Multiple Sclerosis Podcast

Should We Discontinue Medications in Older Patients With Multiple Sclerosis?

Anne H. Cross, MD; John R. Corboy, MD

Disclosures

November 03, 2022

This transcript has been edited for clarity.

Anne H. Cross, MD: Hello. I am Dr Anne Cross, and welcome to Medscape's InDiscussion series on multiple sclerosis (MS). Although many MS patients are diagnosed in their twenties and thirties, the entire population of people with MS in the United States is getting older due to many factors, including a longer life expectancy with MS, better disease-modifying therapies, and better healthcare in general. A health claims data analysis of 45% of the US MS population done by Mitch Wallin and colleagues and published a couple of years ago showed a shift toward older adult MS patients. And in fact, the peak prevalence of MS was observed in those aged 55-64. However, in most of the clinical trials leading to the approvals of various MS disease-modifying therapies, the upper age cutoff was 55, and the median age of people in those trials was typically in the thirties. So, as a result of the near normal life expectancy in MS patients, the number of adult patients who are older is expected to continue to increase. This brings up the idea of discontinuing disease-modifying therapies in older MS patients — in particular, those who have been stable without MS relapses for many years. Currently, there are three trials underway to try to answer whether it is safe to discontinue disease-modifying therapies. We're fortunate today to have Dr John Corboy as our guest. He started the first one of these trials, and it has just recently been completed. He'll talk to us about that. Dr Corboy is a professor of neurology, executive vice chair of neurology at the University of Colorado School of Medicine, and medical director of the Rocky Mountain MS Center. Welcome, Dr Corboy.

John R. Corboy, MD: Thank you very much for having me, Anne. I'm very happy to be here.

Cross: I'd like to start out by learning a little bit about you. What led you into medicine and neurology and, specifically, MS?

Corboy: You know, like many people, I had a significant interest in biology and chemistry growing up. But most importantly, my mother always wanted me to be a doctor. So even though I was in a graduate program at UCLA in anthropology — actually, physical anthropology — my interest then was in the evolution of brain and behavior. When I realized that maybe medicine was a better choice for me, it was a natural fit for me to go into neurology. I had the good fortune to have Arthur Asbury as my attending physician in my very first rotation in neurology. He is one of the godfathers of American neurology and literally wrote the book on clinical neurology — one of them. And so, some of this was just happenstance. I also happened to run into tremendous neurology people where I trained at the University of Pennsylvania. After that, I got interested in MS again, in part because of my interest in virology. For many individuals especially in the last 30-40 years who went into MS work clinically, they were virologists because there was a strong concern, or at least hints, that MS may be in part related to various infections. That's playing out over time with new data on Epstein-Barr virus infection playing a very significant role — maybe not a causative role but certainly necessary, if not sufficient, to be associated with the development of MS. Like many people, I was trained in this mode at my fellowship at Johns Hopkins, and it was natural to continue doing this kind of work at the onset of my career. I started the University of Colorado MS Center in 1997, and after that, it's all been downhill.

Cross: You mean uphill. Or anyway, in a good direction.

Corboy: Yeah, that's right.

Cross: You recently completed this multicenter trial looking at disease-modifying therapy discontinuation in older adults with MS. I'd like to know why you started this trial and why you proposed it.

Corboy: As you mentioned, Anne, a big part of it is that there is a fairly significant disconnect between what we saw in terms of an aging population. I've been in the same location, as you have, for many years now. Many of my patients have gotten older, and we've seen how things have developed with their MS during the treatment era. But more importantly, natural history of MS has been well defined, and relapses and new MRI scan lesions diminish with age. In addition, there's a significant amount of observational data that show the people who benefit the most from the presently available disease-modifying therapies are younger patients and the ones who don't have recent MRI activity or recent relapse activity. Unfortunately for the patients who develop progressive MS as they age, it looks like the therapies presently available are not as useful as we would like them and need them to be. There is this confluence of the natural history of MS, understanding the aging population, and the fact that large numbers of these studies for approval of disease-modifying therapies have been completed in people under the age of 55. All of this led to the question of whether or not it made sense to continue to use disease-modifying therapies in patients older than 55 because we just don't have data showing efficacy, and there's natural history data suggesting it may not be necessary.

Cross: I believe your study was called Discontinuation of Disease Modifying Therapies in Multiple Sclerosis — DISCO-MS or DISCOMS. What were the criteria to enroll in your study?

Corboy: The main criteria were that you had to be 55 or older with no relapse or new MS disease activity for at least the last 5 years and have no new MRI lesion for at least the last 3 years while continuously using one of the standard FDA-approved disease-modifying therapies. We had a couple of exclusions for long-acting drugs or drugs that had very little usage in the United States, such as alemtuzumab. These were the primary criteria. Of the people who ended up in the study, the mean age was 63, and 83% were women. Almost 90% were White. The majority, about 83%, had relapsing remitting MS. That is, we would accept people with progressive MS or relapsing MS, but most had relapsing MS, and they could be on any of a number of different disease-modifying therapies. About 73% were on the older injectable drugs — one of the interferons or glatiramer acetate. A smaller number of them were on dimethyl fumarate or one of the newer therapies, such as the monoclonal antibodies or fingolimod. So, it was a wide range of different therapies and about eight different classes of medications, but the majority, 73%, were on the older injectable medicines and majority were White women — even more so than in some of the routine studies we've seen with MS.

Cross: Was it difficult to convince other neurologists or patients to take part in this study?

Corboy: I think it was both. The reality is that we tried to include sites throughout the United States, so we could get the widest, most diverse population possible. We asked all the usual suspects, if you will, for people who have contributed to a variety of different studies. People who are very good at doing these studies and three or four well-known large centers said they didn't think they could participate, in part because of two things. One, their populations had really never brought it up as an issue. Two, some of the investigators, and especially some of the younger investigators interestingly enough, were uncomfortable with the idea of taking people off medication. I think it is notable that the younger investigators seemed to be more concerned because they may have been raised in an environment where people always got treated. They didn't have an opportunity to see a lot of older patients and people who had never been treated and see how they did over time, so their view of the world was a little bit different.

Importantly for the patients, we did a side study. We did an interrogation of NARCRMS, the North American Registry for Care and Research in Multiple Sclerosis, which is 30,000-plus people who have MS who regularly contribute to a variety of different surveys. We surveyed 1000 people, got almost 400 responses, and asked these people a simple question. These are people who looked very much like the people in our study — that is, over the age of 55, many using older injectable medications, and all on medication. We asked them the question, "Would you be willing to consider a trial off of disease-modifying therapies if you're presently on them?" It was remarkable because 66% said they would not, about 20% were neutral and could go either way, and only about 12% or so said they would be willing to consider a trial off of disease-modifying therapies. We knew as we were beginning this study that there was a significant concern, especially among people whose disease is stable — that if it wasn't broken, why try to fix it? If your disease is stable, you're tolerating your medication, and you've been on your medication for a long period of time — for sure 15 or 20 years for the older injectable medicines — why would you stop if you're stable? That really was a hindrance. We can see this because we screened over 5500 people to obtain 259. A total of 128 were randomized to stay on their drug, and 131 were randomized to go off their drug. It took quite a few people. Many of them, of course, didn't fulfill the inclusion criteria, but many just elected not to participate. It was a barrier.

Cross: Yes, I can attest to that, because as you know, I was at one of the study sites, and I had quite a lot of difficulty convincing people to participate. Some people were worried that if they had a problem, they wouldn't be able to get back on their drug because insurance might say they didn't need it any longer. You did the first study and it's completed. Are you able to share any of the initial results from the DISCOMS study?

Corboy: Sure, I'd be happy to share the results. As I mentioned, we randomized 259 people almost evenly between the two groups of individuals who went into the study. A couple of things I didn't mention that are of note — the average time since disease onset was about 22 years. Interestingly, the average time since the last documented relapse was almost 14 years. These people were quite stable on their disease-modifying therapies, and in addition, they had a moderate level of disability. We have a ten-point scale called the EDSS (Expanded Disability Status Scale), and on that scale, the average was a little bit over three, which suggests that there was a moderate amount of disability but not necessarily any significant gait impairment yet. On average, people were sort of entering into a phase of potential gait impairment. I mentioned that the average age of people in the study was 63. We had people well up into their seventies, so from an age point of view, it was a pretty broad group and mostly patients with relapsing MS. The average amount of follow-up time was about 22.5 months. It was a little bit longer in those who were on medications compared to those who went off medications, but it was not statistically different.

At the 22-month follow-up, we looked at a variety of different outcomes, and the primary outcome was whether or not someone had a new documented relapse or if they had a new brain MRI scan lesion. Patients were monitored every 6 months. They had a baseline MRI scan done prior to their entry, and it had to be proven to have no new activity. They had a scan at 6 months, 12 months, and 24 months. We asked people to have contrast with the MRI, so we could see if there was so-called enhancement leakage of the dye into the brain after its injection. But we knew that many people would not be doing that because it had become the standard in the United States over the last 5 or 6 years to use much less contrast. We did not include the enhancing lesions as a primary outcome measure, but we did look at this a little bit.

The primary outcome measure was any new relapse or any new scan change. We also looked secondarily at confirmed disability progression on the EDSS — that is, if you measured someone, they had a change, and it was confirmed as persistent 6 months later. We also looked at a variety of different quality-of-life measures, symptom measures, and other measures such as these. Interestingly, something that's not often asked, which is satisfaction with treatment at various times, we asked every 6 months, including at baseline and at the end of the study. We did this to get an idea of people's happiness with how they were doing and the satisfaction they had in a trial off medication.

Patients were seen every 6 months. We measured the different outcomes, and we interestingly did something called a noninferiority approach. We tried to look at not whether one condition was better than the other — that is, if you're on or off medication. Since there is a standard of care, which is staying on the medication, was it inferior or not inferior to go off the medication? Statistically, this is a slightly different question. You ask ahead of time, not after the fact, what the margin of error is that you would accept. If we anticipated 2% of people would have a new event, a relapse, or a scan change, how close did we have to be to that 2% to say it was not inferior. We predetermined that a margin of up to 8% would be considered reasonable and if it was 2% in the continued medication group, we would accept up to 10% within the confidence limits. That is 95% confidence limits. That is the error margin, if you will, and that would be considered noninferior.

We looked at the primary outcome measure, and of 128 people who continued medication, six had a new event, one had a relapse, and five had at least one new scan change. Among the discontinued drug group, that number was 16 of 131, or 12.21%. The margin was within 8%. But if you look at the confidence limits, the error margin around it was outside of that. We could not show that it was inferior, but further, we could not demonstrate that it was noninferior. The main conclusion is that it could be inferior. When we looked at only relapses, there was one relapse in the continued group and there were three among the discontinued drug group. This was not statistically different. The major difference that occurred between the groups was that the number of people with one or two new brain lesions on their scans. Of the 22 events, six were in the continued drug group and 16 were in the discontinued drug group. Fifteen of those 22 events were in people who simply had one or two new dots on their brain MRI scan over the 22 months of the study.

The clinical significance of one or two new lesions is not exactly clear, but that was where the major difference was. We also looked at enhancing lesions — again, this was not part of the primary outcome measure because at a maximum, only 83% of people got the contrast injection. By the 24th month, only about 60% had new enhancing lesions, and six people who had a scan had new enhancing lesions. Interestingly, all of these occurred in those who went off their disease-modifying therapy. And interestingly, two of these individuals did not have a little white dot on their brain scan on the flare images; they had an enhancing lesion independent of that. A small number of people had enhancing lesions, but they were all in the discontinued drug group.

I would conclude from this for the primary outcome measure that, clinically, there was not much difference, but there's probably an increased risk of having new disease activity on the MRI scan. And then the question is, is it significant enough that someone would want to stop or consider going off their medication? Or is it modest enough that someone would say they can accept the risk in this context. When we looked at the secondary outcome measure, which was progression of disability, it was 11% in the continued drug group and 12% in the discontinued drug group, and there was no statistically significant difference. In addition, the vast majority of people who had progression of disability were not those with progressive MS when they went entered the study — 83% of the people with progression of disability actually had relapsing MS. And the vast majority of them, or 28 of the 30 people who had progression of disability, had it completely independently of the primary outcome measure. That is, they had no relapse, and then they had no new scan change.

We've now learned in the last several years that this progression, independent of relapse activity, is very prominent, not just in older individuals, but also in younger individuals. Most of the progression in the younger patients when they have relapsing MS is independent of relapse activity, and it persists throughout their lifetime. That's one of the interesting side findings we saw in this study. Other things we looked at in terms of quality of life and symptom measures were no different between the two groups. And as I mentioned, we did look at the satisfaction score. The satisfaction score showed that at baseline, about 75% of individuals in both groups were satisfied with what they were doing. They were perfectly happy on their medication. At the end of the study, that number was almost identical in the continued drug group at 77.8%. But in the people who went off their medication, their satisfaction went up and was over 90%. There was no unhappiness about going off medication. In fact, if anything, those who went off their medication felt well. There were no differences in terms of adverse events or serious adverse events between the two groups. From that point of view, I think people did just fine. The main difference we saw was likely a small increased risk of new disease activity as manifested by scan changes, but only as scan changes, at least during the timeframe of the study.

Cross: That's very interesting. Have you done any subset data analysis like age 65-75 vs 55-65 or by race?

Corboy: Yes. You know, there were so few new relapses that it's not meaningful to do any kind of subgroup analysis. And similarly, even with the timing of the MRI scan lesions that were new, nothing really shook out. We did look at that. We also looked importantly at the different medications because of the small numbers of those who were using the oral medications or also the IV monoclonal antibody drugs, and we didn't really see much. But if you look just among those who were on the different medications that were older injectable medicines, we really didn't see any subgroup analyses that were helpful. The big answer from a subgroup analysis point of view is that we didn't really learn that much. And to have done that kind of subset analysis, given the relatively small number of outcomes we can measure, we probably would have needed quite a few more people.

Cross: I don't think these other two studies that are still ongoing have any more patients than your study. Do they?

Corboy: No, they don't. If anything, they're a little bit smaller. One of the studies Dr Cross is alluding to is a study in France looking at progressive MS patients age 50 and up, and they will have 250 participants. Otherwise, it is a very similar kind of study to ours, but they're looking primarily at progression disability as the main outcome. And then there's a smaller study of 130 patients in the Netherlands with relapsing-remitting MS. Interestingly, they're looking at anybody 18 and older whose disease has been stable for at least 5 years with no significant scan change for 5 years, as well. So, you could be diagnosed at 13, go on medication, be stable at 18, and go off medication in that study. It will be very interesting to see what happens because this is a very broad group. We would expect to see significantly more new disease activity. And one of the concerns, of course, especially in younger patients, is if you go off of one of the S1P modulators or maybe natalizumab, there's a significant concern for rebound of disease activity. Multiple observational studies have now shown that the number one indicator, at least for fingolimod, for disease recurrence or rebound, is actually age. It'll be interesting to see what happens with that. We, again, did not have large enough numbers to show this. But we did look just at the primary outcome measure of the fingolimod patients. We only had the 18 patients. None of the 12 who stayed on the drug had any problem. One of the six who discontinued medication did have a new MRI scan change. With natalizumab, there were only four people in the study, but one of the three people who discontinued the drug did, in fact, have new MRI activity. These are very small numbers. But that's the biggest concern because these are the drugs that really have potential for problems.

Cross: I'm interested in what your thoughts are on de-escalation if you have an older person who's on a stronger and more aggressive but riskier medication?

Corboy: I completely agree. There are three options in this context. One, you could just continue doing what you're doing. Two, you can discontinue all disease-modifying therapies. Or three, you could switch to an alternative because the risks of some of these medications clearly go up as you age, especially risks of infection and things like shingles, which are extremely common in general as you age. But many of the more significant medications, such as the monoclonals, have that as a risk as well, independent of age. There could be a confluence of infection risk, especially cancer risk, and as someone ages, you'd like to try to avoid this. We published a paper last year looking at the impact of different medications when you use them in younger patients compared to older patients. We showed in this paper that that there's a wide disparity when you look at people who are younger. In this case, they were using either the oral medications or natalizumab, and they had a wide difference in terms of outcomes. People are older when they start these medications — about age 53 or so — and there's almost no difference in benefit when you look at those medications. The benefit probably diminishes as you age, yet the risk may go up. We are starting a study soon de-escalating from CD20 agents such as rituximab, ocrelizumab, and ofatumumab to fumarates such as dimethyl fumarate. The logic would be just that to lower the risk because as we know with CD20 agents, the risk of infection absolutely goes up over time with disease duration, using the drug for a longer period of time because your antibody levels, your immunoglobulin levels go down and that is a risk for infection. We found the biggest risk for infection, in the study that we published a couple of years ago, was actually disability. If you were in a wheelchair, you were at about an eight-and-a-half-fold increased risk to have a serious infection with rituximab, such as that requiring IV antibiotics, compared to someone who is not in a wheelchair. And of course, people who are older are more likely to be in a wheelchair. So that kind of risk is very palpable as people age.

Cross: Getting back to the DISCOMS study you did, what would you say are the limitations of that study?

Corboy: Every study has limitations, and ours certainly did. You can only say that in this population, this is what we saw. And this was a population of people age 63 on average and with a last relapse an average of 14 years ago, most of whom were using the older injectable drugs. As we were discussing, we don't have a great idea about specific medications. If we were able to push the age up to an average of 65 and do a subgroup analysis to look at everybody below the age of 63 and everybody above the age of 63, we could see if there was difference, but we didn't have enough people to actually do that. In addition, most of the people in the study were White women. They're all in the United States, so we can't really say anything beyond that. Those were the main limitations — the subgroup analysis and the population we looked at.

Cross: Thank you so much, Dr Corboy, for spending your time with us today. We've talked to Dr John Corboy about discontinuing medications in older patients with MS. Dr Corboy conceived of and led the first ever study of discontinuation of medications in people with MS. Dr Corboy, I've found this extremely informative, and I hope our audience has, as well. I hope to see you again soon and see more data coming out from DISCOMS.

Corboy: Thank you very much, Dr Cross, and thanks for participating in the study.

Resources

The Prevalence of MS in the United States

Discontinuation of Disease Modifying Therapies (DMTs) in Multiple Sclerosis (MS) (DISCOMS)

Stopping Disease-Modifying Therapy in Relapsing and Progressive Multiple Sclerosis

Discontinuation of Disease-Modifying Therapies (DMTs) in Multiple Sclerosis (MS): Extension of the DISCOMS Study

North American Registry for Care and Research in Multiple Sclerosis (NARCRMS)

How MS Disability Is Measured

Treatment Switching and Discontinuation Over 20 Years in the Big Multiple Sclerosis Data Network

Natalizumab Discontinuation in a Dutch Real-world Cohort

Factors Associated With Fingolimod Rebound: A Single Center Real-life Experience

Serious Safety Events in Rituximab-Treated Multiple Sclerosis and Related Disorders

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