Weighing Disease-Modifying Therapy Discontinuation in Older, Stable Patients With MS

For decades, the standard approach to multiple sclerosis (MS) management has centered on indefinite use of disease-modifying therapy (DMT) once treatment begins. That assumption has increasingly been challenged as clinicians confront an aging MS population, accumulating drug exposure, and a growing body of observational and randomized data examining who might safely stop treatment.

Age, time since last relapse or MRI activity, and years since disease onset have emerged as central factors shaping the risk-benefit calculus of discontinuation, though clinicians continue to grapple with how much residual risk is acceptable and for whom. At the 2026 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 27-29, Charlotte, North Carolina, John Corboy, MD, professor of neurology at the University of Colorado, presented data from DISCOMS and comparable controlled studies evaluating outcomes in patients who stop DMT after a prolonged period of stability.^1-3

Following his presentation, NeurologyLive^® sat down with Corboy to discuss how these findings are shaping clinical conversations about DMT withdrawal in older patients. In the conversation, he talked about the factors most predictive of a favorable outcome off therapy, and the questions that remain unanswered, including long-term follow-up data, drug-specific discontinuation risk. Corboy also shared his clinical perspective on the potential role of de-escalation strategies such as extended dosing intervals for CD20 therapies in older patients with MS.

NeurologyLive: How have findings from DISCOMS and other controlled discontinuation trials influenced your approach to discussing DMT withdrawal with older, clinically stable patients with MS?

John Corboy, MD: This has evolved over the course of the last 25 years or so, but there's now, a stronger feeling that there are subpopulations of people, especially as they age, who may do well off of DMTs. There have been several observational trials, as well as now randomized control trials and propensity-matched emulation trials, which have tried to flesh out who those patients might be. It's become clear that older individuals, perhaps over the age of 60 years, who haven't had recent disease activity, with an MRI scan change or relapse, are the ones likely to have the best outcome should they choose a trial off medication.

But we've also learned that even in patients who are over the age of 60 years and who haven't had disease activity for a good period, over 10 years, there's still a low risk of some new, mostly MRI activity. One of the major questions is: what does that mean, and how does that change someone's thought process when they're considering a trial of discontinuing DMTs? Although it remains an ongoing disease process, it just dwindles and dwindles over time, and the question becomes: when is the risk of the medication worse than the risk of the disease?

In your view, what clinical factors are most important when determining whether a patient with MS may be an appropriate candidate for discontinuing DMT?

One is just age. Age is a major factor. It's been known for many years that as people age, the longer the time since last disease activity, the better off. Some people have onset age 50, some people have onset age 15, and so disease onset time, the longer it is, the better off. Older individuals have a better opportunity, potentially, to go off DMY. Then, perhaps, which DMT you're on may make a difference as well. Some may be higher risk, especially the so-called cell-trafficking agents like fingolimod or natalizumab, and others may be much lower risk. For example, the CD20 drugs like ocrelizumab, rituximab, and ofatumumab are perhaps less likely to have that issue or may have a more extended period before it shows up, as may, for example, alemtuzumab or cladribine.

I went to talk at this meeting looking at stem cell therapy and depending on how the stem cell therapy is done, you may not need to use a DMT at all afterward. So that may play a role too, which medication you're talking about. There are also probably a lot of factors we don't know: are genetics involved, things like that. There's still quite a bit to learn about what the risks are, but the risks will diminish, at least with regard to having new relapses and new scan changes. What we've also learned from the more recent studies is that discontinuation of DMT in the older, stable patient probably doesn't have much impact on progression of disability. That is, individuals who stay on the medications versus people who go off the medications, who have otherwise been stable.

In our study, the DISCOMS study, as well as the DOT-MS study from the Netherlands, there was no difference between people who discontinued and those who continued with regard to disability progression, in that population of people who'd been relatively stable with regard to relapses and scan changes for a prolonged period. We still, though, have people who do progress, and we need therapies for those individuals. The hope is that some of the drugs being studied now will have a much larger impact on progression of disability. That will be especially important as people age, because that's when people accumulate a lot of disability, say after the age of 45 or 50 years. It's not uncommon for people who've started progressing to accumulate that over time, and that's the greatest unmet need. I think our studies and others have shown that whether medications are continued or not probably doesn't matter for that population.

What unanswered questions remain following DISCOMS and similar studies, particularly regarding long-term outcomes after DMT discontinuation in routine clinical practice?

The number one thing we probably need is longer-term data. A lot of the studies, the randomized control trials especially, only go out to about 2 to 3 years. It could be that with longer follow-up, we'd see the curves separate out, maybe there is more significant disease activity in those who discontinue. A related issue is whether there's ongoing benefit for people who stay on the drug, because we have very little data on people over the age of 55 years as to whether these drugs do anything for them. We'll also learn more about the risks of ongoing long-term use in the older-age population, which we also still don't have enough of.

Another related topic: in the DISCOMS study, as well as in the DOT-MS study, both showed that the main difference between those who continued and those who discontinued was a small number of new MRI lesions. The question is, what impact does that have on patients' real day-to-day life over time? What impact does it have on disability progression over time? In younger patients, 1 or 2 new lesions on a brain MRI a year or 2 years after starting a medication doesn't have any impact on their level of disability 5 to 10 years later. So, is that also true in the older-age population? We don't know. We need studies that look explicitly at those with no new disease activity versus those with minimal evidence of disease activity versus those with overt new disease activity. What do they really look like 5 years later? That's a major question.

Then also trying to understand the differences between medications. Is it really true, as suggested by one French study published a couple of years ago, that even in this older-age population, stopping natalizumab or fingolimod is associated with more new disease activity? Is that really true in other populations? That population was very different from the MS STAT or DISCOMS populations. They were much more disabled and had used many more different medications, having really failed multiple medications. That wasn't true in the MS STAT population, and not true in the DISCOMS population. So, can we do studies in populations that are really older or quite stable, have them go off those drugs, and see whether that's safe or not? That's another major question.

Of course, there is also what's going to happen with the newer medications? One other big area: the CD20 drugs like ocrelizumab, ofatumumab, rituximab, obinutuzumab, are very prominent in today's world. The question is, can we maybe not necessarily discontinue those, even in younger patients, but really spread out the infusions or injections they receive? There's some data suggesting you can actually get a benefit from 1 to 2 years out from each infusion, say with ocrelizumab or rituximab. Can we mitigate some of the risks that accumulate over time by just giving less medication over time? The whole concept of de-escalation, even very early in the use of these medications, could really change the trajectory of how we use them, change the cost issues, change the risk issues, infection issues, etc. There's a lot to be learned there.

Transcript edited for clarity. Click here for more coverage of CMSC 2026.

REFERENCES
1. Corboy J. Disease Modifying Therapy Discontinuation in MS: DISCOMS and other Controlled Trials. Presented at: 2026 CMSC Annual Meeting; May 27-29; Charlotte, North Carolina.
2. Corboy JR, Fox RJ, Kister I, et al. Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial. Lancet Neurol. 2023;22(7):568-577. doi:10.1016/S1474-4422(23)00154-0
3. Coerver EME, Fung WH, de Beukelaar J, et al. Discontinuation of First-Line Disease-Modifying Therapy in Patients With Stable Multiple Sclerosis: The DOT-MS Randomized Clinical Trial. JAMA Neurol. 2025;82(2):123-131. doi:10.1001/jamaneurol.2024.4164