining clinician.

Eight participants were later found to not meet eligibility requirements and five were lost to follow-up over a median of 24.5 months. Overall, 68% of the patients completed the 2-year study.

Although the number of patients in the continuation versus discontinuation groups with any adverse event (85% and 79%, respectively) or a serious adverse event (16% and 14%, respectively) were similar, there were a greater number of adverse events (347 and 422, respectively) and serious adverse events (30 versus 40, respectively) in the discontinuation group.

The most common adverse events in the continuation and discontinuation groups were upper respiratory infections (15% and 23%, respectively). Three continuation group and four discontinuation group patients had treatment-related adverse events; one in each group was a serious adverse event (relapse requiring hospitalization).

There were three deaths (one in the continuation and two in the discontinuation group). None were thought to be related to treatment.

"Although this study reassuringly showed no increase in relapse rate after stopping disease-modifying therapy, its short follow-up does not allow for conclusions about the long-term effects of discontinuation or the effects of short-term MRI activity on longer-term outcomes," wrote Kristen Krysko, MD, of the University of Toronto in Canada, in an accompanying editorial.

"This limitation is important because, with the availability of high-efficacy therapies in clinical practice, clinicians and patients often aim to reach a state in which there is no evidence of disease activity, as this has been associated with lower odds of long-term disability progression," she added. Given this uncertainty about long-term outcomes, in older adults whose MS is clinically stable on therapy, "uniform treatment recommendations cannot be made from the results of this trial."

Since most participants discontinued interferon beta or glatiramer acetate, results probably do not apply to those discontinuing higher-efficacy therapies, Krysko noted, "especially drugs known to have risks of rebound disease activity on discontinuation, such as natalizumab and the sphingosine-1-phosphate receptor modulators."

Despite these limitations, "DISCOMS is a major contribution to our knowledge of the safety of discontinuing disease-modifying therapy in older adults with stable multiple sclerosis," Krysko wrote.

A 2022 review of aging and MS reported increased risks for side effects caused by some MS therapies. Relapses are also often less frequent with age.

"Although 46% of U.S. adults with MS are aged 55 years or older, most disease-modifying therapies have been approved on the basis of phase III trials with a maximum enrollment age of 55 years," Corboy and colleagues noted.

Limitations included too few participants to evaluate discontinuation of higher-efficacy therapy and the absence of a placebo group.

Although DISCOMS is the first completed trial of therapy discontinuation in MS, others are underway in France and the Netherlands.

This study was funded by the Patient-Centered Outcomes Research Institute (PCORI) and the National Multiple Sclerosis Society (NMMS).

Corboy declared institutional support from PCORI and NMSS for this study; institutional support for research from the NIH, Novartis, and EMD Serono; speaking honorarium from MS Xchange, the University of Chicago, Emory University, Ohio State University, and the European Committee For Treatment and Research In Multiple Sclerosis (ECTRIMS); a fee for sitting on a medical advisory board of Bristol Myers Squibb; being associate editor for Annals of Neurology and former editor-in-chief of Neurology Clinical Practice; and being paid medical director of the Rocky Mountain Multiple Sclerosis Center.

Krysko declared grants from MS Canada; a contract for a study site from Roche; consulting fees from Biogen, EMD Serono, Novartis, and Roche; advisory board membership for Biogen, EMD Serono, Novartis, and Roche; and scientific advisory committee membership for Bristol Myers Squibb.

Corboy JR, et al "Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicenter, randomized, single-blind, phase 4, non-inferiority trial" Lancet Neurol 2023; DOI: 10.1016/S1474-4422(23)00154-0.

Krysko KM "Discontinuing disease-modifying multiple sclerosis therapies" Lancet Neurol 2023; DOI: 10.1016/S1474-4422(23)00200-4.