Choosing Initial Therapy for Treatment of MS

Fred D. Lublin, MD: Okay, now, choosing therapy. Thoughts?

Stephen C. Krieger, MD: Well, I think if there’s mostly 1 debate about whether we should treat early or not, I think there’s a much more active and unreconciled debate about how best to do that. And I think that one can really have reasonable arguments about using the medicines that we think of as our high efficacy therapies early, reserving those for patients who show any early sign of breakthrough disease, or reserving those medicines altogether for people who we are worried about prognostically.

And to the same degree, that lack of knowledge of how someone is going to do in the short term, I think we also have imperfect science telling us how patients are going to do in the long term. And that drives the fact that there is no consensus in our field about how to best choose medicines early for the patient. Although we all have our own strategy, which I think we’ll probably outline.

I’ll say this, that I remember when natalizumab first launched, which we’ll talk about in a little while in some detail. But I feel that that launch of that medicine really made it very clear to me that physicians and patients alike were going to construe that risk of benefit data very differently. I’m sure we all had experiences of talking to patients about that at the time. The notion, now revised, that this medicine might be roughly twice as good from an efficacy perspective as the injectables that preceded it, but it had a 1 in 1000 risk of a potentially fatal adverse effects.

And I remember saying those words to a group of patients at an educational program and immediately half of them said, “One in 1000? That’s never going to happen, sign me up.” And the other half said, “One in 1000? I don’t want to ever hear about this again.” And right there it sort of lays bare the fact that even with the same data, people are going to decide very different things, and that’s only going to become more complicated as we have a dozen more medicines since then.

Amit Bar-Or, MD, FRCP: That’s very important, there’s no 1-size-fits-all. And I think that to me, although I like to think that the proactive approach and try to minimize damage is the way to go— that’s a personal feeling. And I’m very comfortable following people with MS [multiple sclerosis] who don’t want that approach. Then the discussion is simply to follow them proactively enough that if there is new disease emerging, we’ll catch it early and consider a switch.

Peter A. Calabresi, MD: It’s worth mentioning that there are 2 trials going on right now, TREAT-MS and DELIVER-MS, to try to answer this question, randomizing to first-line, or high efficacy therapy. We of course have some prognostic measurements that have been around for 20 years. Poor recovery from first relapse, spinal cord disease, high T2 lesion volume on MRI [magnetic resonance imaging]. But we need to do better, and I think hopefully with things like neurofilament light, perhaps we’ll be able to better prognosticate as to who really needs to get those highest disease therapies right out of the gate, and who we can do escalation on, and have a little bit more time before we’re worried about them accruing disability.

Stephen C. Krieger, MD: You’ve done very elegant work with neurofilament light in a variety of contexts looking at that. What I struggle with is knowing how we’re going to take those data that really are a very useful prognostic tool from a population basis and actually pull it down to use it at the point of care. Do you have a thought on that, because I would love to know your thinking?

Peter A. Calabresi, MD: That’s why it’s not ready to be commercialized, in my opinion. We’re now studying this longitudinally in a large cohort in the context of the MS PATHS study with 5000 patients over the next 5 years. And I think that the need is to know what value is actionable in an individual patient, and we don’t have those data yet.

Patricia K. Coyle, MD: I just want to put in a word. I think treatment is critically important. I think every MS appropriate patient who presents should be on a treatment. And the multiple options that we have, if somebody has concerns about risk, there are very low-risk agents. So we’re matching in shared decision making: disease factors, drug factors, patient factors. But I think we should be convincing our patients to go on treatment, I really believe that.

Stephen C. Krieger, MD: We used to talk about looking for poor prognostic signs to figure out which patients merited higher efficacy therapy. I think where our field has shifted is the idea that most patients require or warrant a pretty high efficacy therapy. And I think what we really need moving forward are prognostic markers for more benign disease. Who among our patients is actually not destined to require the kinds of treatments that we’re using much more proactively now? And I don’t think we have that yet. I would love to know who’s going to do well, because I think we have a sense of who’s not going to do well, and we have a sense of what kinds of treatment strategies, high efficacy medicines they need.

Patricia K. Coyle, MD: A good point, we may be overtreating some patients. But the problem with the very mild MS is that’s a retrospective diagnosis looking back 30 years.

Stephen C. Krieger, MD: Right, it is now.

Patricia K. Coyle, MD: And saying, “Hey, you did great.”

Peter A. Calabresi, MD:You see someone in their 60s who hasn’t had recognized MS, and you look at him and you say, “Yes, this is definitely MS. Your history fits, your MRI fits.” Do you still put them on treatment at that point?

Patricia K. Coyle, MD: I might not put them on treatment. That might be your example of benign MS, looking back.

Peter A. Calabresi, MD:Correct.

Fred D. Lublin, MD: We caution people to use that term very carefully, or better yet, not at all.

Patricia K. Coyle, MD: Well, because the literature is awful.

Fred D. Lublin, MD: Yes.

Patricia K. Coyle, MD: You need at least 3 decades of observation.

Stephen C. Krieger, MD: Wouldn’t it be great if we had a prospective prognostic sign that could tell us who’s going to have that path? I feel like that’s what we need almost more than our worrisome prognostic signs, which we all recognize.

Peter A. Calabresi, MD: We do recognize that inflammatory lesions on MRI have different outcomes, and some become black holes and others don’t. I think that’s the first pass at this, but with future biomarkers hopefully we’ll be able to monitor that more closely.