Director, Montefiore Multiple Sclerosis Center, Montefiore Health System

Lauren Gluck, MD

Let’s look to the future. I’m going to kick this off, as to what we would like, and I think Gavin’s comment gave me the lead-in to this. That is to find markers of individual response because all of the agents we talked about worked. Each one got approved because there was a population of patients who did well on it and continue to do well on it. What we need is individual biomarkers, individual measures of response, and it may be something like neurofilament light, or it may be something else. We shouldn’t do more frequent MRIs because I don’t think that’s practical, but something liquid certainly would help that. Also, this idea of looking at when to do individual dosing decisions. 

We’ve had 2 different conversations about anti-CD20 [monoclonal antibodies]. Gavin said maybe we can wait until B cells start to come back, or more importantly, when memory B cells start to come back, because having naive B cells come back may be a good thing rather than a bad thing. But on the other hand, you also mentioned that maybe we’re not dosing enough. We’re taking the patient down to 0 in terms of the periphery, but maybe there’s more important dosing going on, maybe within the central nervous system, which you alluded to Gavin. Although, trying to treat directly within the central nervous system with anti-CD20 agent rituximab wasn’t a very effective strategy. I think the future, to me, is looking at what we can do individually with our patients to better rationalize our therapies. Now I’ll throw it around to each of you. Let me turn it to you, Lauren. What do you see for the future?

: I agree. I think we’ll continue with individualized therapy plans for patients, and hopefully get better clinical- and research-based data points to guide us toward sequencing drugs better. I think one of the big questions that Gavin has brought up several times is, what do we do about all of the people who we started on ocrelizumab? We’re reaching the 5-year mark of it being FDA approved. At the 5-year point, do we de-escalate? How do we consider the long-term infection, and eventually, malignancy concerns? That’s something I’m looking forward to and am starting to precounsel patients about.

: I agree with Dr Gluck. I don’t have anything further to add.

: Yes, I think we need to do an induction maintenance trial. Fred, I would love to discuss trial design there because it’s quite complicated. It’s not easy to work out how to assess maintenance therapy after saying anti-CD20 therapy is effective or not. I think we’re going to have to go into that smoldering MS [multiple sclerosis] component, so this would be add-on treatments. What can we add to an existing platform, bottom of the pyramid, anti-inflammatory medication to protect damaged axons from dying, to remyelinate them, to promote repair? That’s the sandwich we have to build up, and it’s going to be a nightmare in terms of trial design. That’s where our big challenge is. Then you alluded to it, those other things. One of the components of progressive MS is premature aging. How do we push back aging mechanisms to optimize the brain health of our patients when they get older? Is there anything we can do? One of the things I’ve begun to realize, which we haven’t discussed, is the elephant in the room: poor sleep. Our patients with MS have a whole lot of reasons why they don’t sleep properly…. We don’t address the sleep disorders in our patients with MS. It’s looking after all the small, little things, they all add up. This is what I call a minimal gains hypothesis. If we can focus on those little things that make MS worse, overall they’ll add up, and we can hopefully make a big difference for our patients. There’s a lot of work to still be done.

Yes, especially in progressive disease. Ravi, this is important. Advice for community physicians?

: I think if I had to give 1 piece of advice to community physicians, it would be that we now have upward of 20 different DMTs [disease-modifying therapies] on the market, and rather than getting overwhelmed, the key is to be aware of the key classes and familiarize yourself with, perhaps, only 1 or 2 of each. Know those, let’s say 4 or 5 drugs, well and don’t get bogged down by choosing from 20. Also, don’t forget about resources. I often will get second opinions in particularly difficult cases.

Well, this has been a great discussion, and I thank you Dr Gluck, Dr Dukkipati, and Dr Giovannoni for your contributions. I’ve enjoyed listening to your views.

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Key opinion leaders in multiple sclerosis (MS) discuss the future of relapsing MS management and unmet needs.  

Future of Relapsing MS Management 

Let’s look ahead a bit. Gavin, I want you to take the lead on this. We mentioned biomarkers a little, at least neurofilament light, but where do you think we’re going with biomarkers?

 I don’t think there’s any 1 biomarker that’s going to take the storm and that’s going to be it. They all add to the picture. We’ve been using CSF [cerebrospinal fluid] neurofilament as an activity marker for about…5 years in our practice. We find it very helpful in terms of not being sure if somebody has ongoing activity, and if the patient has raised neurofilament levels, that gives us some confidence. About 1 in every 10 patients will have raised neurofilament levels and the MRI will be inactive, and they wouldn’t have had obvious relapses or pseudo relapses. It helps sort out pseudo relapses from true relapses. So yes, I think it’s going to be incorporated into clinical practice, but it’s unlikely that it will be used in isolation. It’s going to have to be combined with all the other things we measure. And what’s going to be more valuable is not just 1 measurement, but a trajectory of measurements, to see what happens over time with the neurofilament levels. It’s going to come. The data are overwhelming. It’s a good prognostic marker, and it’s a response marker, but I think overall, it’s looking more like an inflammatory activity marker than a neurodegenerative marker.

 That’s the disappointing aspect, I think, of neurofilament because if you think about its measure of axonal damage, we would have hoped it would be a better marker of neurodegeneration. It’s the opposite, just what you said, it’s a very good predictor of inflammatory activity, on the order of close to MRI. In fact, combining the 2 is a very good way of looking for activity. But in and of itself, I find that a little disappointing in neurofilament.

I think the problem is, we don’t know enough about the peripheral metabolism of neurofilament, but I suspect it’s cleared quite rapidly. I think in the more advanced, progressive, smoldering phases of the disease, the dropout rate is so slow that you’re not going to be picking up raised levels.

 Any other fluid biomarkers that have grabbed your attention?

Yes, this is not in clinical practice, but I think we’re going to have to at some stage target those intrathecal B and plasma cells. I think the intrathecal B cell and plasma cell response is driving some of the progressive component of the disease. We’re going to have to start in the future to clear the CSF of oligoclonal bands and drop the free light chain levels. That’s a biomarker for a specific therapeutic target. There’s nothing in the periphery; you may say GFAP [glial fibrillary acidic protein], but I’m not sure how much that’s going to add to neurofilament in terms of monitoring. So nothing stands out as a prognostic or a treatment response marker. I think in terms of when to retreat, that’s a different story. You alluded to the concept that maybe we’re overtreating with anti-CD20 [monoclonal antibody] therapies and we should only redose when B-cell reconstitution occurs, but that’s a different question. That’s about optimizing the dosing frequency of anti-CD20 therapies, and that’s going to require a lot of work. I don’t think B cells are enough. We may have to look at memory B cells or subpopulations of memory B cells, for example.

 And maybe T regs [regulatory T cells]. Ravi or Lauren, any thoughts about biomarkers?

I don’t have any additional thoughts. I think it’s a matter of establishing more data sets for neurofilaments, for example, and making them more adaptable to day-to-day practice, as an added way to monitor how patients are doing. The goal is to have reliable markers that we can institute early to ensure that our patients are responding to therapy.

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Expert neurologists discuss current and future biomarkers relevant to relapsing multiple sclerosis including cerebrospinal fluid neurofilament.  

Biomarkers for Monitoring Treatment Response in Relapsing MS 

 I want to get into a very important area that Ravi’s going to take the lead on, and that’s shared decision-making.

We touched on this earlier, but shared decision-making is imperative in terms of ensuring patient compliance and adherence. I think our role, as neurologists, isn’t only to provide the most objective information for patients to have, but to direct them to safe treatment options, let’s say, rather than Dr Google or internet chat rooms. But there’s no question that if patients have a clear understanding of their disease, their potential prognosis, the risks and benefits of each choice, they’re more likely to stay on therapy or to be compliant with monitoring requirements. There’s a spillover effect. If they’re engaged with their disease and treatment plan, they are more likely to embrace other treatment options: diet, exercise, and such. There’s no question that we have to incorporate shared decision-making into our practice, and not be too archaic in our approach, throwing a drug at a patient and saying, “This is what I’ve chosen for you.” That’s an extreme. But the other thing that we should shy away from is handing patients 8 booklets and saying, “Read these over call me back in a week,” or, “Call my nurse in a week.” That isn’t of service to a patient. That’s overwhelming and breaks the fundamentals of treating and individualizing treating a patient.

 We can’t minimize this, especially now, with so many agents to inform patients of and to have them engaged. Lauren, tell us a bit about your experience with this.

I agree with everything Dr Dukkipati said. I often say that I can prescribe anything to a patient that I want to, but at the end of the day, they have to take it. So, if they don’t trust what I’m saying, if they don’t believe the reason for me prescribing or recommending certain medications, they’re not going to take my recommendation and they’re not going to do well. I try to understand where they’re coming from, their level of medical understanding, and their willingness to accept different risks. Whether it’s the patient who, if there’s any chance their MS [multiple sclerosis] could get worse at all, they won’t be able to tolerate it, and they want the strongest, most effective medicine, or the patient who can’t accept any risk of a small adverse effect to a drug. We discuss different options for safer DMTs [disease-modifying therapies], but yes, it’s definitely about talking to the patient, understanding their values, and understanding what their life plan is.

Yes. I’ve moved away from this term “patient decision-making” to “guided decision-making” because we’re the experts, and we have so much more understanding. I try to steer the patient down to 1 or 2 choices. I also give them, Ravi, the option of them throwing it back and saying, “You make the decision for me,” because that’s a choice. Paternalistic medicine is a choice. Some people don’t want to be involved. It causes great anxiety, they get panic attacks trying to decide. They just can’t decide between drug X and drug Y. I remember with one of my highly active patients, I caused her almost to have a psychiatric breakdown because I told her she had to choose between alemtuzumab and natalizumab. This was about 4 or 5 years ago, and she was a nurse. I thought she had a lot of insight, and when I phoned her up, she was so relieved that I took the decision away from her. I think we have to identify that some patients don’t have the right makeup to make decisions, and we have to make those decisions for them.

Yes, you bring up a good point, Gavin. I would call it guided decision-making. I typically will educate a patient about 1 or 2 options, and ultimately, allow them to decide whether they would like to move forward.

 Part of the art of medicine is being able to read your patient and meet their needs. There are some people who are very engaged, who say, “Listen, I want to be heavily involved in what I put in my body.” And others are quite the opposite, saying, “This is why I came to you. Tell me what’s the best possibility.” But you still need to consider that there are a number of different choices. This gets into something I wanted to discuss briefly, and that is lifestyle issues because it’s part of the counseling we do with people, things like smoking and weight control. I’d also say diet, but given that we don’t have any good data yet on diet, it’s more a matter of debunking myths. Also comorbidities, which are becoming more important. We’ve alluded to the issues of the older patient with MS and some of the consequences of the medications, but part of those consequences relate to the comorbidities that come with older age that appear to have adverse effects on the underlying MS. Thoughts?

Yes, those are some of the most important things, especially once you have the DMT talk with patients that there are very few modifiable risk factors in multiple sclerosis. The biggest one, arguably, is smoking. If you have a patient who smokes, tell them the data behind the relationship between smoking and MS, and why the risk of increased relapse burden in smokers is so important. Encourage them to get to a place where they’re ready to quit smoking. Get their family involved in it as well. With nutrition, there is a lot of debunking. I tell patients, “You could go on the internet and find a lot of radical ideas. If you think it will benefit your life, go for it. But ultimately, by being at a healthier body weight, and potentially being on a heart-healthy type of diet, the rest of your body will be healthier. Your brain will likely be healthier, and try to control for obesity, which is a baseline inflammatory state.” I think all of those are very important. We talk a lot about vitamin D. There are some data that suggest it improves inflammation in the brain, but at the very least, vitamin D improves mood, energy, and bone health. Especially where I’m located, in New York, no one gets enough sunlight to utilize vitamin D properly, so we should all be supplementing.

A panel of experts emphasize the importance of shared decision making in relapsing multiple sclerosis and discuss lifestyle choices that impact the disease.   

Shared Decision Making and Lifestyle Issues in Relapsing MS 

Gavin, take us through sequencing. We have all these agents, and we talked about the various agents. What do we do next?

 I don’t think there’s any reason why you can’t sequence in any order, so I don’t think starting DMT [disease-modifying therapy] X precludes any other DMT, and vice versa. All you have to do is apply the baseline screening for those DMTs, so sequencing can be driven by tolerance issues or adverse events, be it liver function tests, but that’s a different story to efficacy sequencing. There are different types of efficacy sequencing. There’s upward or downward efficiency sequencing. The reason I say that is, obviously, if you have breakthrough activity and the drug has failed you, you need to move up.

I tend to not move sideways, but to move up in efficacy class, so we go from say the platforms to the intermediate to the high- efficacy treatments. What I find difficult is when you’re at the top end and you’ve gotten breakthrough activity, where do you go? My threshold for shifting there is a little higher, simply because of the question, where do you go? Obviously, for the derisking strategy, let’s give the typical example of PML [progressive multifocal leukoencephalopathy] risk on natalizumab. We would do sequencing there to derisk the patient, in other words, we would try to lower the risk of PML. That is a whole story of its own; how do you derisk a patient? How do you switch from natalizumab to prevent rebound? Which agents do you go to? We have quite a big protocol. We’ve almost completely shifted to anti-CD20 monoclonal antibodies post-natalizumab. We used to go to fingolimod, but now we’re going to ocrelizumab in almost all of our patients. I’ve had a few patients where we’ve moved on to cladribine, and even a few on to alemtuzumab.

You have to be extremely careful when you move to a depleter agent because if you get carry-over PML, then you have a problem because the patients are immunosuppressed by the depletion cycle, and they need their immune systems to recover from PML. We have a very strict protocol to make sure there isn’t any PML, or asymptomatic PML, before switching medications. But Fred, you wanted me to summarize. I think the other message people need to appreciate is that you have to have a lot of detailed information and knowledge about each DMT when you do sequencing because some of the issues around specific sequencing, let’s give you an example. Moving from fingolimod to cladribine, for example, you have to wash a drug out, and not everybody reconstitutes their lymphocyte counts quickly enough. 

We, in our center ,Blizard Institute, Barts and The London School of Medicine and Dentistry, measure the lymphocyte counts weekly, and when they get above 800 per μL, we dose the patient with cladribine. The reason we don’t want to wait until they get above 1 1000/μL, which is on the label, is because you go into that period where you get rebound. You don’t want to have them uncovered, so this is why the issues around sequencing are quite complex and not easy to get across in a 2-minute or 3-minute discussion. I don’t know if Ravi or Lauren have any comments about specific sequencing.

I don’t have anything to add. I think mechanism of action is very important and needs to be taken into account with the considerations of sequencing.

 We’ve had a concern about anti-CD20s and S1Ps [sphingosine-1-phosphate receptors] as well, at least the longer-acting ones, as to whether we might miss the B cells that are sequestered. In practice, we haven’t seen it, checking B-cell counts moving forward, but it is something that needs to be explored more carefully when you switch from one to the other. But one of the other issues that I personally have is that we don’t have good data to define inadequate response. Our goal, our aspiration for any therapy, is neither—no activity whatsoever, no relapses—nothing new in the MRI. It’s a nice aspiration to have, but it’s not the reality of any of our agents, at least early on. How much activity is acceptable and how much says, “No, you need to switch?” At what time point? For example, we do a baseline MRI on all of our patients when we start them on therapy at 3 months. Some people prefer 6 months, but we give the drug at least 3 months to kick in because, I think, that holds for almost all of the agents. We use that moving forward, but even when you move forward, is 1 new MRI lesion per year a reason to switch, or 2? If it were 10, you probably would, but where do you slice it? Thoughts?

 Yes, that’s a very good point, Dr Lublin, and I think clinical trials have rigidly defined parameters, but real-world practices are just that. How many lesions are too many, and how many new symptoms are too many? I think we have to find the balance between switching too prematurely vs waiting too long. To follow up on what Dr Gluck mentioned earlier, in addition to required laboratory monitoring, we see our patients 2 to 3 times per year for follow-up, and more often if they’re having active symptoms. Imaging is a fluid thing in real practice. We image, on average, every year, but sometimes we’ll go longer if a patient is doing well. But we emphasize the importance of periodic surveillance imaging to screen for breakthrough radiographic activity.

Fred, one of the things we’re seeing now, and you must have the same issue, is that you have people who have been stable, without relapses or MRI activity, for several years on fingolimod or any DMT, and then they start coming to you with worsening disability. I would call this a delayed, smoldering component of the disease. But I’m not sure if the drug is failing those people because it’s keeping the relapses and the focal MRI activity away. What’s driving that worsening is probably the processes that our therapies aren’t targeting, and I feel very uncomfortable switching those patients to other anti-inflammatory DMTs because I don’t think it makes a difference in those patients. I don’t know what your opinion is about those. My clinic is now full of these patients who I call, “NEIDA”—no evidence of inflammatory disease activity—but they are getting worse.

Yes, this is a new issue. It’s brought up by this concept of progression independent of relapse activity, which is secondary progressive MS [multiple sclerosis], and how best to deal with that.

Experts in multiple sclerosis (MS) discuss key factors involved in the sequencing of therapies for relapsing MS.   

Lauren Gluck, MD

Articles

Future of Relapsing MS Management

Biomarkers for Monitoring Treatment Response in Relapsing MS

Shared Decision Making and Lifestyle Issues in Relapsing MS

Sequencing Therapies in Relapsing MS