Timing for Myeloma CAR-T Therapy: A Debate | Rahul Banerjee, MD and Sridevi Rajeeve, MD | IMS 2024

Hi, my name is Sridevi Raju. I'm an attending and memos on Kettering Cancer Center in New York City, focusing on multiple myeloma and cell therapies. And my name is Dr. Rahul Banerjee. I'm a physical professor of medicine at the Fred Hutchinson Cancer Center in Seattle, focusing in myeloma, CAR-T therapy, and other palmitcal disorders. Here, we're here live at the International Myeloma Society, IMS meeting in Rio de Janeiro in Brazil. We're excited to be here. One of the big oral sessions today, one of the key abstracts was presented was the CAR-T4 study, which is a study of stilt to cell, also called CAR-VCT, or stiltocatogenatidinolus, a type of CAR-T therapy versus standard therapies, showing that in lines two through four of therapy, CAR-T actually not only led to patients being in remission for longer, improved PFS, but also improved overall survival as well. So this first CAR-T therapy in myeloma to demonstrate an overall survival benefit in lines two through four, there's debate in the field, actually true debate in the field, about who needs CAR-T in line two versus three versus four. So we're here to debate that topic. In real life, we agree on most everything, but we'll try to make this fun for the audience. Yes. So, you know, I will be taking the contentious topic of, yes, it is, you know, we should be considering CAR-Ts in earlier line settings, meaning from line two to four. And Dr. Banerjee here will be talking about why it's a good idea to probably reserve CAR-T for later lines. So, you know, we can hit the ground running. So as Dr. Banerjee said, there were two main phase three studies that came out that showed the survival advantage, both progression free and overall survival advantage for CAR-T cell therapies. Specifically, IDA-captogine, viculose, or IDA cell were shown in the pivotal phase three CAR-M3 trial to have a PFS and OS advantage in from, for patients who had lines one, two lines prior. And siltocaptogine autoglossal was shown in the pivotal phase three scar-titude four trial to be beneficial in patients who had at least a minimum of one line of therapy prior to be beneficial and showed a benefit in both progression free and overall survival. Now, the whole argument hinges upon now that these trials have shown its efficacy and a favorable safety profile in earlier lines of treatment, should we be actually doing this in clinic? And you know, while we agree on most things and because it is imperative that I argue for it, my argument is going to be, yes, we should be considering CAR-Ts in earlier line settings. Here are a couple of reasons why. So if you look at how patients with multiple myeloma progress, you know, like the initial way we all treat is an intensive phase called induction therapy, followed by for those who are eligible, stem cell transplantation or those who do not wish or are ineligible, we go for a more intensive induction therapy, followed by a phase of maintenance therapy. Patients who relapse afterwards have shorter intervals in which they are responsive to each therapy. And then by the time patients reach, for example, the fifth line or sixth line of therapy, we do not have, unfortunately, if we start off with 100 patients in 2000, by the time we are reaching 2024, we do not have as many patients. And this loss of patients at each relapse is called as attrition. By the time we reach subsequent lines of therapy, a lot of patients will not have lived that far along. Their disease would have unfortunately overtaken. Their disease biology changes in the sense that they have been exposed to multiple different types of treatment and they become resistant and they have resistant clones, therefore making it much more difficult to treat. And thereby, you know, you're kind of depriving patients of this extremely efficacious therapies by withholding to a later line of possible benefit. Now, in almost all forms of treatment of cancer, you know, the approach should be to put your best foot forward. So you go with the induction therapy that makes the most sense to patients, you know, within the limits of tolerability, but that which can achieve the deepest form of remission status. So why should we not carry forward that principle to earlier lines of treatment? Because at first relapse or second relapse, you need to hit the myeloma or their cancer with the form of treatment that has been shown against other second line treatments to have much better overall response rate, a significant advantage of progression free survival and overall survival. Now, granted, there are caveats of CARPs not being accessible to all. And you know, there are significant wait times or slot allocations and then disease really progressing as one waits for the manufacturing of CAR T, etc. But if one can get past all that, the best option that is now almost definitively been shown to be much more superior to a lot of the standard of care, second line or third line therapies is CAR T. So therapy. So my argument is that we should be considering that and offering it to patients. Very well stated. I'm nodding again, because I agree with you on just about everything. You know, the nuance that I'll add that truly in my heart, I don't think that CAR T therapy needs to be used a second line for everybody in the U.S. As you mentioned, obviously, globally, CAR T, there are a lot of issues getting access to it, even within North America. I think the issue, there's two issues, but I think jumping the second line CAR T for all of our patients. When I say second line, I mean at first relapse, the myeloma first starts to come back. I think one CAR T, as you alluded to, is logistically a lot. You know, I think I often tell my patients that the time footprint from the moment that I first talk about CAR T with them to after 28 days after getting CAR T, we can return home can often be like four to five months. That's a lot of time. And so where I practice, I have a lot of patients from Idaho, Montana, Alaska, Eastern Washington. And so for them, CAR T, they are moving to the city, uprooting their life, taking time off from work. Them and their caregivers often required for CAR T therapy. That's a lot. Are some patients with what we call functional high risk disease biology, where the myeloma comes back sooner than expected, like within 18 months of starting a front line treatment? Absolutely. I would say CAR T, this is what they need. They need something novel. But for a patient who's gotten several years of mileage out of lenalidomide maintenance, doesn't live close to a CAR T center and is wondering, should I uproot my life and get CAR T now versus get a regimen like ESA KD, you know, ESA Tuximab, CAR T, or DARA KD, DARA Tumenmab, CAR T, something like that, many options. I would say that the risk benefit, I'm actually favorite getting the treatment that close to home, continuing your life and then saving CAR T for later. The other thing is that CAR T therapy is constantly improving. Diltacel, as the CAR T4 study again, has this overall survival benefit. In that particular study, there was no crossover allowed, meaning that the patients who didn't get CAR T, it wasn't part of the protocol to give them CAR T in the other arm getting standard treatment if the myeloma came back. We don't know if second line versus third line CAR T is better in that particular trial. CAR T does have some potentially long term side effects. You'll hear about this in other videos on health tree for sure. You know, they can cause like infection risk. There are rare cases of what we call delayed motor and neurocognitive toxicities. Very, very rarely, like less than 0.5% of the time patients can get, you know, for Guillain-Barré syndrome, which is a weakness, or nerve palsies, or even Parkinsonism, where it looks as though they have Parkinson's disease. You know, they're tricky. And newer CAR T therapies are on the horizon. You know, there are other being presented here with allogeneic CAR T's or rapid manufacturing CAR T. And so a lot of, you know, because these newer treatments are available in a couple years, some could argue that why rush to BCMA targeting CAR T therapy now, when in reality you could wait, stay close to home, and then in 2028, when the myeloma decides to come back, at that point get the best CAR T available in 2028. CAR T therapy has come a long way since the initial approval. I would still say since teenage years, you know, a little bit positive, some long term side effects, and we have some work to do to make CAR T safer and march up more for our patients. Absolutely agree with again, everything Dr. Banerjee said. You know, every patient who comes to our clinic at first relapse, while, you know, patients thanks to health tree are extremely well informed, you know, they do come asking us about CAR T. So we have an overall, you know, comprehensive discussion of what are the options. Yes, CAR T is indicated, but is this the right treatment at this time for them? For example, as Dr. Banerjee said, if someone who has had a significantly long time on their maintenance and the disease biology as we know it is not that very aggressive or they're not functional high risk, you know, perhaps it's a good idea to keep CAR T's for a later time, but if they're not able to keep it, then they're not going to be able to keep it. So, you know, we have a very broad discussion of what is the best way to get a second line and really try to get more mileage out of a very effective another second line dose. So it's very much of a nuanced discussion. And, you know, we don't need to go all the way to the west coast of the U.S. You know, in my own practice in New York City, I can say that I do have a clinic in New Jersey as well. My patients in New Jersey do not want to come to New York City all the time because again, So again, you know, they do sometimes even though they discuss about them when they hear about the logistics and the timeline and sometimes for working people when they think that they have to take time off work, often they do choose to not go to CAR T. So it needs to be a comprehensive discussion with your health care provider, with your caregiver, you know, and even within yourself if CAR T is right for you at this time. So just because and as you know, my boss, Dr. Osmani, very recently talked at the SOHO meeting in a very catchy but very prominent meme that went all around just because you can do it, needn't mean you should do it. But we will try to do the best we can for patients and continue to have these discussions. Dr. Juice on point. I mean, the final parting thing I'll say about the particular topic is that definitely it's worth, as you said, discussing CAR T. I think that's the most important part, being informed about it by virtually watching this video. You probably watching this are very familiar with CAR T, have learned about it, you know, the toxicity, how it works, the efficacy, etc. I would say that because CAR T is constantly evolving and getting safer and more effective, we have clinical trials of adjunct therapies that make CAR T work even better. I think it's always worth discussing with a CAR T capable center, having a referral with them just to get to know them and for them to get to know you. I would always encourage that because as many of you know, you know, most patients with myeloma are not primarily followed at a CAR T center. They're followed in the community by an oncologist much closer at home, treats all kinds of cancers, knows them the best. We know CAR T the best. And so we're happy to help out. I would say if you're watching the video, you're like, oh, you know, I'm not having a relapse. Should I even talk about CAR T now? Yes. Welcome to Come CF and at least learn more about it. Get on our radar. And that way, when the time comes, hopefully never, but if the time ever comes that we need to talk about an eggplant or therapy, we're ready to hit the ground running.