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WEST PALM BEACH, Fla. — Discontinuing disease-modifying therapies (DMTs) for multiple sclerosis (MS) after prolonged disease stability poses minimal risk for patients aged > 60 years, highlighting the importance of weighing the potential harms of continued treatment when counseling patients on long-term disease management, new data suggest.

For older patients considering discontinuing treatment, the primary concern is often the risk for relapse or renewed disease activity. However, research presented by John R. Corboy, MD, professor of neurology and former director of the Rocky Mountain MS Center at the University of Colorado Anschutz, Aurora, Colorado, suggests this risk is likely low in those who have been on stable therapy with minimal or no recent disease activity. 

However, the risk is not entirely eliminated, whether patients discontinue or remain on therapy, he noted. Therefore, older patients with stable disease should carefully weigh the risk/benefit ratio of both options.

A Highly Individualized Decision

Corboy noted that the relative risks and benefits are especially relevant for patients on high-efficacy therapies like alemtuzumab or natalizumab, which are closely linked to significant immune suppression. Ultimately, the decision to discontinue or continue treatment is highly individualized and should be guided by patient concerns and goals.

Importantly, there is no age at which a patient with stable disease can be told they have no risk for relapse, said Corboy who reviewed the evidence on February 27 at a presentation at the Americas Committee for Treatment and Research in Multiple Sclerosis Forum.

Before outlining the current data, Corboy cautioned that many older MS patients may not be waiting for formal discussions about risks and benefits before discontinuing treatment. According to data from North American Research Committee on Multiple Sclerosis registry, only 40% of MS patients aged > 60 years in the United States are still on DMTs, with even lower proportions reported in other registries.

Conversely, some surveys suggest that while a smaller group, a significant proportion of older patients are unwilling to discontinue therapy, Corboy noted. He added that this may reflect two distinct patient populations, one open to stopping treatment and another firmly opposed — even before the discussion with a healthcare professional begins.

Of the four randomized controlled trials (RCT) designed to explore the safety of discontinuing DMT, two have been completed. The first, DISCOMS, was led by Corboy. Published in 2023, the multicenter, randomized, rater-blinded noninferiority trial enrolled 259 patients 55 years of age or older. Entry criteria included no relapses on stable DMT for ≥ 5 years with no new MRI activity within 3 years.

The study missed the 8% noninferiority margin for the primary endpoint of no new relapses and no new expanding T2 lesions, but not by much. At 2 years of follow-up, most activity involved minor changes on MRI, said Corboy.

“If we had evaluated relapse activity alone, it would have met the noninferiority endpoint,” said Corboy, whose 18-month follow-up study, published last month, also showed very little activity in the discontinued arm over this longer time period.

The second randomized study, DOT-MS, differed from DISCOMS in many important ways. For instance, the study was not restricted to older patients, and it employed slightly but meaningfully different criteria for the primary outcome of disease activity.

In a noninferiority trial, DOT-MS was terminated early when a higher proportion of patients had disease activity in the discontinuation arm (17.8% vs 0%) at a median follow-up of 15.3 months.

“A younger age [median 54 years vs mean 63 years] and shorter time since last relapse [median 9 years vs mean 14 years] likely accounted for the greater disease recurrence” in this study relative to DISCOMS, Corboy said.

Two more randomized trials being — one enrolling patients with progressive MS and the other with relapsing MS — are underway, but Corboy turned to an observational propensity-matched study to consider the question of risk for relapse after discontinuing a high-efficacy DMT.

In addition, in the observational study, which used data from 1620 patients aged ≥ 50 years to create two propensity-matched groups of 154 patients each, the comparison for time to relapse was between those discontinuing or continuing natalizumab, fingolimod, or the anti-CD20 therapies rituximab or ocrelizumab. All had nonactive disease for at least 2 years.

Over a mean follow-up of 2.5 years, patients who discontinued natalizumab or fingolimod experienced a faster time to relapse compared to those who continued treatment. In contrast, after propensity matching, the time to first relapse did not differ significantly between patients who discontinued or continued anti-CD20 therapies.

To better inform older patients considering DMT discontinuation, several key data gaps remain, said Corboy. These include insights on discontinuation in patients with progressive MS, the potential role of biomarkers in guiding risk assessment, and whether de-escalation strategies can help minimize the risk for disease activity after stopping treatment.

Better Quality of Life?

While awaiting more data, Corboy emphasized the importance of balancing the risks of discontinuing therapy with those of staying on DMT, including potential side effects. He noted that some studies have even suggested improved quality of life in patients who chose to discontinue treatment.

If patients choose to discontinue treatment, MS disease management does not end, Corboy cautioned. He emphasized the need for continued monitoring after stopping therapy. If disease activity resumes, restarting DMT can be considered. Corboy also noted that, in his experience, insurance coverage has not been a barrier to resuming treatment.

Nancy L. Sicotte, MD, Chair of the Department of Neurology at Cedars-Sinai Medical Center at Los Angeles, agreed with most of these points. In her own center, she said the approach is “very individualized.”

Like Corboy, she said that it is reasonable to recognize and discuss the risks of remaining on DMTs in older patients with stable disease, particularly in those taking high-efficacy agents. She said the risks of these agents are greater in older individuals, particularly those with comorbidities.

Like Corboy, she emphasized that disease management does not end when patients stop treatment.

“We always monitor patients after they discontinue therapy,” said Sicotte, who warned that there can be surprises in regard to relapses and renewed signs of disease.

She also highlighted the potential role of treatment de-escalation as a step toward full discontinuation, especially for high-efficacy agents linked to rebound effects. She emphasized the need for more research on the relative effectiveness of different strategies, including de-escalation, to minimize the risk for renewed disease activity after stopping treatment.

The DISCOMS study received funding from EMS Serono. Corboy reported no other potential conflicts of interest. Sicotte reported a financial relationship with Biogen.