Evolve | What You Should Know About Advances in CAR T-Cell Therapy for Myeloma

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Transcript:

Katherine Banwell:

Hello and welcome. I’m your host, Katherine Banwell. Today’s program is part of the Patient Empowerment Network’s Evolve series, which was developed to provide you with the latest treatment information and research, helping you to feel empowered and confident during conversations about your care. In today’s program, we’re going to hear from an expert in the field discussing CAR T-cell therapy and the evolving treatment landscape. 

Before before we get into the discussion, please remember that this program is not a substitute for medical advice. Please refer to your healthcare team about what might be best for you. Joining us today is Dr. Rahul Banerjee. Dr. Banerjee, it’s so good to see you. Welcome. Would you please introduce yourself? 

Dr. Rahul Banerjee:

Of course. Thank you, Katherine, for taking the time to interview me. Thank you to everyone who’s listening. My name is Dr. Rahul Banerjee. I’m an Assistant Professor of Medicine at the Fred Hutchinson Cancer Center in Seattle, Washington.  

I specialize in multiple myeloma, which is a form of blood cancer that we’ll talk about, and other precursor conditions, for example, smoldering myeloma and AL amyloidosis. I have a heavy interest in CAR T therapy and bispecific antibodies and other types of immunotherapy for blood cancers, and I’m sure we’ll be speaking about that as well. It’s great to be here. 

Katherine Banwell:

And thank you so much for taking time out of your busy day. I’d like to start by talking about your role as a researcher. You’re on the front lines for advancements in the myeloma field. What led you here, and why is it important to you? 

Dr. Rahul Banerjee:

Absolutely. So, the short answer is that I love the art and the science of oncology, of cancer care. I feel like it really gives us a great chance to work with patients and really help them through the difficult chapter of their life. And the science, particularly in malignant hematology, is a word we use for blood cancers like myeloma, lymphoma, et cetera. There’s a lot of fascinating science about how do we train the immune system to overcome cancers of immune cells? 

In terms of why myeloma, you’ll probably hear this from many physicians who speak on this program. Part of it is the patients, and I love treating my patients with myeloma. They have the most interesting stories for me. Many of them are older and have been through a lot, and I worked with them for years for diagnosing myeloma, treating them through myeloma, monitoring for relapses, and so forth. 

And also the mentors whom I had. So, when I was a trainee in fellowship, I was not sure where I would go. I knew it was somewhere within blood cancers, but I had a mentor, Dr. Nina Shah, who is phenomenal, and she did a lot of work in multiple myeloma in particular, including around CAR T therapy, and I kind of molded myself, imprinted myself on her. And now several years later, here I am kind of working in this similar space, focusing again at the intersection of multiple myeloma and these immunotherapies, like CAR T therapy. 

Katherine Banwell:

We’ve been talking about CAR T-cell therapy for a number of years now. How has this treatment revolutionized care for patients? 

Dr. Rahul Banerjee:

Absolutely. So, the biggest benefit of CAR T therapy, I think, is how well it works. So, I’ll predominantly focus on multiple myeloma, but of course there are CAR T therapies that are approved for different kinds of lymphoma, and B-cell leukemia as well. But in brief, CAR T therapy, we train the immune system to fight back against the myeloma, against the cancer that’s there. And it’s phenomenal, because it’s the only living drug we have, really, in our toolbox. Everything else is dependent on the dose, right? As soon as the drug is out of your system, it stops working. CAR T-cells don’t work that way. They can live and expand and proliferate to get rid of the threat within. 

And at least in myeloma, for example, CAR T therapies regularly have response rates, meaning complete response rates, how quickly they knock all the myeloma parameters down to zero basically in the 70, 80, 90 percent range. Many patients achieve measurable residual disease, or MRD negativity, meaning by all the best tools available in 2024, no sign of the myeloma anywhere.  

That doesn’t mean cure, to be fair, but that’s wonderful. With other conventional therapies, to have one drug with one infusion have that big of an impact on the myeloma is phenomenal.  

The other benefit of CAR T therapy is that it is a one-time infusion. It doesn’t mean that patients can get one-time CAR T and never have to see a cancer doctor again because again, at least in myeloma, I don’t consider CAR T to be uniformly curative for patients. However, if you look at the studies, and there’ve been two randomized studies in myeloma of CAR T therapy versus standard therapies. One was a KarMMa-3 trial with a drug called ide-cel, a CAR T drug also known as Abecma. And the other one was CARTITUDE-4, which was a study of cilta-cel versus standard treatment. And cilta-cel is a kind of CAR T also known as Carvykti.  

Both studies saw improvements, dramatic improvements in the response rate, how many patients had the myeloma numbers come down, but also durations of response and progression-free survival. How long patients were alive and disease-free for.  

Literally just a month ago, we found out officially that the cilta-cel trial and the CARTITUDE-4 study, CAR T actually prolonged overall survival compared to standard therapies, which is what patients are looking for.  

But for me, what I love about CAR T the most is not just that you’re in remission for longer, or with cilta-cel you live longer, but that you live better. Both studies, and I’m very happy to see this incorporated, what we call patient-reported outcomes, which is an area of research of mine. Patient-reported outcomes are, as you can imagine, outcomes that are reported by the patient. Not the blood test for the myeloma, but how are patients feeling in terms of their quality of life, in terms of their fatigue, in terms of their pain.  

And in both studies, off the charts. CAR T does way better and way faster in terms of improving quality of life than standard treatments, to the point where the studies, for example, often for both of them, if I recall correctly, the first time point where they looked and compared the two arms was three months after CAR T. And already by then, night and day difference.  

The patients who got CAR T, the first month a little bit rocky, but after the first month or two, they’re doing better, because they’re not on myeloma treatments continuously. They’re still getting blood work checked and so forth, but they’re not on treatment. It’s a one-time infusion and monitoring thereafter. 

And I love that about it, and I think that explains a lot of the quality of life benefits that we see.  

For my other patients with myeloma, outside of CAR T, there is never a scenario where they’re observed. The vast majority of patients because myeloma is considered incurable, we keep them on some form of maintenance treatment, and those come with side effects. Those come with financial toxicity. That’s the word we use for high out-of-pocket costs. They come with what I would call time toxicity. That’s time spent on the phone coordinating shipments or coming in for this infusion or that infusion. 

CAR T has much less of that, and I think that’s phenomenal. So, I would say that it’s revolutionized the field, not just scientifically from the things that you’d expect a researcher to care the most about – for how long, you know, how deep are their remissions and how durable are their remissions, but also for the things that I care about. The art of oncology is how our patients are living, and that’s why I think CAR T is revolutionary. 

Katherine Banwell:

Dr. Banerjee, would you walk us through the currently approved CAR T-cell therapies for myeloma and share how these treatments work to combat myeloma? 

Dr. Rahul Banerjee:

Absolutely so. So, there’s two FDA-approved CAR T therapies right now for multiple myeloma. One is ide-cel, also known as Abecma. One is cilta-cel, also known as Carvykti. The mechanics of them are pretty similar. Both involve T-cells being collected from the patient and then turned into CAR T-cells, cancer fighting cells in a lab, then put back into the patient after a small dose, what we call lympho-depleting chemotherapy, that creates a void and makes room for the T cells. 

And then the T cells come in and are able to activate and proliferate and respond and kill off the myeloma. In terms of the two drugs, the differences between them, we might come back to that a bit in terms of just how they’re approved. Cilta-cel is currently approved as early as first relapse. So, second line treatment onwards in myeloma for patients who have disease that is refractory to lenalidomide (Revlimid) or a similar class of drugs.  

So, lenalidomide is Revlimid. So, if someone’s been on Revlimid and it stopped working, they could technically go to cilta-cel, which is Carvykti, as soon as second line. 

Ide-cel or Abecma is approved for third line treatment, meaning at least two prior relapses or two types of therapy that were stopped unexpectedly because of not working or toxicities or so forth. And those patients would have had to have received both an iMiD, like Revlimid, which is lenalidomide, a proteasome inhibitor, which is like Velcade or bortezomib, and a CD38 directed monoclonal antibody like daratumumab, which is also called Darzalex or Darzalex Faspro.   

Katherine Banwell:

CAR T therapies have been in use for several years now. As a clinician, what challenges are you facing with this treatment option? 

Dr. Rahul Banerjee:

Absolutely. So, I would say threefold, is the best way to describe it. So, I think the first and most practical, like the most important one is obviously access. It’s very easy for me to talk about CAR T therapy. I had the privilege of working at a big center, where I was just last week attending on our CAR T service. We’re big enough to have a CAR T service. 

Most patients are treated in the community, and they don’t have access to a doctor who’s personally familiar with CAR T. And so for them to get to CAR T requires a move to a big academic center, a big tertiary care center. Obviously, I think this talk is geared more towards the U.S. audience, but most of the world has no access to CAR T, period, except for research protocols, and that makes things really tough. So, I think that’s one unmet need in general, where those patients who cannot get to CAR T never see me, and that’s a big disparity in the field.  

Two, I would say that the autologous CAR T products we have, autologous is the word that we use for the T cells that are coming from the patient themselves. Both Abecma and Carvykti, again, it’s the patient’s own cells that are being taken out, turned into CAR  
T cells, and put back. That manufacturing process takes time. Typically, I tell patients to expect about one to two months, closer to two months often, between the day that the T cells are taken out and the day they’re put back in again, what we often call the quote unquote “vein-to-vein interval.” And that’s hard because for some patients that’s not practical. 

The myeloma is, you know, so aggressive, behaving aggressively, that they cannot wait. There’s no drug I can give them where I can wait two months for the T cells to be manufactured. We’re getting better at it. The drug company is working better at it. There are a lot of investigational products that are not FDA approved yet that are looking at rapid manufacturing, where can you grow these  
T cells and the CAR T cells in two days or one day, instead of several weeks? I think that’s really interesting. 

There are studies of allogeneic CAR T cells, where the T cells are pre-manufactured from a healthy donor and manipulated so they won’t cause any other problems, but will attack the myeloma. So, a lot of research happening there, but that’s the problem for patients where they cannot get to CAR T therapy.  

And then the third unmet need would be – I’m seeing more of this, unfortunately, right? CAR T therapy is not considered curative for myeloma. Have I met people who are doing great years out from myeloma? Yes, from CAR T therapy, and I love that. In the original LEGEND-2 study, the study that led to the CARTITUDE-1 study that led to the approval of cilta-cel, which is Carvykti. 

If I recall correctly, about 20 percent of patients on that first Chinese study years ago are alive and disease-free five years later. That’s not enough, right? I don’t want it to be 20 percent, I want it to be 100 percent. And so we have work to be done there in terms of what do we do when the myeloma, the CAR T cells stop working, or they’re out of the system and are no longer there to fight back. What do we do next? And I think that’s another unmet need still. Despite all the advances, what to do after CAR T, no one really knows. 

Katherine Banwell:

Yes. Well, how is success measured for CAR T-cell therapy? 

Dr. Rahul Banerjee:

It’s a great question. So, traditionally, the metric in multiple myeloma has been achieving a complete response. So, having the M-spike, the antibodies that are produced by the myeloma cells, come down to zero.  

So, either the M-spike, or for some patients, that may be the kappa or the lambda, which are fragments called light chains of antibodies, coming down to the normal range. The hard thing about those is that they take time. I’ve had patients who get CAR T therapy, and their bone marrow is completely clear, including MRD, measurable residual disease, as I’ll talk about in a second, but the M-spike takes months. 

I had one patient where it took a year and a half for the M-spike to finally come down to zero. And it’s frustrating because I would say that, look, in my heart, you’re in remission, but if I were a lawyer, I wouldn’t be able to say that, because technically the M-spike is not quite zero yet. Your body’s just recycling that antibody. It’s not all the way down to zero, and that makes things tough. So, I don’t think that’s a great barometer to use.  

I think MRD, which is again, a bone marrow test that we can spend more time talking about another day, is helpful. And at the one-month mark, achieving MRD negativity.  

So, if you look in the bone marrow, by all the best tests available in the United States in the year 2024, and you can’t even find one out of a million cells that are myeloma, that’s obviously great to see.  

That doesn’t mean that if it doesn’t happen, the patients are going to do poorly. There’s a lot more to CAR T than that. So, I think MRD negativity is probably the best short-term barometer. I think the best long-term barometer would be progression-free survival, which is, again, the medical word of saying how long is someone alive and in remission for. 

With cilta-cel, which is Carvykti, again, in the CARTITUDE-1 study, which led to its approval, its first approval for four prior lines of therapy. There, most patients, the median progression-free survival was 35 months. So, almost three years. That’s amazing, right? Three years of mileage of coming in for blood work, some supportive care, IVIG, which is a type of antibody transfusion, but not needing myeloma treatment. That’s great. That’s the bar that we’d be looking for from an efficacy perspective. I think the other thing, just to talk about it, I’m sure we’ll come back to it, would be safety, right? Because these cells, these therapies do come with side effects.  

And so I think the other bar by which, in the future, I may compare CAR T therapies as more come to market, would not just be this progression-free survival, which is how long are patients in remission for and disease-free and alive. Not just MRD negativity, which is how the bone marrow biopsy looks at day 28, one month after CAR T. But also the safety profile. Are we seeing any scary, concerning, delayed toxicities? And if we don’t, that would be another bar for success in my mind, especially as we move CAR T to earlier lines, where other treatments are available. 

We have to make sure that the benefit-risk ratio for CAR T remains favorable. 

Katherine Banwell:

Yes. Well, let’s talk about side effects of CAR T-cell therapy. What advances are being made in managing them? 

Dr. Rahul Banerjee:

Excellent question. So, I break the toxicities into short-term and long-term toxicity of CAR T therapy. And this is actually fairly similar for both, regardless of the underlying disease, whereas lymphoma, leukemia, or myeloma, very similar. Just so everyone, just to reorient the audience, short-term toxicities, people often talk about the big two. I’m going to say the big three, actually. The first one is cytokine release syndrome, or CRS, which is inflammation, typically causing fever, sometimes low blood pressure. 

The second is neurotoxicity, or ICANS. For reasons that aren’t entirely understood, sometimes all those chemicals from inflammation can cause people to feel a bit off mentally or cognitively. Sometimes people might not be able to talk, or might not talk correctly, or sometimes have issues along those lines. 

And the third, I would say, is low blood counts or infections. Both the lymphoma, leukemia CAR Ts and the myeloma CAR Ts very rapidly deplete the good plasma cells or the good lymphocytes, the good cells in the bone marrow, and so immediately you see patients at risk of infections. 

And for a complicated number of reasons, one of which being cytokine release syndrome, CRS inflammation within the bone marrow, where all these cancer cells are hiding, the stem cells in the bone marrow hide away, right? They kind of go into a bunker to stay away from all of this. And so patients often have low blood counts for significant amounts of time after CAR T therapy, something called hematotoxicity. 

Those are short-term toxicities. Long-term, very briefly, that risk of infection and low blood counts is still there, I would say, for up to a year after CAR T therapy, sometimes longer for some patients. There is a risk, obviously, of the original cancer coming back, in this case the myeloma, particularly myeloma.  

And three, there are rare delayed toxicities to be on the lookout for. So, one of them, for example, with cilta-cel or Carvykti, the numbers are hard to see what the rate is prospectively because it’s been going down with time.  

But rarely, I would truly in my heart say 1 percent of the time, if not less, patients can get Parkinsonism, where they’re not able to move as rapidly, they’re not able to, they’re kind of shuffling gait, having tremors, et cetera. Not the same as normal Parkinson’s disease, because the normal meds don’t work, just time is often the only thing that really makes a big difference. 

Technically, there’s a box warning on all CAR T therapies now about a risk of second cancers. That risk is not new to anyone who’s ever received any treatment for myeloma because from the very beginning, we tell people that these drugs have been linked to a potential risk of second cancers in the future.  

In terms of strides that are being made to improve that, I think we’re making a lot of improvement. So, I think the biggest thing that we’ve learned, and I remember when I was a trainee, for example, when I was in my medical training, the early days of CAR T therapy – actually out in Philadelphia, I trained at Penn – and there, we were scared about trying to tone down the inflammation.  

When these side effects happen in the short term, the goal is if the patient’s obviously having side effects, and the question is, “Can we not kill the T cells? Can we just dial that down?” Say, “Look, I’m happy the T cells are angry. I’m happy they’re killing the cancer, the myeloma in this case. But can you just dial it down a little bit with a medication called tocilizumab (Actemra), or corticosteroids like dex?” 

We used to be very nervous about doing that because we said, look, the patient’s put all this blood, soil, sweat, and tears right into this CAR T therapy, and we don’t want to do anything that can hinder the T cells from working.  

Now we know that that level of inflammation is not doing anyone any favors at all, and so we’re able to really start these medications to just dial down the immune system faster. As soon as someone has a fever, for example, at many centers, we do consider, within an hour or two, giving one of those medications. Don’t wait till they’re in the ICU, give it then.  So, I think just tweaking our algorithms has made probably the biggest difference, in my mind, to make CAR T safer.  

Other things that have helped, I think, are better understanding of why patients have these other toxicities and strategies to prevent it. And so, for example, the neurotoxicity risk, some of it is part of disease burden. We think that patients who have a lot of disease going into CAR T therapy may have more toxicities. So, giving better treatments as, quote-unquote, “bridging treatment” before CAR T therapy that we have better, newer treatments now, have sometimes helped to really debulk the disease before going to  
CAR T.  

That’s helped a lot with side effect management. In terms of long-term risk, the third thing that I really encourage all my patients and all my oncologist partners in the community to really push for is the infection risk and how do we prevent it? So, I think probably the biggest thing that we’ve recognized is intravenous immunoglobulin, which is IVIg, which is basically an antibody transfusion.  

When people donate blood, they also donate plasma, often, and the plasma contains antibodies against whatever they themselves have fought off circulating in the area – viruses, colds, et cetera. 

You can take all those antibodies, put them all together into a sterile bag, and give it to the patient who’s gotten CAR T therapy. Because the patient’s gotten CAR T therapy, assuming it’s working, which it normally does for several months, right, to knock out all cells, good and bad immune cells, that patient is not making any antibodies at all. They’re a sitting duck for infections. And so I would say IVIg, using that routinely now is not just the exception once they’re having infections, but even in the absence of infections, just giving it.  

Insurance companies are not happy with me when I suggest that because it’s expensive, but that’s the right thing to do for patients, and I think that has helped a lot, in my experience, for all of these immunotherapies, both CAR T and bispecific antibodies, to lower the risk of infections.  

Katherine Banwell:

Can you share any updates in CAR T-cell therapy research? 

Dr. Rahul Banerjee:

Sure. So, several. I would say the first, I alluded to very briefly earlier, was how do we make that vein-to-vein time shorter? So, the vein-to-vein is, again, from the moment that the T cells are collected to when they’re put back into the patient.  

And so a lot of research is how do we make that better? We have rapid manufacturing protocols that, again, where the T cells are taken out and manufactured within a couple of days and brought back into the patient. They’re still testing for safety and sterility and everything that needs to be done, so it’s not overnight, but still, one or two weeks’ worth of vein-to-vein time is way better than one to two months.  

The allogeneic CAR T cells that are coming from a healthy donor, those are fascinating, right? Because if the cells are pre-manufactured, there’s no risk of them not manufacturing or manufacturing in an odd manner, what we call auto-specification. They’re ready from a healthy donor, ready to go. 

And one of the studies that was presented last month at our International Myeloma Society meeting in Brazil, the time, the median time from when the patient went on the study to when they started that lympho-depleting pre-CAR T therapy was one day, and that means they got CAR T therapy within one week of going on the study. That’s phenomenal. And so I think that research is ongoing.  

There are some side effects about allogeneic, healthy donor CAR  T-cells in terms of making sure the T cells stick around and don’t cause other issues. Sorry, for another day. I think that’s one area of research.  

I think the other big area of research is how do we make CAR T-cells work for longer for more people? There are easy ways, and there are controversial ways to do that. So, I think the easy way is can we use MRD negativity or other tests to identify who is at very low risk of relapse and monitoring them appropriately.  

There are patients where, in the future, we may talk about doing some form of post-CAR T maintenance therapy. Again, the bar for that should be set pretty high, and it is set pretty high because as I mentioned earlier, many patients prefer CAR T therapy, not just because of the deeper remissions and longer remissions, but because it truly is time away from treatment. But they’re still coming in for the IVIg and the blood work and seeing a doctor, et cetera, but they’re not getting daily treatment with lenalidomide, which is Revlimid, or pomalidomide, or Pomalyst, or something like that. And that’s wonderful. 

However, there may be some patients where some form of strategy will use one of those medications or experimental medications. There’s a newer class of the lenalidomide, Revlimid, pomalidomide, Pomalyst called CELMoDs.  

They’re not approved yet, but drugs like iberdomide or mezigdomide that work better, and not just against the myeloma. They actually make T cells stronger, believe it or not. 

And so in the future, there may be scenarios where we recommend for certain patients that, hey, in your particular case, after CAR T therapy, to keep the myeloma away, I’d recommend using this form of maintenance, a pill or something like that, just low dose to, again, keep the myeloma at bay and keep the T cells, in this case, the CAR T cells strong. So, I think those are all areas of exciting research.  

And then the last thing I would say is, we have several novel CAR T therapies that are being studied that may work better and safer than the existing products. Some of them, which are in early phase studies, actually target two proteins at once. The idea, going back to one of the earlier topics I mentioned, is that if the CAR T cells see that protein BCMA, they immediately destroy the cell that’s holding that. But what if the cell learns to turn off BCMA? All of a sudden, it’s invisible to the CAR T cells, and you’re right back to starting square one again. 

And so the idea is that there are CAR T cells that are being developed that target two proteins at once, kind of what’s called origating, where if it sees this or this, it’s immediately able to attach and bind that cell.  

The idea being that it’s easy for a myeloma cell – not easy. It’s possible for a myeloma cell, just by dumb luck, bad luck for the patient, to mutate in a way that shuts off that one protein. For it to simultaneously be able to do that for two separate proteins at once, the odds are much lower.  

And so the idea with dual targeting is you may be able to knock out more cells more durably, or even knock out the myeloma precursor cells that aren’t quite myeloma cells, but are there, what we call stem cells under the hood that are still malignant? So, a lot of those areas, I think, are really fascinating. Obviously, we need a lot more research in those particular areas before they’re ready for prime time. 

Katherine Banwell:

Yes. What is GPRC5D? 

Dr. Rahul Banerjee:

Great. Yes, so it’s a mouthful, is the best way to describe it. It’s an interesting protein. It’s a protein that, I alluded to that, it’s a second target that’s being targeted by some CAR T cells, for example, either in addition to BCMA or by itself. Several companies are looking at that in trials.  

GPRC5D is interesting because we don’t know what it’s for. BCMA, we know exactly what it’s for and why good and bad plasma cells, again, the bad plasma cells being the myeloma, why they express it. No one knows for GPRC5D.  

In the field, we’ve put almost all of our myeloma eggs into the BCMA basket, historically speaking, and all the approved immunotherapies, CAR T and bispecifics in myeloma, with one exception, which is talquetamab or TALVEY, all target BCMA. So, we need to not put all our eggs in that basket. And so GPRC5D targeted therapies, again, there was one approved bispecific antibody, which was not the focus of today’s talk, called talquetamab or TALVEY.   

There are investigational CAR T products that target GPRC5D as well. At least from the limited experience that we have, there seems to be no correlation between them.  

In the future, do we know that someone needs to get BCMA therapy first and then GPRC5D therapy later? We don’t know that, actually, and that’s one of our areas of research and one of my areas of research as well. What if we do it the other way around, right? What if we give GPRC5D first and then do BCMA? We don’t know. 

So, I think one of the big questions in the field is sequencing, which is the word of like, what drug do we use first and when? We’re working on a paper, the International Myeloma Working Group is working on a big, extensive paper to try to put all the evidence together, but that’ll be a moving target.  

Katherine Banwell:

Yes. Patient participation is essential in advancing myeloma research. How do clinical trials impact care? 

Dr. Rahul Banerjee:

Absolutely. So, phenomenally and importantly, I think it’s a short answer. It’s worth noting that clinical trials come in all shapes and sizes. People often assume that clinical trial means, by default, a Phase I study, first time in human being, a quote-unquote “guinea pig.” That’s true for a minority of studies, and that’s very important for us to understand how best to make the drug work better. I would say the vast majority of trials that I put my patients on are not like that. They’re often bigger Phase II or Phase III studies. 

As an example, you know, both Abecma and Carvykti, those were already approved in later lines, but to get them approved in earlier lines, we had to run a study of using them earlier versus not using them earlier. So, that’s a good example where the drug is FDA-approved, it’s just the sequencing of it that’s new.  

There are trials of supportive care. We’ll be opening a study, I alluded to this, the side effects of GPRC5D targeted therapies with taquetamab. We’ll be opening a study that randomizes patients to one of four different supportive care strategies to figure out which one actually works to make the taste issues better. Because we don’t know until we try, right? If we don’t do a rigorous study, and we just go by, “Oh, I had one patient once where this worked, and one patient once where this worked,” that’s not a scientific way of answering questions, and we’re not really able to advance the field to help all patients.  

So, that’s where I think clinical trials come in handy. That, and I alluded to all these newer investigational CAR T therapies that might actually work better and be safer than the existing one. They’re all coming through investigational trials.  

So, trials is kind of how we get these drugs, one, these newer ones to market, but also how we learn to make them better. And we have trials, all sorts of trials, looking at all sorts of, again, not just new drugs, but also where to put the drugs, right? Where to sequence the CAR T therapies, or what supportive care strategies do we use? And the trials are kind of the linchpin of making the field work better. Again, not just for some patients who happen to do well, but for all patients. The only reason we’ve found out what works for all patients is by doing clinical trials.  

Katherine Banwell:

I’d like to get to a few questions that we received from our audience members prior to the program.  

Dr. Rahul Banerjee:

Yes, of course. 

Katherine Banwell:

This one is from Jennifer. Why do CAR T-cell transplants not last longer? Is it possible to do a second transplant if the first CAR T transplant stops working?  

Dr. Rahul Banerjee:

It’s a great question. So, it’s an excellent question. So, the only thing I would say semantically is, right, in my head, CAR T cells are not transplants per se, because I’m not changing the bone marrow. So, I would transplant a stem cell transplantation, separate from CAR T.   

Why do CAR T cells stop working? So, the short answer is we can speculate. We don’t know for sure for any individual patient. Three different buckets are involved. Three different things can happen. One, the T cells can stop working or disappear from circulation. So, that’s possible. CAR T cells don’t last forever. That’s actually okay, right? People often wonder like, “Man, I wish the CAR  
T cells could last forever.” I don’t know that I’d want that because as I alluded to, for as long as the CAR T cells are there, patients are immunocompromised, and so that can certainly interfere with the quality of life.  

So, it’s not necessarily true that the CAR T cells need to be there forever, but if they’re not there, or if they’re exhausted, which is actually a true scientific word for them not being able to activate and kill that cell when they recognized a protein, the BCMA, that’s one problem.  

The second problem is the myeloma cells can mutate. I alluded to this briefly earlier, where the cells can learn to shut off the protein, BCMA, or they can mutate the protein in just a way that the CAR T is no longer able to bind.  

And the third is something called the tumor microenvironment. And this is a little bit more complicated, kind of a grab bag of different things here. The idea is that myeloma cells have a lot of tricks, and they can use all of the cells around them to make it hard for the CAR T cells to get in, to get into the bone marrow and kill them all. And the T cells can be shut off before they even get there.  

So, it’s one of those three things in general. Which one is it for an individual patient? Hard to say. And so hopefully in the future, we’ll have better diagnostic tests to be able to identify who is a patient where another BCMA targeted therapy would work well versus, “Oh no, these myeloma cells are no longer expressing BCMA, let’s move on to a different target like GPRC5D.” We’re not there yet. We’ll get there hopefully in a couple of years, is my goal.  

Then, you know, Jennifer, that’s a good question. Well, can we do a second CAR T? And that’s very practical. What I would say is if the first CAR T therapy did what we expected it to do, if it lasted for as many years as I would expect for Abecma, that’s typically 12 to 18 months. For Carvykti, that’s typically over 24 months.  

If it worked and then it stopped working, and then probably the T-cells are long gone, it’s reasonable to try CAR T therapy again. In general, I would recommend, I strongly recommend a different CAR T-cell therapy, even if it’s targeting the same class, like BCMA, it’s going from Abecma to Carvykti or vice versa. 

The risk with giving the same CAR T-cell product again is that even though the T cells are a patient’s own T cells, the protein is slightly foreign. Abecma was derived from decades of mouse research. Carvykti was made from decades of llama research, believe it or not. Again, there’s no mouse or llama involved with the actual products nowadays, but in making the sequence years ago that came to them, they are foreign. There are foreign sequences on them, and so everyone’s host immune system eventually recognizes these cells as foreign.  

And so if you were to give the exact same product again, immediately the body would reject it the second time around, because it recognizes them and has learned to recognize it as foreign. But changing to a different CAR T cell is very reasonable. 

And again, for these newer GPRC5D targeted CAR T cells that, again, don’t target BCMA the way that Abecma, ide-cel or cilta-cel, Carvykti do, but target a different protein entirely, for those patients generally there’s no restriction on whether they’d received a prior CAR T cells. Ideally, it should be at least several months away, at least like a year or so, but if that’s happened and they stopped working, very reasonable. In fact, some of the trials actually require that patients going on to the study of a GPRC5D product have had a prior BCMA therapy of some sort before, and so they’re kind of built into the architecture of things. So, I think it’s very reasonable.  

Obviously, there are some unknown unknowns, right? What do you do if the T cells are being manipulated twice, so to speak. Patients ask me about that. I will say just to put that fear to rest, in general, by the time that someone’s had myeloma come back after the first CAR T cells, I alluded to this, the CAR T cells are long gone. So, there’s nothing left. But again, every case is different, and future research will help us kind of figure out how best to do this. 

Katherine Banwell:

Yes. We have one more question from Rita. She wants to know if there is an age limit on CAR T-cell therapy. 

Dr. Rahul Banerjee:

It’s a brilliant question. So, in brief, no. It’s a short answer. My oldest patient who got the CAR T is in their 80s and handled it across all my years at UCSF and here at Fred Hutch. More important than chronological age is physiologic age in terms of how robust they are, how robust they feel in terms of going through this. What I recommend, I’ve heard of centers that do CAR T therapy for patients in their 90s, for example. So, I think it’s not so much age, it’s how fit they are. 

Fit is easy for me to say. What does that actually mean? Typically it’s a combination of, you know, like cognitively, how are people doing? Because obviously if someone has baseline dementia, which is pretty uncommon, for example, maybe CAR T is not the best use of their time. The biggest thing that I think gets some of my older patients in trouble is frailty.  

So, just not being as fit as they were before in terms of muscle strength, being able to move around quickly, and so forth, or cardiovascular issues. Because it’s worth noting that with CAR T therapies that we have now, probably 60, 70 percent of patients will get CRS, cytokine release syndrome. So, that’s fevers and low blood pressure, that’s what I said earlier.  

But if you think about it, a fever of 104 degrees Fahrenheit, your heart rate’s going to be like 130, 140 beats per minute, beating very fast for several hours, sometimes longer than that. If you’re having low blood pressure, it’s your heart that has to push blood to overcome that low blood pressure. Can someone’s heart handle that level of stress? As people get older, that obviously gets harder.  

So, if someone is already just 75 and were being considered for CAR T therapy, certainly I think it’s very reasonable to talk about it. I would ask someone where I may have them meet with a cardiologist beforehand, possibly a geriatrician as well beforehand, just to see how can we optimize their health to make CAR T as safe as possible for them? So, it’s definitely possible. 

Katherine Banwell:

Well, thank you for that, Dr. Banerjee. And those were all great questions. If you have more as part of the audience, please continue to send them to question@powerfulpatients.org, and we’ll work to get them answered on future programs.  

Dr. Rahul Banerjee:

Absolutely. 

Katherine Banwell:

Well, Dr. Banerjee, we learned that the field of myeloma care and CAR T-cell therapy is advancing quickly. As we close out the program, what are you excited about? Why are you hopeful? 

Dr. Rahul Banerjee:

Absolutely. So, I think I’m excited because, especially for CAR T therapy in particular, at our center, for example, we used to only be able to do like one or two patients per month. It was a very steady, low stream, because there were a lot of issues with manufacturing, and it was during the COVID pandemic, and there were supply chain issues, et cetera. 

And there were studies, and I remember them, very dark studies in 2021, 2022 even, that patients were more likely to die on the  
CAR T waitlist than they were to actually get CAR T therapy. That’s terrible. And we’ve come a long way since there, where our capacity, every year we’re doing more and more patients to CAR T therapy per month, which is wonderful. 

And so what I would say is that makes me hopeful, right? Because CAR T therapy, I’m not saying that everyone is required to get CAR T therapy. I have plenty of patients who hear about it and are like, oh, no thanks. I’d rather stay with what I’m getting right now with my local oncologist. And that’s okay, but I want it to be an option for as many patients as possible, and I think we’re making strides there. 

And so I think what I would say, the kind of closing words here is, we only can get you CAR T therapy if we know about your case and if you know about us. And so what I would say, I’m sure to people listening to this, you’re very motivated. And so you know the importance of having a myeloma specialist in your field. 

What I would say is my patients who do the best are the ones who are co-managed. They have a doc out in the community. I have patients from Idaho, Montana, Alaska, Eastern Washington, et cetera. They have an oncologist who knows them well, who knows their community well, easy to get to, can handle everything. They’re a jack of all trades and very good at it. And then they have me, who they see periodically for CAR T evaluation, just discussions about CAR T by telehealth, something along those lines. 

And I’m able to talk about CAR T therapy in detail and answer their questions. And so what I would say is, I’m hopeful that that trend will continue, and that if someone’s even interested in hearing about CAR T therapy, they don’t meet me for the first time when they actually need CAR T therapy right then and there. They meet me years beforehand to just talk about CAR T, so they know it’s an option for them. 

And that time – because we don’t have as long of a wait list as we do, and we used to do, if and when the time comes that we all talk, me, the patient, the caregiver, and the primary oncologist, and say, “Look, I think now is time,” we’re able to make it happen. 

Katherine Banwell:

Yes. That’s a promising outlook to leave our audience with, Dr. Banerjee. Thank you so much for joining us today. 

Dr. Rahul Banerjee:

Absolutely. The pleasure was all mine. Looking forward to seeing many of you on a future episode of this. 

Katherine Banwell:

And thank you to all of our collaborators. To learn more about CAR T-cell therapy and to access tools to help you become a proactive patient, visit powerfulpatients.org.  

I’m Katherine Banwell.

Thanks so much for being with us today.