19min chapter

HealthTree Podcast for Multiple Myeloma cover image

Today's CAR T Options in Multiple Myeloma Care with Luciano Costa, MD, UAB

HealthTree Podcast for Multiple Myeloma

CHAPTER

Advancements in CAR-T Therapies for Multiple Myeloma

The chapter explores ongoing clinical trials for CAR-T therapies in earlier lines of therapy for multiple myeloma, showcasing positive results with over 50% reduction in progression risk. It compares CAR-T and Biaspecific antibodies, discussing mechanisms, sequencing strategies, and potential approval timelines. The importance of myeloma specialists in guiding treatment decisions, development of CAR-T with multiple targets, and the progress towards allogeneic CAR-T therapies are also discussed.

00:00
Speaker 2
And as we mentioned earlier, these two drugs are approved for after-forth line of therapy. But I know that both companies have clinical trials in place that are testing these in the earlier lines of therapy. Do you want to speak to what you think the timeframe might look like to get these drugs approved or these treatments approved for patients who have maybe one line of therapy or two lines of therapy? Yeah, absolutely.
Speaker 1
So both companies have conducted trials, and those were called Phase III trials, so essentially you compare this therapy with the existing available regiments in patients with earlier therapy. In the case of a back in the trial, we call Karma III, we're fortunate enough to participate in that trial. I had patients with 2-4 prior therapies who have received all the three main classes of myeloma therapy, and this drug, this therapy, CAR-T was compared with eight conventional regiments. And that study has been completed, has been published. It was highly positive study with the CAR-T having nearly more than 50% reduction in the risk of progression for those patients. In the case of CAR-VICTI, there was also a study. We also were happy to participate on it, called Cardi-Tut-4. They compared CAR-VICTI with conventional regiments in patients who had had one to three therapies. And different fun what we saw with the back map, the patients here did not have to, even had received a 3-3-3-8 monoclonal antibody, like DART to mummab. They just had to be resistant to revlimid, which is most time it is on patients with faculty and blind or beyond. And that try was also very positive with more than 50% reduction in the risk of progression or death with CAR-VICTI versus a conventional regimen. Now, this data is out. The regulatory authorities are looking at that, both for a back main CAR-VICTI. I hear this can be as early as first quarter next year. That one or more of those therapies might be available for patients earlier in their journey with myeloma.
Speaker 2
Yeah, that's fantastic. Because I think what you said at the beginning is true that when you have a more resilient immune system, for every therapy, everything works better when you're first diagnosed versus later. Well, let's talk a little bit about CAR-T versus Biaspecific antibodies, because all these immunotherapies, kind of, you know, CAR-T was a little bit earlier, and now we have like this flood of Biaspecific antibodies that are coming out and talk about sequencing strategies. I know at the recent International Myeloma Society meeting in Greece, some of the data showed that if you can get it, and if it's available, CAR-T might be better in first-in sequencing, but, you know, you still have the question, can you get it, and what you were saying earlier, like, will your myeloma wait until you can get it? So that's still kind of
Speaker 1
open.
Speaker 2
But what's your opinion on the whole sequencing of these different
Speaker 1
drugs? Yeah. So that is very interesting. So for your audience, now that we talk about how we want to use T-cells to fight the cancer, CAR-T is one way to do it. The other way to do is what Jenny has mentioned by specific cell engagers. So those are off-the-shelf therapies. There are antibodies, very much like darzalax or cerclesia or implicit are antibodies, but they bind two things. They bind something called CIRI-3, which is on the T-cells, and they bind a target on the myeloma cell that can be either B-CMA, like the CAR-T, or it can be another protein called GPRC5D. So what they do is they bring together, they force the T-cells to get in close contact with the cancer cell, and that is sufficient for activation of the T-cells and killing of the cancer cell. Those drugs don't require the patient to collect cells, don't require time to manufacturing. Essentially, once the patient needs it, you can give that in a couple days. And those therapies are also extremely active. We talk about response rates in the neighborhood of 65 to 75%. And it's natural that we cross-compare that with CAR-T. You say, well, CAR-T is better. It's 75 to 95%. We've got to keep in mind that those are very different patient populations. For example, somebody with a varied grasp of disease, they get the bi-specific, they can get therapy in a couple days. And if it doesn't work, they count as a failure of the treatment, while if they had received CAR-T, they would probably have not done well and never received the CAR-T infusion because their health would have deteriorated, so they're not counted. So there's always a 10% or so difference that favors the comparison to CAR-T. The other thing to keep in mind is CAR-T has those advantages that quote unquote, one and one. You get your therapy, you don't have to be on ongoing treatment. And that is marvelous because our patients can enjoy sometimes months and months when they're well without being on treatment. They're going to trip, they're enjoying time, they love to have a break from seeing the doctors and nurses as often as they usually do. However, those CAR-T's speak around for a few months and they're gone. And then eventually the myeloma kind of abounds them back. The bi-specific for being ongoing therapy, it's inconvenient because you're not really signing off from the treatment center, but that can be a double-edged sword because you continue the therapy that is engaging or immune system against the cancer. And some of those responses can be very, very long. I have patients, for example, approaching five years on a bi-specific to cell engage or after having typical factor in myeloma. So it's not as simple as CAR-T works more often than bi-specific. Now the challenge is in a scenario where we have all those things available, how do we choose? And that is the question we don't have a good answer for. We're starting to learn how one therapy works after the other. And if somebody has CAR-T and he works in a year or a year or a year down the road, the myeloma comes back, we can pretty much say the likelihood of responding to a bi-specific, even with the same target. It's very close to those patients who never had received a CAR-T. So the CAR-T doesn't seem to burn any breach in any meaningful way. The response is a little bit less, but still very meaningful. So we know a little bit about this path of CAR-T followed by a bi-specific. The other way around is not very well known. And a little bit of data that there is seems to not be very encouraging for somebody coming off of a bi-specific with progression and jumping to a CAR-T. Sometimes you cannot manufacture the CAR-T so fastfully. And even when you do, often times it doesn't work. And we're only trying to understand why, maybe because that continuous suppression of the myeloma lacks out the cells that have lost the target, which still don't know. But that path tends to be a little bit less successful. So how do we make decisions when you have a patient in front of you? Very, very hard. I would say if you are somebody who, and that how I counsel my patients, you are somebody who we think can safely do CAR-T. You can safely wait for the manufacturing. We have a lot available. Go ahead. Do the CAR-T, the other options still going to be there. What we have to be careful about is not losing an important therapy, which are the bi-specifics, waiting for that, you know, waiting to go from something that is excellent for something that we might perceive as being quote unquote better, which is the CAR-T, and lose that option, and lose the chance of receiving meaningful therapy. There are also patients who, the other things taking consideration, and I discussed that with the patients, the toxicity with the bi-specific is certainly less and more controllable. As many of the audience might know, the bi-specifics are given in a measured approach. You don't give the full dose on the first day. You do what's called step up dose. So the given commutiary dose is which gives you some control of the pace of that engagement and those reactions. With CAR-T, you unleash the cells, and all you can do is hope for the best, and if a complication happens, you try to mitigate with treatment. You don't have much control of that reaction. So if somebody who is older or have a more frail health that you think this person is, you know, will be unable to endure a severe CRS, that's certainly not a patient that you should pursue in CAR-T. And I have several patients on my practice who have successfully treated with bi-specific, but who now would have never proposed a CAR-T.
Speaker 2
Well, all these nuances are the exact reason why you need my one specialist on your team, in my opinion. You think about all the things you just considered, and it's just so critical that people come to experts like you, especially for these newer and very nuanced therapies.
Speaker 1
I just think it's important. I have a portrait with you, Jenny, and I think it's the... I know we're a bit of the self-serving advice, but I think the sooner you get a myeloma specialist on your team, the better. Even if the specialist is not the one you're seeing for your ever-month treatment, you'll have somebody closer to home with a general oncologist who's willing to work with that myeloma specialist. It's very important because there are a few things that, as you're sensing from our discussion, timing is very important, having a few for one's disease. See how a patient tolerates this therapy versus that therapy. And in CAR-T, for example, other logistics involved in SLOT, insurance verification, collection, bridging, having somebody with first-hand experience that has been involved in your team from the very beginning is incredibly helpful. Yeah,
Speaker 2
wonderful. Well, do you want to talk about new approaches in CAR-T? So we have these two approved drugs, and there are some new things coming out like using two CAR-T's together, or using new targets like CS1 or GPRC5D, or even having a facility develop their own CAR-T. Do you want to kind of review what, in your opinion, were the most promising looking approaches? Absolutely.
Speaker 1
So the two CAR-T's that are currently approved, they target the same target called BCMA or B-cell Maturation Antigene. And of course, they have been very successful. That's not the only target that is relevant in myeloma. We have, for example, GPRC5D, which is the target of the QEDAMAAP, for example, which is now an FDA approved by specific to SL Engager. And there are CAR-T's in development, and we are actually, our center has had a lot of experience with a GPRC5D directed at CAR-T. And, again, very active, and if you're asking me quite safe. And we spend, in my opinion, a necessary energy arguing, is this going to be better or not better than the existing CAR-T? But the, while in reality, I would truly believe it doesn't have to be better, it's just being different, because there's a different target. It gives people other options. And we have had several patients who have received two different CAR-T's with two different mechanisms of action, and derive incredibly disease response and longer emissions from both in sequence. So, in the future, people might benefit from CAR-T in more than one point into the treatment trajectory. The other approach that is only starting now is to design CAR-T's that don't have one target but two. And this is very intuitive how two can do a better job than one. That's how you use chemotherapy, right? And many successful curative chemotherapies are using cancer or is using more than one drug. The hope that it's felt that it's resistant to one is not resistant to the other. So, there is one in development that targets CD19, which is a very early marker in B-cells, as a transition to plasma cells in BCMA, and there's some down the road with BCMA and GPRC5D. So, that is certainly an exciting new development. The other part that is exciting is, of course, the biggest challenge of CAR-T is the time that it takes to collect the cells, manufacture the cells, get the cells back. So, it wouldn't be wonderful if you could do the same thing with a product that's already on the shelf. You need to get it. And that would only be possible with kind of a universal donor CAR-T or allogene CAR-T. So far, the initiative to have been taking in that direction have been hindered by the problem that if you get a cell that is not yours, you can reject the cell and the cell can reject you. And what it takes to overcome that is some very strong immunosuppression that causes a lot of infections. But thanks to modern technology, now there are some initiatives of editing the DNA of that cell to essentially make that invisible to your immune system and make that incapable of attacking your normal organs. So, you can have a cell that is super focused on finding and killing the cancer without causing any other trouble. So, that would be ideal, right? You have an off-the-shelf product that is safe. That would be amazing. And you don't have to go through a for-aces collection and individual patient manufacturing. So, I think those are the things that if I have to highlight the three things that I'm most excited about, future cell therapy, it will be those three. Wow, that's
Speaker 2
totally amazing. I have a few more questions for you, but I also want to leave a few, a little bit of time for caller questions. So, if you have a question for Dr. Costa, you can call 347-637-2631 and press 1 on your keypad. And there is a caller that has a question. And then I'm going to jump back to my additional questions. And so, this is caller that ends in 2255. Go ahead with your question. Hello. Hello? Yeah, we can hear you. Oh, hi. Yes, I was most interested in the allogenic CAR-T. I appreciate the comment that was just made. Could the doctor speak a little bit more about the timeline on having that available to patients as an alternative to regular CAR-T?
Speaker 1
Thank you so much. That's a great question. And the honest answer is we don't know. There are several that are in clinical trial. As a matter of fact, this morning, I just had a meeting to activate one of those slides here in the U.S. But from this phase where things are on trial to become approved, we're looking at at least two or three years, if assuming those trials are successful. So, we still have a ways to go. Okay, perfect.
Speaker 2
Thank you.

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