For Older Patients With Multiple Sclerosis, Discontinuing Disease-Modifying Therapy May Be an Option

Discontinuing disease-modifying therapy (DMT) for multiple sclerosis (MS) appears to be a reasonable option for older patients with no relapses or MRI activity during the previous five years, conclude investigators with the multicenter DISCOMS trial. After assessing 259 patients randomized to continue or discontinue DMT for up to two years, they found only a small increased risk of new MRI activity following discontinuation. The study was published in Lancet Neurology (2023;22:568-577).

“In this noninferiority trial, we could not conclude with certainty that discontinuing DMT is noninferior to continuation,” says co-author Robert Fox, MD, “but most of the difference between the two groups was from more patients who discontinued DMT developing one or two new or enlarging brain MRI lesions, which may or may not have clinical significance.” Dr. Fox is a staff neurologist with Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research.

Does the risk-benefit ratio of DMT rise with age?

Whether and when patients with MS can safely discontinue DMT is a long-debated and unanswered question. Most evidence on this subject is from younger patients ― who are at higher risk of relapse than patients who have had the disease for decades ― and not from randomized controlled trials. Furthermore, most clinical trials leading to approval of the various DMTs excluded patients older than 55 years, so evidence of benefit for this group is sparse.

The safety of continuing with DMT in older patients is also unclear: infectious and other risks of DMTs likely increase with age. Finally, the financial costs of DMT can be substantial.

DISCOMS, the first randomized controlled investigation of DMT discontinuance in MS, was designed to study a population that was likely at low risk of disease recurrence and with limited evidence of benefit from continued DMT use.

Study design and results

The study, conducted at 19 sites in the U.S., randomly assigned 259 patients between May 2017 and February 2020 to continue their existing DMT regimen (n = 128) or to discontinue DMT (n = 131). All patients had confirmed MS (of any subtype), were at least 55 years old (average age was 64 years in each group), and had no relapse within the prior five years and no new MRI lesion in the prior three years while taking a DMT. Relapse assessors and MRI readers were blinded to patient assignment, but patients and treating investigators were not, owing to the logistical challenges of creating placebos for the various drugs patients were taking.

The primary outcome measure combined clinical criteria (indications of a relapse) and imaging criteria (any new or expanding brain MRI lesion) over two years. The statistical analyses assessed noninferiority, with a predefined noninferiority margin of 8%.

Key results were as follows (over mean follow-up of 22.4 months):

• The primary outcome was met by 6 DMT continuers (4.7%) versus 16 DMT discontinuers (12.2%).
• The absolute difference in the primary outcome was 7.53 percentage points (95% CI, 0.63-15.00), which was not noninferior (i.e., stopping might be inferior to continuing).
• The absolute difference in relapse rates between the two groups was 1.5 percentage points, a difference that met the standard for noninferiority (i.e., it was not inferior).
• The absolute difference in development of a new or expanding T2 lesion was 6.78 percentage points (95% CI, 0.25-13.81), which indicated that noninferiority could not be concluded (i.e., stopping might be inferior to continuing).
• The absolute difference in the proportion of patients with confirmed clinical progression (defined by Expanded Disability Status Scale scores) was 1.2 percentage points (11.11% among continuers vs. 12.31% among discontinuers), which was not statistically significant.

Numbers of adverse events and serious adverse events were similar between the two groups. Three continuers and four discontinuers were determined to have treatment-related adverse events (one in each group was a serious event).

Clinical takeaways

“Although discontinuers had a slightly higher rate of MRI changes, clinical relapses and progression did not appear to differ between groups,” says Dr. Fox. “Given the results, DMT discontinuation can reasonably be considered as an option for patients older than 55 years who have had stable MS for five years.”

Dr. Fox notes that most of the study participants were taking older injectable medications that are known to be less effective than more modern ones, some of which are known to associated with significant risk of rebound upon discontinuance. “The results may not be applicable to patients on more contemporary drugs,” he cautions.

He adds that additional important data on this subject are expected shortly, with an extension of this trial underway and two randomized controlled discontinuation trials being conducted in Europe.

“Clinicians and their older patients sometimes consider the possibility of stopping DMT,” Dr. Fox says. “The DISCOMS trial provides concrete data on what can be expected when these patients stop and thus informs that conversation. In this study, there was a small difference in MRI activity in those who stopped DMT, suggesting that stopping might be inferior to continuing, although the clinical relevance of one or two new MRI lesions over a couple years is not fully clear. For patients who stop therapy, clinical and MRI monitoring can identify the return of disease activity in the rare case when it returns.”