Hot Topics in Multiple Myeloma: What Patients and Families Need to Know

Robin Tuohy:
It's my pleasure to ask Dr. Joe Mikhael to come up here and talk about hot topics in myeloma.

Dr. Joseph Mikhael:
Thanks so much, Robin, and thanks everybody for being here. This is our flagship Patient & Family Seminar, being in our backyard. It's always a pleasure to be in Los Angeles. You don't have to worry about slides because this session is so hot, it doesn't even have slides. So for those of you who may remember from last year, we introduced this last year where at the start of a Patient & Family Seminar, I'm going to spend about 15 minutes just giving you some highlights of really what is the latest and greatest in multiple myeloma. And we purposely, as I mentioned, not even made slides because we've had several of these over this last year where literally events that morning influenced what we discussed that afternoon.

So the idea here is to just get you excited about what's happening in myeloma. Most of these topics will make their way back in through the agenda over the next day or two. Some of them in particular, when we go over what we have called tomorrow "The Controversies." Robin just shared with us that we'll have a whole virtual regional community workshop dedicated to controversies. But we'll have a bit of a discussion about controversies tomorrow as well when many more of our faculty join us. So typically I would choose three topics. Don't tell the other cities, but because you're Los Angeles, you get four, right? Some of you'd be like, "I wish you only gave me two." But anyway, we'll stick with four.
So four quick things that have just literally happened over the last month or two, and even some over the last several weeks that I think are relevant to us. Number one, we have yet another new FDA approved drug in the form of linvoseltamab. This is a bispecific antibody that is created by Regeneron, and you can learn more about it outside as well, but it now joins the other bispecific antibodies that we have that are almost identical in their, what we call indication, when we can use them. So this is a drug that patients have to have had at least four prior lines of therapy. They had to have had a proteasome inhibitor, a monoclonal antibody, and an immunomodulatory drug, one of the three classes of drugs that I'll go over with you when we have our myeloma one-on-one shortly.

And this was based on their clinical trial, which had demonstrated about a 70% response rate in patients with really quite heavily treated multiple myeloma. So that's genuinely remarkable. Up until we had CAR T and bispecifics, almost every drug approved for myeloma had a response rate between 22 and 32%. And then all of a sudden, we doubled it, and we tripled it even to some degree with bispecifics and CAR T-cell therapy.

So linvoseltamab, which is just now being rolled out, some centers are still having it brought into their clinics, and you're going to hear more about it, of course, over the course of the weekend and coming forward. But this is a bispecific antibody. And, quickly, if you're not familiar with what that means, you can watch the videos that I make with Roman and Colin who are here today recording. If you know that we do a series of these short Dr. Joe videos where I explain things. We have a Myeloma Made Simple series and various others. But to keep it simple, what is a bispecific antibody? A bispecific antibody is called "bi" because it has two arms, one arm grabs onto the myeloma, the other grabs onto one of your T-cells.
So T-cells are like soldier cells that have the ability to destroy other cells, and it introduces them how you do one, right? It brings them together and says, "Look, this is the target that you want to destroy. Go ahead and do it." And what matters in these bispecific antibodies and particular is, where does it hook on to the myeloma cell? And linvo hooks onto what we call BCMA, which some of you I'm sure are very familiar with, the same target that we use for the two CAR T-cell therapies. The same target as two of the other bispecific antibodies. And we know that target is really valuable, important because it's expressed on almost every myeloma cell. So more to come with linvoseltamab, but that's very exciting for us to have yet another drug.

I often say when I started a myeloma 25 years ago, we had two drugs, now we're over 20. It's remarkable the change that we've seen with these new drugs. So that's number one. Number two, you may know several weeks ago there was a challenging meeting, right? I don't hold back. Sometimes news is good, sometimes news isn't so great. But we had what was called ODAC, or an oncology drug advisory committee. This is where when the FDA is evaluating a drug or a program or some kind of intervention for patients, it says, "Look, we have some concerns. We're going to let another sort of independent committee review this topic," and they reviewed the use of a drug called belantamab or Blenrep, that some of you may have been familiar with. Some of you actually may have been treated with it a few years ago. It was approved by the FDA, waiting for a confirmatory trial. That confirmatory trial was not confirmatory, so it was withdrawn from the market. But now we have two very potent clinical trials, two quite amazing clinical trials showing that this drug is very effective.
To give you a quick background, the drug is what we call an antibody drug conjugate. So whereas a bispecific antibody, like I described before, or a monoclonal antibody hooks onto a myeloma cell so that it can kind of trigger the immune system to destroy it, this antibody drug conjugate has another feature. I think of it as a drug that has a backpack, a very toxic backpack, that when it hooks onto the cell, and interestingly, it also hooks onto that same target BCMA, it drops that toxin into the cell, and it can help destroy the cell. So this is a drug that we don't have to collect T-cells on. It doesn't have some of the other side effects we see with certain bispecifics like cytokine release syndrome and other things that we're going to be discussing this weekend. So it's actually quite easy to administer. But there have been a couple of challenges with this drug, including the fact that it has some eye-related side effects that can cause some blurriness of vision and dry eyes.

And so this ODAC meeting was held to review it, and the ODAC committee did not recommend to the FDA that it be approved at its current stand. Interestingly, it has been approved in multiple other countries, including my original homeland of Canada. Yes, shout-out to you, Martine, for all my Canadian homies in the crowd, Japan and many other places. But it does not mean that the FDA won't approve this drug. That's simply the recommendation of the FDA. The FDA has moved ahead its date where it will make some kind of announcement about whether or not it would approve it or need more time in October.

And the bottom line for all of us is that we actually think this drug works very effectively, and we've strongly advocated for it. On that day of the ODAC, Diane Moran, our interim CEO, spoke very passionately about having access to this for our patients. One of my patients actually spoke because she's still on this drug, and it was miraculous for her. Her husband, sadly, had purchased her grave site and was ready to plan her funeral, she was so unwell, and we were able to get her access to this drug. And here we are three and a half years later, and she's doing extremely well. So we have a lot of experience with this drug. There are some issues related to the side effects related to the dosing that we hope can be sorted out before too long.

All right, last two. Number three, which I'm only going to briefly mention because you're going to hear it all weekend, but I had to include it as a hot topic because you cannot go to a myeloma meeting and not hear these three letters over and over again. Say them with me, M-R-D, M-R-D. You're going to hear MRD repeatedly. What is MRD? MRD means minimal residual disease. So when I started myeloma 20 years ago, when we'd treat people for myeloma, they had whatever measure of the disease, the M-spike, the light chain measure, we just hoped to get it down. We would feel great if it went down by 50% or even could have possibly get down to 90%. Well, now with these great therapies, we're getting it down to where we can't measure it all in the blood. So we go into the bone marrow to see if we can find any residual amount of multiple myeloma. And that test is called the MRD test.
And sometimes we can get to true, and some of you in this room, I know a lot of you in a lot of your blood work, have shared it with me. Some of you have become MRD negative. And the reason why we talk so much about it is that MRD negativity is a very powerful tool to predict that someone is going to stay in remission for a longer period of time. Now, it's not perfect. No tool is perfect. There are interestingly, and paradoxically, some patients whose disease literally goes away but then comes back very quickly. That's often what we call high-risk multiple myeloma. But why I want to mention it now in the hot topics is we're seeing more than ever very recently clinical trials that are using MRD to decide the next step in someone's treatment.

It used to be we would just treat, and then if someone got to MRD negativity, we were happy about it. But now clinical trials are being designed saying, "Okay, well if you get to MRD negativity, maybe we can stop treatment or maybe we can alter treatment. But on the other hand, if you stay MRD positive, maybe we need to also make a change to treat you with more." And we're trying to figure that out, and perhaps the most important of these trials of late was something called the MIDAS trial that our French colleagues led, which took people with newly diagnosed myeloma, gave them six cycles of treatment, and then decided based on whether or not they were MRD negative or MRD positive to give them different strategies.

And those who were MRD negative were either just given more of that same drug or were given a transplant. And it's too early to make a determination, but those two groups seem to do the same. Meaning we may not necessarily need to transplant patients who have already achieved MRD negativity. So that's the kind of implication that this could have. Now, don't leave and say, "Dr. Joe said, we don't need to do transplants anymore." No, no. Let's leave that for the controversy discussion tomorrow. But what I want to share with you is how important and how wonderful it is that we have this powerful tool and that we're using it now to help determine. Because my goal, as I've said at this meeting, and someone reminded me earlier, is to get as many of my patients onto my favorite drug, nada, nothing. If we can get people onto nothing, every insurance company covers it. Everybody's a hundred percent compliant and adherent to it. We would love to do that.

Last hot topic, and I hesitate a little bit to talk about this, but we had this discussion at the International Myeloma Working Group that Robin made mention of earlier. One of the clinical trials that was presented at our spring meetings, both in Chicago and in Milan, was the long-term follow-up of a CAR T-cell therapy trial called CARTITUDE-1. This is when patients were given a CAR T-cell therapy. Some of you in this room have had it, I know, called CARVYKTI or cilta-cell, and we had the long-term follow-up of this study. And it turned out that one-third of the patients on that study, five years after being given that one dose of drug, are still completely disease free.

Now I recognize that's only a third, but these are patients with the amount of treatment they'd had before, we would've expected them unfortunately, to not have even survived a year. And here they are, five years out, disease free. So why do I include this in the hot topic? Well, we had a discussion at the International Myeloma Working Group in June about how are we going to define cure in myeloma. I'm not saying that those third of patients were cured, but it's making us say, "How do we even define cure?" And we do think that cure will have something to do with MRD negativity. Of course, it's going to have to include a timeframe. I mean, if I just walk out in the streets here in LA tomorrow or today and ask someone, say, "Hey, how do you cure a disease?" They're probably going to say, "Well, you give some treatment and then you don't have to think about it anymore."

That's, of course, the nirvana that we all have, that's what we long to do. Robin shared both our mission and vision earlier that we want to achieve that cure in multiple myeloma. And I'm not saying we're there yet, but we are much closer to it now than we were even just two, three years ago based on the results of these kinds of things. So a new drug approval, a drug that is not yet approved, but we hope still has a great opportunity for approval, the importance of MRD. And, lastly, our focus now on defining and ultimately achieving a cure in myeloma, and that's the way it is. I sort of feel like I'm a news reporter. I'm not exactly Walter Cronkite. For those of you on staff who don't know who that is, you're too young to take care of my patients, but you were in utero when he used to say that, but it really is remarkable what's happening in myeloma.