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Are There Myeloma Trials Investigating CAR T for Frontline Therapy?

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Are There Myeloma Trials Investigating CAR T for Frontline Therapy? from Patient Empowerment Network on Vimeo.

Is it possible for CAR T-cell therapy to be used as a frontline therapy? Expert Dr. Krina Patel from The University of Texas MD Anderson Cancer Center sits down with her patient, Lisa Hatfield to discuss CAR T-cell clinical trials, including CARTITUDE-4, KarMMa-2, and KarMMA-9, and trials currently under study. 

[ACT]IVATION TIP

“…talking to a myeloma specialist about different options that are out there for trials because different centers will have different trials that are open and you need someone to help you navigate with that. Which ones are the best ones for you? And then I would say talking to your patient advocacy groups, because that’s really where a lot of my patients hear the information. And then they come to me and say, ‘Listen, I heard this, what does it mean?’ And I think that really helps you kind of even know where to start from.”

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 What Patient Types Are Good Candidates for CAR-T Therapy?

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 A Look at Promising Strategies to Improve CAR T-Cell Therapy Access

A Look at Promising Strategies to Improve CAR T-Cell Therapy Access

Transcript:

Lisa Hatfield:

So, Dr. Patel, for this next question, I’m going to preface it by saying that anybody that I have ever talked to in my advocacy work about myeloma and how to get care for myeloma, I’m a huge advocate for seeing a myeloma specialist. And I will tell everybody out there that Dr. Patel at MD Anderson is my myeloma specialist, and I’ve been with her since I was diagnosed in 2018. I live in an area where we don’t have any myeloma specialists. And so I’m an advocate for that. And anybody listening, I hope that they know that they can seek out the care of a specialist even for initial consult or even once throughout their journey.

Having said all that, I know Dr. Patel, because you’ve talked to me about them before, that you’re involved in some clinical trials for CAR T therapy. Can you talk a little bit about your trials that you’re doing right now that offer CAR T in earlier lines of therapy, including frontline therapy, and what this could mean for patients?

Dr. Krina Patel:

Yeah, no, I think the CAR T trials are what allowed us to even get to second and third line. The KarMMa-3 and  CARTITUDE-4 were the two trials that brought ide-cel (idecabtagene vicleucel) [Abecma] and cilta-cel (ciltacabtagene autoleucel) [Carvykti] forward, which is fantastic. And I think now it’s how can we improve even further? So some of our clinical trials are even earlier line, like you said, frontline. So we have one called KarMMa-9 that is for patients who have less than a VGPR, meaning that they didn’t get all their myeloma gone after their initial transplant, if they went to transplant, you can do consolidation with CAR T. And we’ve had a few patients that we did on a smaller study called KarMMa-2 that are doing really well after they were on that cohort for that study.

So that’s sort of why they’re doing a bigger study for FDA approval now. And then CAR T 2-5 and 6, we don’t have that at MD Anderson, but a lot of centers do. But that is now trying to see if cilta-cel can actually beat stem cell transplant, which again, a lot of us are really excited about, but we need to do the trial to make sure it’s just as safe and hopefully more efficacious. So I think those are really, really important. Auto-transplant, I was a transplanter when I first became faculty at MD Anderson.

And so I do think it has a role, but it’s high-dose chemo and there are secondary potential side effects that can happen. And people really have to kind of stop their lives for at least two, three months, if not longer, to go through that. Where in CAR T, I think it’s that quality of life piece. Again, it’s one and done. It doesn’t take as long to recover for the majority of patients. And it really is using immune therapy instead of chemo to kill that myeloma, right? So it is very different.

And we’ve seen some amazing depth of response for CAR T compared to what we see with the normal chemotherapy. So the other piece is how we have other trials that are doing earlier lines. So there’s new CAR Ts that are coming out, hopefully in the near future as a standard of care. So there’s one called ddBCMA. It’s a study by Arcellx. And the big news was that Kite, which is one of the big lymphoma CAR T companies, just took over to do their big Phase III study.

So hopefully we’ll have FDA approval for this in the next year with our Phase II study. But the Phase III will be in second line forward just like the CAR T 2-4 was. And this CAR T, it’s different in the way it’s built. And we really don’t see any of the neurotoxicity at all so far, which has been pretty impressive. But we see the same efficacy that we saw with cilta-cel. So this could be sort of best of both worlds, knock on wood. But so far we’ve seen some really great responses. And I think that trial being offered earlier will be great as well for a lot of our patients to get something that might be better than what we have already. The other trials are with other targets.

So we do have some studies that are looking at different targets instead of BCMA. So now we have patients who have already had CAR T with BCMA and over time, years, for the most part, they’re relapsing. And so now we have GPRC5D CAR Ts that are actually being combined with different things to then be able to give them a little bit earlier rather than waiting till after BCMA or fifth line, etcetera. So we have lots of trials looking at all different ways to combine CAR Ts or newer versions of the BCMA CAR Ts that I think are really, really exciting. And I think it’s really hard to keep up with this.

So my activation tip here is really talking to a myeloma specialist about different options that are out there for trials because different centers will have different trials that are open and you need someone to help you navigate with that. Which ones are the best ones for you? And then I would say talking to your patient advocacy groups, because that’s really where a lot of my patients hear the information. And then they come to me and say, “Listen, I heard this, what does it mean?” And I think that really helps you kind of even know where to start from.

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How Can Variable Patient Groups Be Addressed in CAR T?

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How Can Variable Patient Groups Be Addressed in CAR T? from Patient Empowerment Network on Vimeo.

Can CAR T-cell therapy address variable patient groups? Expert Dr. Krina Patel from The University of Texas MD Anderson Cancer Center discusses variances in different myeloma patient groups, the KarMMa-3 study, and proactive advice for patients.

[ACT]IVATION TIP

“…if you are in a area, let’s say rural America where you don’t have access or you are in a minority population, African American, Hispanic, etcetera, or older, frail patients who are older that are considered vulnerable as well, absolutely make sure to talk to your doctors about these novel therapies because you still can get them safely and they will work. They can work. You just have to go to a center where they know how to adjust those types of therapies to make sure you get the best options out there as well.”

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 Are CAR-T Clinical Trials Studying Use As a Frontline Therapy?

Are There Myeloma Trials Investigating CAR T for Frontline Therapy?

 A Look at Promising Strategies to Improve CAR T-Cell Therapy Access

A Look at Promising Strategies to Improve CAR T-Cell Therapy Access

Transcript:

Lisa Hatfield:

Dr. Patel, how might the heterogeneity of patient populations impact the standardization and reproducibility of CAR T therapy outcomes across different clinical settings, and what initiatives are in place to address this variability?

Dr. Krina Patel:

Yeah, I think that’s a great question because again, this is a personalized therapy. So it depends on what your myeloma is like, the genomics, the genetics of your myeloma, how aggressive is it, plus your T cells, right? And so everybody’s genetic ancestry, etcetera, is very different. So the idea of a personalized medicine, more than just even across groups of people, it’s at the individual level. And I think when you talk about different races or ethnicities, we have seen some differences in our real-world data, in very relapsed/refractory patients, where people can get great response rates still.

So, for instance, Caucasian patients versus African American patients, our response rates are still high in the 80s and 90 percent, but the toxicity is a little bit higher in our African American patients. It’s still not high grade. It’s not anything that makes me say, I’m not going to give this, but the baseline inflammatory markers are a little bit higher. And so once we get the CAR T, our patients tend to get a little bit more CRS.

They end up in the hospital a little bit longer. Now, again, this is a multivariate analysis and we couldn’t find any other difference, but when we look at KarMMa-3, which is one of our big studies that led to ide-cel (idecabtagene vicleucel) [Abecma] being approved early, we actually had an outcomes of African American patients only that we looked at and that we presented just this past TCT, and response rates were actually a little bit better.

Again, you can’t compare them because the numbers aren’t there to power that to compare, but numerically the numbers were better in terms of response rate, in terms of progression-free survival, it was actually more months that it beat the standard of care and we didn’t see more toxicity.

And so I think we do need to look at these things and make sure there’s not one group of patients has a lower efficacy for some reason, and why is that and how can we improve that? And so far, we don’t really see that. And the other is the toxicity piece, to make sure that these therapies that do cause some strange toxicities that we’re watching and seeing who might be more vulnerable to those toxicities, who do we need to maybe even prevent, do prevention strategies for, but so far we haven’t seen it.

And then I think coming back to the individual, right?So again, all of us have these different T cells that have different mutations in them, and some folks, for some reason, even with less myeloma, their T cells just expand really fast and other folks, they don’t. And so in the future to get best outcomes, we need to see how we can turn the volume lower for those folks who have really sensitive T cells.

And for those who don’t, how do we, what else can we add in combination to actually increase those T cells so that they’re actually doing a better job at killing the myeloma, right? And including the microenvironment too. So I think there’s a lot of translational work as well as the epidemiology side of things to say, okay, how do we first diagnose the problem, find the problems, and then how do we figure out how to intervene to then improve outcomes for all our patients? I think the activation tip here is that if you are in a area, let’s say rural America where you don’t have access or you are in a minority population, African American, Hispanic, etcetera, or older, frail patients who are older that are considered vulnerable as well, absolutely make sure to talk to your doctors about these novel therapies because you still can get them safely and they will work. They can work. You just have to go to a center where they know how to adjust those types of therapies to make sure you get the best options out there as well.

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What Patient Types Are Good Candidates for CAR T-Cell Therapy?

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What Patient Types Are Good Candidates for CAR T-Cell Therapy? from Patient Empowerment Network on Vimeo.

For CAR T-cell therapy, what patient types are good candidates? Expert Dr. Krina Patel from The University of Texas MD Anderson Cancer Center discusses patient situations that qualify them for CAR T-cell therapy and shares proactive patient advice.

[ACT]IVATION TIP

“I think a lot of people have this misunderstanding that CAR T isn’t for everybody, but I will say it’s actually more likely that you’re going to be eligible for CAR T over auto transplant. So I think it’s just bringing it up, talking to them, and seeing a specialist to discuss which ones are the right one for you and when to go.”

Download Guide | Descargar Guía

See More from [ACT]IVATED CAR T

Related Resources:

How Can Variable Patient Groups Be Addressed in CAR T?

How Can Variable Patient Groups Be Addressed in CAR T?

 Are CAR-T Clinical Trials Studying Use As a Frontline Therapy?

Are There Myeloma Trials Investigating CAR T for Frontline Therapy?

 A Look at Promising Strategies to Improve CAR T-Cell Therapy Access

A Look at Promising Strategies to Improve CAR T-Cell Therapy Access

Transcript:

Lisa Hatfield:

Dr. Patel, given that CAR T is approved for earlier lines of therapy, can you describe the type of disease characteristics of patients that are likely to be considered first for CAR T?

Dr. Krina Patel:

Yeah, I think it’s a really exciting time, we got approval for two different CAR Ts that were approved in fifth line. So patients had to relapse four times before they could get to CAR T therapy. And now one of them, cilta-cel ciltacabtagene autoleucel [Carvykti], is approved in second line, so people have to relapse once before they can get it.

And the other CAR T, ide-cel (idecabtagene vicleucel) [Abecma], is approved in third line, so you have to relapse twice. There are reasons why that is the way it is, but both of these CAR Ts are pretty fantastic, and we’re really excited that more patients will now have access. As you can imagine, relapsing once, it’s already hard enough to then say, okay, I need a different therapy, but to go through four times before you can do something like CAR T is really, really important.

So I think the biggest characteristic, and I would say for my patients, it’s really their ability to keep their myeloma controlled for at least six to eight weeks, potentially, right? Because this is a personalized therapy, unlike most other myeloma therapies where we have to take the T cells out, we have to then send them to a lab to make the CARs, then it takes about four to six weeks to get them back. During that time, I just have to know that your myeloma can stay controlled or even improve with whatever bridging therapy we decide to do during that time.

And we know that when patients have myeloma that is on its way down, that it’s actually improving, by the time they get to the CAR T therapy, the infusion part, they tend to do better in terms of efficacy, but also have less toxicity. So there’s a few different toxicities that we can talk about with CAR T that are very distinct compared to most other therapies, that again, if you have less disease burden, the rates of that toxicity and the high-grade toxicity goes away, right? It’s much, much lower than if you have a lot of myeloma coming in.

So, again, for my patients who have disease that I know I have other therapies to keep it knocked down or to knock it down during that bridging, that really is the main difference between, can I take this patient to CAR T or not? But I think there’s some nuances too, again, that idea that one CAR T is approved in second line, another one is approved in third line, I do think they’ve never been tested head to head, so we don’t have data in a clinical trial, but in the real world, we’ve used both of these products, a lot of us have, and I think most of us will say that one of the products is probably stronger, it probably works better cilta-cel, and that is the one that’s approved in second line, which is great.

So for my fit patients who don’t have a lot of comorbidities, who do really have high-risk disease that I need to be as aggressive as possible and do something very different, hands down, it makes sense that cilta-cel is the right thing to do right at second line, but the toxicity is also a little bit higher with that, meaning that patients are more likely to potentially get some of these strange neurotoxicities that we see, that we didn’t really see before with other therapies, some of our myeloma patients get neuropathy and we think about that as neurotoxicity, but this is different.

This is more patients after 30 days of having had their T cells can all of a sudden get a facial palsy where they’re having drooping of their face and it can affect their eating and their speaking. Now those things are not fatal, we can treat it with steroids, things like that, but they can affect your quality of life. And if it doesn’t resolve, that can affect down the road, all the other therapies we want to give you, right? But the more dangerous one is something called delayed Parkinsonianism or delayed motor neurotoxicities.

And again, we know the best prevention of that is decreasing the myeloma burden before going to CAR T, but if we can’t do that or some patients can still potentially get this Parkinsonianism, we really want to make sure there’s a risk-benefit discussion, right? That we say, okay, this is why we should go in second line.

Again, the risk is less than 1 percent now based on how we’ve done things for prevention. But on the other hand, with ide-cel, most of our patients, even on dialysis, our patients that are getting CAR T and doing well, patients with heart failure, I’ve had a 90-year-old go through ide-cel without any issues and have great responses. So I think both of these offer, one of the first times they offer time without any therapy for myeloma. And so I would say this is something most of my patients should ask their physicians about, but really then it’s nuanced in terms of when we should do it and which product.

Lisa Hatfield:

Okay, thank you. And do you have an activation tip for that question, Dr. Patel?

Dr. Krina Patel:  

Yeah, so I think the activation tip here is bring it up, bring up CAR T to your doctors, right? I think a lot of people have this misunderstanding that CAR T isn’t for everybody, but I will say it’s actually more likely that you’re going to be eligible for CAR T over auto transplant. So I think it’s just bringing it up, talking to them, and seeing a specialist to discuss which ones are the right one for you and when to go.

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Developing Research and New Myeloma Treatment Options

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Developing Research and New Myeloma Treatment Options from Patient Empowerment Network on Vimeo.

What are the new developments in myeloma treatment and research? Dr. Brandon Blue discusses how the landscape of myeloma care has changed in recent years and treatment options for high-risk myeloma, and he shares developing research that patients should know about.

Dr. Brandon Blue is Assistant Member and Clinical Instructor in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, FL. Learn more about Dr. Brandon Blue.

See More from Evolve Myeloma

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What Myeloma Patients Need to Know About Bispecific Antibodies

 Myeloma CAR T-Cell Therapy_ How Does It Work and What Are the Risks

Myeloma CAR T-Cell Therapy: How Does It Work and What Are the Risks?

 How Is High-Risk Myeloma Assessed

How Is High-Risk Myeloma Assessed?

Transcript:

Katherine Banwell:

Dr. Blue, the landscape of myeloma care has changed significantly in recent years. Are there new factors to consider when working with a patient to choose a treatment approach?   

Dr. Brandon Blue:

Yeah. The good thing about myeloma is it’s literally always changing, and that’s a great thing. Compared to some of the other cancers, or really even other diseases, sometimes we’ve been using the same things since the ‘90s. But luckily for myeloma every couple years we get something that’s bigger, and typically better. So, right now some of the new things that are available for patients are all the way from newly diagnosed, all the way to people who have relapsed disease. So, we have a lot of different options that we can potentially go into.  

Katherine Banwell:

Dr. Blue, what treatment options are available for myeloma that’s considered high-risk?  

Dr. Brandon Blue:

Yeah. So, unfortunately, there’s some people who have multiple myeloma whose disease does not follow the standard pattern. Unfortunately, what happens is that there are certain mutations that actually happen in the biology of those cancer cells that actually cause them to survive when they should be dying. And unfortunately, that means that sometimes the chemotherapy and the medicines that we give them becomes a little bit more resident. 

A lot of times when we give people treatment the one question they ask is, “How long will it last?” But, unfortunately, there’s some people who have those high-risk features that unfortunately, despite whatever numbers we tell them of how long it may last, theirs actually may last a little bit shorter, and the disease may come back a little bit quicker. So, what we have to do as the doctors, and as the team, taking care of these patients is maybe do things a little bit more outside of the box, and do things that might tend to be a little bit more aggressive. 

Because sometimes we have to match the aggressiveness of the disease. If the cancer itself is starting to be high-risk or aggressive, sometimes we may have to do some nontraditional things to kind of make sure that they have a good outcome and a good result.  

Katherine Banwell:

Dr. Blue, is there developing research that myeloma patients should know about? And what are you hopeful about?  

Dr. Brandon Blue:

Yeah. One of the things that happens right now is that we have CAR T that’s available for patients got approved by the FDA. However, the CAR T product that we currently have available only have one target, which is called the BCMA, or B-cell maturating antigen. 

Which is part of the plasma cells, however, there are so many other targets on the plasma cells that potentially can be targets for new medications. And the good thing is that there are actually new CAR T and medications that are being developed that actually target other things other than the BCMA.  

So then, it may come to the point where people get more than one CAR T down the road, and I think those are exciting clinical trials. Because if there’s multiple targets, and there’s multiple CAR T, maybe we can sequence them in a way that maybe we find a cure for the disease one day.  

Katherine Banwell:

That’s exciting.  

Dr. Brandon Blue:

It is.  

Katherine Banwell:

Dr. Blue, thank you so much for joining us. Do you have anything else you’d like to mention?  

Dr. Brandon Blue:

I just want people to know that it’s okay to get a second opinion. I think that regardless of what’s happening in your care, sometimes it’s always good just to have someone, especially someone who’s what they call a myeloma specialist, to review your case, and just make sure that you’re on the right road, and that things are going well for you. So, it’s something that I would recommend for anyone to do. 

What Emerging Myeloma Treatments Are Showing Promise?

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What Emerging Myeloma Treatments Are Showing Promise?  from Patient Empowerment Network on Vimeo.

Myeloma specialist Dr. Mark Schroeder reviews the latest advances in myeloma treatment, including a discussion of CAR T-cell therapy and bispecific antibodies.

Dr. Mark Schroeder is a hematologist at Siteman Cancer Center of Washington University School of Medicine in St. Louis. Dr. Schroeder serves as Associate Professor in the Department of Medicine. Learn more about Dr. Schroeder.

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 Expert Perspective Advances in Treating Relapsed and Refractory Myeloma

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Transcript:

Katherine Banwell:

What about emerging therapies for myeloma? What approaches are showing promise? 

Dr. Mark Schroeder:

So, I think the biggest news in myeloma, and across a lot of cancers now, are immunotherapies. We know in myeloma – now we have two CAR T-cells –  

Now a CAR T-cell is engineering your own immune cell called a T cell to express a receptor on its surface that binds to the myeloma, and then those immune cells go and kill the myeloma. That’s a form of immunotherapy.  

There’s two CAR-T cells for treating myeloma after the myeloma has come back four times, has needed four treatments. Those are very active in that line of therapy, and we can see response rates over 80 percent in patients who otherwise weren’t responding to other approved therapies for myeloma.  

On the other hand, there are other immunotherapies that are used earlier in the treatment course of myeloma. One that is not incorporated more frequently for the initial treatment is a drug called daratumumab – it’s an antibody. It’s a protein that binds to the surface of myeloma and stimulates the immune system to react against the myeloma. And so, it’s not a traditional chemotherapy, but it’s using your own immune system to attack the cancer.  

And then a third one that’s probably just as – it looks just as potentially effective as CAR-T cells are called bispecific antibodies. And that would use a protein similar to daratumumab which is an antibody, but it uses parts of antibodies to bind to – it could be two different proteins – one expressed on a T cell, the other one expressed on the myeloma cells. And when it binds, it brings those two cells together and causes your own immune system to attack the myeloma. Those are also very effective, and within the next month or two, there will be a bispecific antibody approved for treating patients with myeloma. 

Katherine Banwell:

Oh, that’s great news. Any others? 

Dr. Mark Schroeder:

Yeah, well – I mean, the other potential – there are other immune cells called natural killer cells that are also in clinical trials for development to attack myeloma, and potentially even engineering those natural killer cells to attack myeloma.  

There are other antibodies; sometimes the antibodies of protein bind a specific target on the surface of the myeloma. I mentioned one – daratumumab – but there is a whole list of others that are in clinical development. The one other antibody – or two, couple of other antibodies that are approved for treating myeloma are isatuximab which also binds to CD38. And another one called elotuzumab which binds to a protein called CS1 or SLAMF7 on the surface of myeloma.  

That’s more information than you probably wanted or needed, but those antibody therapies can be very effective in treating myeloma. There is another antibody therapy that has a payload of a toxin on the antibody, and it binds to BCMA or B-cell maturation antigen.  

That’s the same antigen that the bispecific antibodies as well as the CAR-T cells are targeting on myeloma surface, and so that is potentially one that is approved by the FDA also to treat myeloma.   

Katherine Banwell:

As we close out our conversation, Dr. Schroeder, I wanted to get your take on the future of myeloma. What makes you hopeful? 

Dr. Mark Schroeder:

Well, I am hopeful – just within the last five years, there have been a number of new drugs approved for myeloma. They are approved for later lines of therapy, but they are being moved earlier in the treatment. And within the last 10-20 years, we’ve seen an improvement in the survival of patients with myeloma. As these new therapies are in development, as they’re being moved earlier in the treatment line, I’m very hopeful that survival and potentially cure for this cancer is possible. The only way that we’re going to get to that point is through clinical research and for patients to partner with their physicians and to consider clinical trials because that is the only way that new drugs get approved and are available to other patients with myeloma. So, I’m excited about what is approved; I’m excited about what’s coming through the pipeline to treat myeloma.