Noopur Raje, MD
Massachusetts General Hospital
Interview Date: April 16, 2021
The door to a new era of immunotherapy has CAR T therapy in multiple myeloma has been opened with the recent approval of Abecma (ide-cel) by Bristol Myers Squibb. Dr. Noopur Raje shares more about the history of CAR T therapy, its potential use in multiple myeloma, who can obtain the treatment and more about the CAR T process. As one of the initial investigators on four years of clinical trials for this treatment, Dr. Raje provides in-depth information about this groundbreaking new therapy.
To find an open site for Abecma CAR T treatment, click here.
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Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. We’d like to thank Oncopeptides for their support of Myeloma Crowd Radio because without our sponsors, we couldn't provide such a wonderful program for you.
Our program today is a very fascinating one. It will be about the new, the very first CAR T cell approval in multiple myeloma. We have waited for this, I think, for decades. So we're thrilled that we'll be able to listen on this program.
This is a topic that we'll cover multiple times. For example, we have an upcoming roundtable where we will also be covering this Ide-cel approval on April 24th, just so you're aware of that. We'll be discussing three drugs in that: Ide-cel, venetoclax, and melflufen in that particular event.
We will also be covering the Abecma approval again on May 18 in our Myeloma Crowd Community Immunotherapy Chapter which will have a 30 min Q&A with Nina Shah, MD of UCSF.
I would like to start by introducing Dr. Noopur Raje, who is going to be joining us today. Welcome Dr. Raje. We're so pleased to have you with us.
Dr. Raje: Thank you so much, Jenny, for having me. This is absolutely an honor. Thank you.
Jenny: Well, we're so appreciative that you are willing to spend your time helping us understand this better because it's so new. Let me give an introduction for you and then we'll jump into our questions that we have. Dr. Noopur Raje is a physician/scientist with a focus on the development of innovative therapies for multiple myeloma. She is the Clinical Director of the Center for Multiple Myeloma at the Massachusetts General Cancer Center in Boston. Dr. Raje leads a dedicated clinical team engaged in investigator-initiated multicenter national and international clinical trials that are all aimed at developing new and promising therapies for this disease. She also leads translational efforts at Mass General with her laboratory's efforts focused on identifying cellular signaling pathways that contribute to the survival and proliferation of myeloma cells in the bone marrow environment.
She has received her medical degree from the B.J. Medical College, Pune University in India, trained in internal medicine in Mass General, and completed a fellowship in hematology and medical oncology in a joint Mass General, Brigham and Women's, Dana Farber program. She's the first incumbent of the Rita M. Kelly Chair in Oncology at Mass General and is a recipient of numerous awards, including the Multiple Myeloma Senior Research Award, Leukemia & Lymphoma Society Clinical Scholar Award, and the Claflin Distinguished Scholar Award.
Dr. Raje, we know that you were very instrumental in some of the early bb2121 clinical trials, and so you're just the perfect person for us to talk to today about this program.
Dr. Raje: Thank you so much for having me, Jenny. This has been an effort on multiple fronts as you know, and we are so grateful to all the patients who actually participated in this very normal strategy for multiple myeloma. I could not be more excited that we have this now approved by the FDA. There's more to come down the pike. This is really going to open up a whole new way of taking care of multiple myeloma. It's already there, so this is very, very exciting. Thank you for having me on.
Jenny: Well, we appreciate you so much. Maybe you just want to give us a little more relevance about what you just said. This is the first CAR T therapy. There will be more. But will you kind of give us a sense of the gravity of the CAR T therapy in myeloma? What this first approval means for patients? Because I think, in my opinion as a patient, it is a really big step.
Dr. Raje: Absolutely. You couldn't be more right about this, Jenny. This is for now a first in class drug product for myeloma. This is sort of the first immune therapy strategy, and it is the most personalized way of giving treatment. What is CAR T cells? I'm just going to get started from there, Jenny, because I think that is important for people to understand. This is where we take out your own T cells from your blood circulation. Once those T cells are taken out, we genetically modify them, insert what is known as a chimeric antigen receptor. That's what CAR stands for, a chimeric antigen receptor that is included on to your T cells. What a CAR is able to then do is recognize your myeloma cells.
Now, in the case of myeloma, most of the CAR T cells, which are in clinical trials and are in development, are against a protein which all of you are now familiar with. This protein is called B-cell maturation antigen or BCMA. The reason to use BCMA is BCMA is a protein which is essentially expressed on all multiple myeloma cells and on all plasma cells. The importance of doing sort of targeted treatment is you have to find a protein which is present in tumor cells and not present in other normal cells because you essentially want to target tumor cells. That is something we have with this BCMA. Therefore, it's not just CAR T cells that are using BCMA as a target, but all of you are familiar with a whole host of other approaches as well.
We have, for example, belantamab mafodotin or BLENREP, which has already been approved that this is a drug antibody conjugate. It has been approved in the context of myeloma. For CAR T cells, Abecma or Ide-cel, which is a BCMA CAR T cell approach is the first of its kind to be approved in the context of myeloma. Again, a very personalized way of taking care of your disease wherein we are using your own cells. We are training them ex vivo, that is training them outside of your body, and then giving them back to you so that they can go and hunt out those myeloma cells and get rid of those myeloma cells and control the disease. So a very normal way of taking care of it and a very specific way of taking care of patients with myeloma.
Jenny: Can you give us an idea of how long CAR T cell therapy has been in development in general, and then how long in myeloma?
Dr. Raje: Sure. CAR T cells research has been going on for years now. It's going on for more than 15 and 20 years. It's been specifically helpful in the context of blood-related cancers. You all know of the approval of CAR T cells for leukemia. For example, it was approved first in childhood leukemia wherein a CD19 CAR T cell was used. Now more recently, we've had approvals in lymphoma as well. For key malignancies, once you know that you have a reliable target on your tumor cells, CAR T cells were able to be generated. Right now we are in the phase where we are using second generation CARs. So early on, very early on. Now this is many years back, 15 and 20 years back, we use the first generation CARs, that is we were able to insert this CAR into T cells we had what we used to refer to as the CD3 zeta chain. Those CARs were able to do their job but for a very short period of time. So you were able to activate the T cells. They were able to show some killing, but they didn't last in the body for too long.
What's happened over the last close to now more than 10 years is we've started using second generation CARs, and what second generation CARs include are you have the chimeric antigen receptor. You're able to recognize the tumor compartment of the tumor cells by recognizing the specific antigen. You have the CD3 zeta chain which activates the T cells. In addition to that, we have now inserted what we refer to as costimulatory domains. What this costimulatory domain does is not just activates the T cells, but allows for expansion of the T cells so that they stay in your system for a little bit of time and is able to do the job over time. Remember we're still very early with CAR T cell development. We are still with second generation CARs. We have the first, second generation CARs approved in myeloma.
Now in the context of myeloma specifically, Jenny, we've been working on this -- I'm going to talk to mostly the clinical development. We've been working on it now for the last I want to say at least four years. With ide-cel specifically, we treated more than 400 patients now. There are other CAR products which are being tested such as cilta-cel (by Janssen) and a couple of others which are in clinical trial as well. So still early experience in myeloma, but the drug product or Ide-cel or Abecma (by BMS) has been approved based on a study of more than 100 patients. It was 128 patients.
I think before we jump into the details of this, what is to me most remarkable is a couple of things which I do think your audience needs to understand and appreciate. One is myeloma is an immune disease to begin with. Before going into this, Jenny, we were never sure about how effective a patient's T cells are going to be and how amenable they're going to be to us inserting a CAR and inserting those constructs that I talked about and seeing whether or not they would in any way be even functional, especially when you've had myeloma for many, many years, and have had continuous therapy for many, many years. Are we even going to be able to generate T cells which are going to be functional, which are going to be able to recognize tumor, and which are going to be able to expand in people after we give them to you?
The starting point, to me what was absolutely remarkable about, even our first-in-human study, which we did, I think it was about three or four years back now, which is when we started, is to see that patients who were getting these drug products, so the CAR T cells, we were seeing complete resolution of disease with complete clearing of bone marrows which had been unheard of when we're starting to treat relapse of the four, five, and six lines of treatments. It's really remarkable. The first step is able to generate CAR T cell product which is going to be efficacious and which is giving patients MRD negative disease state so late in their lines of treatment in itself was, I think, a huge step forward.
Jenny: It's unbelievable, in my opinion. I mean, I don't know if you've ever seen anything like it in your experience.
Dr. Raje: Absolutely never. We weren't expecting this when I first started out. I was a little bit skeptical when I first started out saying, are we going to be able to see any impact of these T cells? What we saw was absolutely incredible in terms of, you know, in the old days, we used to, after giving CAR T cells, do a bone marrow at day 14 and then at one month. Those folks who had CAR T cells know this. We ended up doing quite a few bone marrows post-CAR T cells. This is essentially learning about this process. I will tell you, in day 14, patients who have packed marrows going into this modality of treatment, we have seen complete clearing of that bone marrow. I have never ever seen this. Even with newly diagnosed myeloma, it takes a little bit of time for whatever treatment we're on for that to start working. We typically don't even do a bone marrow until you've had four or five cycles of treatment.
Jenny: It's unbelievable. To have this now FDA approved to me is super, super exciting. You said that it had been used in leukemia and lymphoma. In terms of efficacy or impact, how is CAR T different in myeloma versus lymphoma or some of the other blood cancers? What have you seen?
Dr. Raje: So I think in essence, when you look at CAR T cells, the technology is very similar. The targets we use are obviously different. For leukemia and lymphoma, for example, the target protein that they are focused on is CD19 which is essentially expressed on leukemia and lymphoma cells. We clearly are not doing that. We're using CAR T cells against BCMA. If you look at responses, the responses are pretty similar across all cancer types and that is to say that we have seen very high response rates in excess of complete responses of close to 50% in whichever tumor types you see.
What we are not seeing in myeloma compared to say leukemia and lymphoma is necessarily a plateauing of the curve in terms of duration of response because we are seeing patients continue to, you know, patients are relapsing, so it's not something like a cure for myeloma just as yet. But I think, as I've mentioned already, Jenny, this was chapter one of CAR T cells in myeloma. As we start improving upon this, I think we have strategies which we are already doing is how can we make the duration of response better with a cellular therapy product? So we have to start improving upon the duration of response in our patients. I think that is the biggest distinction.
As far as toxicity is concerned, in myeloma, I will tell you that, again, I was pleasantly surprised. In leukemia, you see a lot more toxicity in terms of CRS neurotoxicity, but it also may be a question of time. We are sort of the last ones to get approved in myeloma. We've had the experience of leukemia and lymphoma colleagues on helping us understand some of the battle physiology of the toxicity, and we are better at managing it. So at least with the Ide-cel product and even Cilta-cel, which is on clinical trials, the toxicity does exist when it's extremely manageable. We have tools such as drugs like tocilizumab which we can use in the context of CAR toxicity. I think knowledge and education around the toxicities has made us recognize them earlier. Having the tools to treat them early has also helped us alleviate some of these toxicities and made us more comfortable using these CAR products in the context of myeloma.
Jenny: Absolutely. You kind of already talked about why BCMA is being used as a target. Do you want to share early results of some of the -- they call them the KarMMa trials, right?
Dr. Raje: Yes.
Jenny: So some of the results from those trials?
Dr. Raje: Sure. So I was talking about what Ide-cel got approved based on. The first-in-human study, which we did was a couple years back now, that's been published. The new follow-up KarMMa study was -- so the first study was about 43 patients. The follow-up study was 128 patients. That's what the FDA has based their approval on. Now, when we started the study, we used those levels all the way from 150 million cells to 450 million cells. The target dose for CAR T cells is going to be 450. But essentially, when you look at all comers, the overall response rate was close to 80% with about 35% of these patients achieving a complete response or a stringent complete response. These responses kept increasing once you got to that target, those 450 million cells.
Now, if you look at all comers, the duration of response is close to about a year, which is in keeping with what we've seen with our first-in-human study, which again is reassuring because first-in-human studies always look better than their follow-up studies. With the KarMMa trial, we were able to duplicate the results of our Phase I trial. I think the other important thing to remember, Jenny, is the fact this was a multicenter international effort. It was not just done in the United States. It was done across different countries, across the Atlantic. We were still able to reproduce the same data that we saw with our Phase 1 first-in-human study which is really reassuring because it speaks to the fact that this can be genuinely applied in centers all over the world, and toxicity can be managed by people all over the world.
When you start honing in on now on people who actually got either a complete response or a stringent complete response, these patients actually did a whole lot better where the median progression-free survival or duration of response was 20 months. Obviously, again, that's not a homerun, but you have to remember that these are patients who had at least more than four lines of treatments. They relapsed after four lines of treatment. The majority of these patients have had both bortezomib and carfilzomib, lenalidomide and pomalidomide. The majority of patients have had the CD38 monoclonal antibody, either isatuximab or daratumumab. Those of us who treated patients who had all of these lines of treatment and then have progressed after this to see stringent complete responses and to see duration of responses of inpatients achieving stringent complete responses of up to 20 months, again, is quite remarkable in the myeloma space.
Jenny: Well, right. I mean, a lot of the other drugs have gotten approval, like single-use drugs, like daratumumab or Kyprolis or something like that with a 30% response rate. But you're saying that was like 80 plus percent response rate. So yes, I mean, you have to think about combination.
Dr. Raje: Most duration responses with some of these is close to three and four months. Certainly, it is a big event. I think the future is going to be on trying to do even better. The other important thing, Jenny, which I did not kind of focus on, is most of the drugs we use in myeloma and I think all of you are familiar, once we start you on something, we keep you on that drug pretty much forever. You're on some form of maintenance treatment or what have you. With the CAR T cells, we've given the treatment once. As of right now, with the duration of response, which I'm talking about a year or more and stringent complete response of 20 months, it's single dose administration of CAR T cells and you've been on no treatment thereafter, which again for myeloma is a huge change in the paradigm of how we take care of multiple myeloma.
Jenny: Yes, it's a completely new approach. I think every patient would appreciate a one-and-done therapy. But as you think about these, like how we use combination therapies and how you're applying those in myeloma, you haven't even started to apply any idea of combination therapy with CAR T, like what's the optimal to do before CAR T? We can talk about this later in the show, but what's optimal to do prior to CAR T, or when do you do CAR T? What do you follow it up with? So that is all really unexplored territory.
Dr. Raje: Absolutely, absolutely. But that's exactly the place where we are doing a lot of investigation right now. One of the things, as we've gotten with every drug product that you all seen in myeloma, typically we first tested in kind of late to end stage because we want to make sure that it is safe. It is something which patients are able to tolerate. So again, with the CAR T cells, we've done exactly that. We've shown that there's safety, and we've shown that there's remarkable efficacy. The next step then is obviously to move this earlier on. I will tell you that we are doing a lot of different trials. We are using it in patients who have high risk disease. For example, we are using it instead of transplant in a trial, we're using it early on after one to three lines of treatment in a randomized fashion. We are also using it in patients who relapse early post-transplant as a normal strategy to see if we can actually improve upon the current responses.
You spoke about other right now this is a one-and-done strategy. But with that, we're getting disease control for over a year, depending on how the patients are responding. One of our thoughts is if we do this kind of an approach very late, your T cells are probably beat up. So wouldn't it be nice to do it early? Those trials are happening. The second question is if they're getting this response with the one-and-done, is there room to sort of combine it with some of the other things? We are doing those studies as well wherein to improve upon this response rate, do we need immune modulate some more so that those T cells can hang around longer and can have better control of all of those and the setting of clinical trials right now.
Jenny: Yes, well, that process needs to be run, right? Let me ask you about the sites because this is not an insignificant therapy to provide, even though you had said earlier on the show that the side effects are very manageable now and you know how to do it. But having this treatment at the right site is really important for the first few days especially. Do you want to go into --because I know a lot of patients might think, okay, well, I'm going to go out and talk to my local cancer center and see if they can provide this to me. Can you talk about sites, like how sites are being brought on for this treatment? What's required for the site, and what kind of expertise they need?
Dr. Raje: Sure, absolutely. As a starting point, I think the way the drug product is approved right now, the CAR T cells is approved, is for patients who have had at least four prior lines of treatment and then the disease has come back. That's not an insignificant number of patients. There's a lot of patients who are going to meet the criteria. Typically, you've seen an image, you've seen a proteasome inhibitor, and you've seen a CD38. But this has to happen four lines of treatment and that's not uncommon for myeloma.
As far as sites are concerned, there are a few basic things which are going to be required, although we're going to try and make this as accessible to patients. Some of the toxicities, and I think this would be a good time to talk about what are the side effects of these and what does it entail or what does creating a CAR T cell product entail. Well, to start off with, it entails us being able to collect these T cells off of you, first of all, to manufacture the T cells. That is what we refer to as a leukopoiesis process. That means we put you on, you know, those of you who had your stem cells collected, we put you on a machine, take out your stem cells, and it's usually an outpatient procedure. But prior to that, we give you growth factors so that you can actually spill out those cells. CAR T cells is a little bit difference. You do not need any growth factor. We only collect the lymphocytes of the T cells from your bloodstream. It does include being on the machine for three to four hours to collect those T cells. It has to be at the center which has the ability to do this leukopoiesis, to do the collection.
The other thing which we are looking into and which requires sort of basics, and this is our stem cells, the ASCT, which is the American Society of Cellular Therapy, or the BMT Society is now called ASCT. We've changed the name from bone marrow transplant or stem cell transplant to cellular therapy now to include these therapies. We need a few things for that institute to be accredited. One is they need some kind of fact accreditation where the transplant societies, you have to meet a certain bar. One is you have to be able to collect this leukopoiesis product. You have to have certain knowhow in how to manage toxicity. You have to be able to hospitalize patients because as of right now they are being hospitalized, or they will need to be hospitalized for at least the initial part of their treatment. Then you have to have access to sort of critical care medicine because in a minority of patients who may require ICU support, you might require things like neurological support or things like ventilatory support.
So those things should be taken into consideration. You have to have access to drugs such as tocilizumab. This is a monoclonal antibody, again interleukin 6. We found that it is extremely helpful in patients who develop a toxicity called CRS. I’m going to just take a step back here, Jenny, and I'm going to go over first is the leukopoiesis collection. Once you collected it, it takes typically anywhere between three and four weeks for that product to get ready and then sent back to the site. Before we give that product back to patients, we actually give you chemotherapy for three days. This chemotherapy is nothing like what you've had during your transplant. Very different. This is chemotherapy called Cytoxan and fludarabine. I think a lot of you are familiar with Cytoxan. Fludarabine is generally new to myeloma patients, but it's given over three days. This can be given as an outpatient. You do not have to be hospitalized for this. Then you get two days of break, and we give you back the cells up to the fifth day. That is considered sort of your day zero of getting the cells back.
Getting your cells back is almost anticlimactic. It literally takes two minutes to push it through a syringe. The cells are, you know, it's not a high quantity. It's a small amount of cells that we inject into you. The big thing which can happen, though, is because these T cells are very active and because they can go find your myeloma cells and get rid of them quite quickly, they do produce two specific toxicities. One of them is called cytokine release syndrome. That happens when your CAR T cells go find your myeloma cells, get rid of your myeloma cells, and by doing so, your myeloma cells break down. When they break down, they produce a whole lot of proteins. These proteins can cause a cytokine storm. That's why it's called cytokine release syndrome. This is very commonly seen. If it's not appropriately diagnosed and treated, it can become very -- it actually can be fatal and life threatening.
Therefore, you have to pick the center. You asked about the center, centers with no house, centers who know how to manage this, and that comes with experience, obviously, and centers who have the supportive care abilities of ICU support is required. I will tell you, we've needed ICU support in the minority of patients. But you have to be ready for that if you're going to be putting a patient through this and then drugs like tocilizumab because we know that this CRS responds very nicely to this antibody treatment. Although we want to make it available to all patients, it should be done at centers which have access to all of these facilities.
Jenny: Right. No, it's critical because they know what to watch for and then you're close to the center or at the center. Is there a certain number of days that you have to be hospitalized for this particular treatment?
Dr. Raje: So I think that will probably change by product. Right now on clinical trials, we're generally admitting patients anywhere between 10 and 14 days. With the standard of care products, I don't think you need to be in the hospital for the full 14 days. Some few patients may need that, but most patients should be fine for a week of hospitalization. Again, depending on which car product you use, and what's the rate of toxicity because the toxicities are quite predictable. We're also looking into can we do these outpatient. If you do these outpatient, you have to be very careful and have to really have a center of excellence which understands what they're doing and knowing when to anticipate that toxicity. Certain drug products, for example, so to sell the CRS happens a little bit later. If that gets approved, I can foresee seeing as we may be able to do the early part as an outpatient. These are things which need to be worked out. But again, it would require at least early on when we're using this drug product to be used in centers who have experience and centers who have access to some of the supportive care strategies that I talked about.
Jenny: How long will it take for this particular approval? Do you think it will take sites to come kind of online? Because I know that there's a -- for this particular product, there's a website that's called celltherapy360.com that there's like a site locator, because it's not like, okay, it's available today, go ask your doctor about it and get started next week type of thing, right, at this point?
Dr. Raje: That is correct. But I will tell you that BMS has done actually a really good job. I will tell you that my site is up and running. We've been activated. That means just be that we've done all the clinical trials, so they're very familiar, but they've been proactive about getting sites on board. I'm sure that websites will tell you which sites have access. I haven't yet given back my standard of care, but I have referred my first patient, so I will see how long it takes. Initially, we always go through a little bit. But I think the process has been ironed out already at places like academic centers only because we've done a lot of them already. You do have to go to sites which have it up and running.
Jenny: You mentioned the four lines of treatment. I just want patients to understand because I quite didn't understand this either. When something gets FDA approved like this, they make the FDA approval based on the clinical trial kind of inclusion criteria, or what they did. You mentioned patients had to already get a proteasome inhibitor and an IMiD like Revlimid or Pomalyst and a monoclonal antibody. That is the same criteria as patients who can do this therapy as now a standard of care type of therapy, correct?
Dr. Raje: That is absolutely correct. It's really important to see how you count treatments. Typically, when we are counting treatments, whatever you had initially, for example, a patient has had RVd or KRd as their initial treatment, had a transplant and had maintenance treatment, that would not be three lines of treatment. That's still one line of treatment, Jenny. Then when their disease has progressed, the second line of treatment per line for signs. As of right now, they've had to have had four lines of treatment. When I looked at the label, what the FDA has not done as often is most of the patients, as you know, have been exposed to some of the drugs that I've talked about. But the FDA is not necessarily looking at whether you've been exposed to every one of them as long as it's in four lines of treatment.
Jenny: Oh, I see. Okay. Well, that's good clarification. Yeah, like you're saying, I had induction therapy, few stem cell transplant back to back because they were tandem, a year of consolidation, a year of maintenance. That was ONE line of therapy. That's a lot of therapy.
Dr. Raje: That's exactly right. It's important how we count treatments, right?
Jenny: Yes. If this is your first relapse, then you probably don't qualify for this therapy. That's what I want just to emphasize for patients.
Dr. Raje: Correct.
Jenny: Yes. Okay. You talked about the approval for this. You kind of hinted that the other trials are underway. Now they're being used earlier in therapy and with other treatment combination to increase durability and to increase just depth the responses and duration of responses. We talked a little bit -- well, let me ask you some practical questions. In older patients, because you think about stem cell transplant. I think we're kind of translating sometimes this CAR T therapy, oh, it's kind of like stem cell collection. We've got this leukopoiesis process. It's kind of like a cellular therapy because stem cell transplant is like a cellular therapy. They're quite different. Sometimes in stem cell transplant, it's not that great for the older population because it's hard on your body. But for older patients, what's the impact on older patients for CAR T? Can anyone kind of do it regardless of fitness status or things like that?
Dr. Raje: That's a really good question. I think it's really important to highlight the differences between an autologous transplant and cell therapy, what we're talking about with CAR T cells. Remember, when you do an autologous transplant, you had your induction treatment and an autologous transplant or a stem cell transplant is almost to consolidate whatever response you had from induction treatment. You're actually feeling your best before you go into your autologous transplant. You're in a remission, and then you get mega high doses of chemotherapy, which makes you extremely sick for the two weeks or so. Then you come out not feeling extremely well, right? With CAR T cell, that's sort of reverse order. Most of these -- not most, all patients who go into CAR T cells are not in a remission. They've actually had progressive disease. They have a high disease burden. That's the reason why they're getting CAR T cells. They're no way in a remission as of right now, and they're being treated for their relapses.
We do need to sort of bridge people during the time because they have active myeloma which is progressing, and we need to control it. The second thing to remember is we're not giving the mega doses of melphalan which is 200 mg per meter square, and you have to be hospitalized. When you get that dose of chemotherapy, it's a myeloablative dose. When I say myeloablative, it wipes out your bone marrow and lets you get those stem cells back. Your bone marrow would take very, very long to recover if you didn't have that. Now, with CAR T cells, we actually don't give you any kind of myeloablative chemotherapy. We give you just three days of chemotherapy, which is outpatient chemotherapy, which is generally well tolerated. The reason to give that chemotherapy is to make your immune system such that it will be able to accept these activated T cells. It's not to wipe out your marrow. It's just to regulate your immune system so that we get rid of some of the negative immune effects, and your T cells can go and do their work.
Again, when you're getting CAR T cells and you get the chemotherapy for the CAR T cells, there's nothing like hair loss which you see with an autologous transplant. Folks won't even know that you've had CAR T cells if you don't share that with people. You get the CAR T cells back and as I mentioned to you, the toxicities of CAR T cells are very specific. The tool we care about most is CRS and neurotoxicity. You don't see that with an autologous transplant. You can get neutropenia. You can require blood and platelet product, but it's nothing to the level of what you have with the autologous transplant. So quite different.
Now, in terms of who are the patients? Certainly, we don't go by age ever for either a transplant or for CAR T cells. But there are certain sort of criteria that people have to be able to meet. Specifically for CAR T cells, we do want your kidney function to be adequate. The reason for that is when we give you fludarabine, fludarabine is cleared by your kidneys. When I say you don't necessarily have to have an absolutely perfect kidney function, but you have to have a creatinine clearance of about 30 at least. That's largely because we do need to give you fludarabine, and the data we have is CAR T cells work better when you're able to get fludarabine. That's one sort of distinguishing factor here.
The other few things, when we talk about toxicities like CRS, you have to have reasonable cardiac status so that you're able to tolerate. If I need to give you fluids, you should be able to tolerate fluids. You should not be somebody who's already requiring oxygen, for example, because then if you end up with the toxicity like neurotoxins to your CRS, that can have really negative impact. You have to have a certain fitness level so that you're able to handle the toxicity of neurotoxicity and CRS. Age is not certainly, you know, we've done CAR T cells in people in their late 70s and they've tolerated it fine. I think it's been done in 80-year-old also. But again, you have to -- it's more the other comorbidities that you have to be careful about.
Jenny: Okay, I did not know that, so that's great information. Very practical. Now, we've heard about this idea because you've looked at who's responded, who hasn't responded to CAR T cell therapy, or who's getting more durable responses. You mentioned this earlier in the show that sometimes the immune system has been beaten up a bit. Is there any way of developing or is that in process to develop an immune system panel? Because you can imagine like this is not an insignificant process. You kind of want to know, is it going to work for me? Is it not going to work for me if I'm going to go do it? So what kind of work is being done right now on creating that immune panel to screen patients, I guess, to say, oh, this would be a great therapy for you, you should go do that?
Dr. Raje: Yes. The short answer to that is no, we don't have the immune panel. But if you look at the responses, Jenny, we are seeing very high response rates, right? Eighty percent of people responding. So I would argue and say that the majority of patients are going to respond. I think what we have to focus on then is what can we do to make that CAR T cell product better? I will tell you that we are already doing a lot work in that space. What we are trying to understand is in people who have had a great response or where you've had good expansion of your T cells, we've begun to appreciate what the T cell phenotype for that subset of patients should be. Even if you don't have it in your body right now, can we do something to make that better? There are already trials which are ongoing and we know that if you have more of a memory T cell phenotype, your CAR product is going to be better. Those studies are ongoing. We are also trying to understand when would be the right time to collect your T cells to make these CAR products? We know that if you are newly diagnosed and you look at your T cells then, which is up to four lines of treatment, there is a difference in your T cells function. What we are trying to do as of right now is understand the differences and figure out whether or not we need to collect early.
The other thing we're already doing, Jenny, is we are doing CAR T cells earlier with the same idea that the T cells are going to be fitter if we do them earlier. They're not going to be beat up by that treatment. We'd have to wait and see if that by doing so, it's going to improve upon responses in our patients. We think it will, but we don't know that and that's why we do the studies as well.
Jenny: Then there are other versions or revisions like isn't bb2127 kind of a next generation - like it will continue to evolve, right?
Dr. Raje: Correct. So bb21217 is getting to that. So what we're doing there is to improve the T cell function. What we are trying to do there is, as I mentioned earlier, we already have clues that if you have a memory T cell phenotype, your expansion is going to be better. Your response is going to be better. So bb 21217 is a CAR T cell product which is being exposed to bb007, which then enhances this memory T cell phenotype. That's one strategy. The second strategy is doing other ligands. We are using not just against BCMA. Can we do BCMA plus something else? Or can we look at the CAR product to improve upon that T cell functionality? So all of those things are happening as we speak.
Jenny: The development that's happening is amazing. Are boosters being considered as well? Like, okay, maybe down the road a year or something like that or every six months or, I don't know, or maybe you look at a different kind of immunotherapy as maintenance, you know?
Dr. Raje: So that is also absolutely something under development. What we have now are “umbrella” trials where we have one CAR product, and then we have different groups of patients where some will get CAR product alone. Some will get CAR product with product, whatever else, which we think is going to have an impact. We're trying to do these quickly so that we can get them to patients quickly as well. Those are ongoing studies with all of these drug products. We just don't have the data just as yet as to which one is going to be the most effective.
My sense, to be honest, is going to be, again, this is going to be more patient-specific, Jenny. I don't think it's going to be one size fits all. The more information we get on these drug products. I think what we're seeing with Ide-cel right now or Abecma is our first foray into CAR T cells, and I think folks need to stay tuned because, honestly, with this technology, the sky is the limit.
We are already using healthy donors to create CAR T cells. We are not even relying on patient derived T cells. We have allogeneic CAR T cells which we're using. We're using CAR T cells followed by other drug products, other immunotherapies. You've already seen the promise of bi-specific T cell engagers with some of the data out there. The question is should we be combining CAR with a bite, for example, and seeing if he gets more durability with responses? Really an exciting, exciting space to sort of test all of this. For patients, I think it could not be a bit of time. I'm so excited to try and get all of these treatments to all of our patients.
Jenny: Oh, absolutely. The work that you've done for years now is paying off. I hope you're proud of what you've done because we're just thrilled you're doing it. It's really amazing. You’ve worked hard on this.
Dr. Raje: I can't say enough about patients because I still remember my first CAR patient where I knew so little about this. But patients go into this with complete trust, and I cannot be more grateful for that. We can do this by ourselves. It is a team. You know this, Jenny. We've always said this, and everybody has played a huge role in trying to -- for us to understand this better and to get it to even more people.
Jenny: Yes, absolutely. Well, I want to give some time for caller questions. So if you have a question for Dr. Raje, you can call 347-637-2631 and press 1 on your keypad if you have a question. While we're waiting for people to do that, I did have an emailed in question that talks about cost a little bit. For people who are on Medicare or Medicaid, it might pay for part of it, but maybe not all of it. Do you know how that works yet?
Dr. Raje: I know. On clinical trials, we've never had to worry about that too much. But my understanding is Medicare is going to pick up the cost for these. The way to think about this really is as we look at myeloma and we look at the drug combinations that we use, we've now gone -- we started with two drugs, Jenny, then we went to three drugs. Now we're using four drugs, whether it's at new diagnosis or relapse. Again, we're using all of these drugs forever. None of the drugs for myeloma have been cheap, and most of our patients, with the nature of the disease, majority of our patients have Medicare as the coverage. We've generally been able to provide care to all patients with help. I do think that that's exactly what's going to happen given that this is more of a one-and-done. So although the cost of it seems a lot as the beginning, if you think about it and if you're using, for example, RVd as a combination and calculate up or reduce costs for a year, it would amount the same as the drug product for CAR T cells.
I think over time, this is going to get ironed out. I would tell patients, all our centers have a social worker, a financial person who works with us. We try and make this as easy as possible. We negotiate with the insurance and repeating that this is what's right for you. Whoever your treating oncologist in the cancer center is will help iron out those details. There is going to be a little bit of a learning curve, I think, for Medicare, for the company, and for us as institutions as to how best to try and handle this. But at the end of the day, I don't think it should be, you know, this is our problem. Given that we've seen so much promise, I do believe it's going to get worked out.
Jenny: Great. Okay. Well, we have a question from a caller. Go ahead with your question.
Caller: Hello. Hi. Thank you, Doctor, for a very informative presentation. I appreciate it. I'm headed for admission on April 26th for my CAR T infusion. I was just wondering, I don’t know if you touched on the average durability or what the incidence of durability is. The other question I have is, what is the incidence of loss of BCMA target? Have you seen much of that?
Dr. Raje: All good questions. Thank you for your questions and good luck with your hospitalization. I tell most of my patients it is going to be a boring two weeks when you're in the hospital. So prepare yourself and bring stuff to do. You may end up with a fever. That's something you know in a strange kind of way we want to see that because we want to see those T cells expand. As far as durability of responses concern on an average per year right now, if you achieve a stringent CR or a CR, I told you on an average we see 20 months and beyond. Our hope is that we see durable and good responses to this. In general, as I've mentioned already, it's actually well tolerated. So you, hopefully, will be very bored wherever you're at.
Caller: I'm praying for that.
Dr. Raje: There you go. Ten days. I wish you all the best. I'm sure you're going to have a great response.
Caller: Thank you. What about the BCMA target question?
Dr. Raje: Yes, sorry, your question on loss of BCMA. I know there have been case reports of BCMA loss, but I will tell you that most times when relapse happens, it is BCMA positive. That's why, you know, the other question which always comes up is we have so many drug products which are going to be in the myeloma space. I say, hey, more products, the better it's going to be. It's going to be competition. It's not as if BCMA loss is the primary reason for you to lose response. The primary reason for you to lose response is the T cell start just petering off, and they are not around. So giving another drug product down the line would be something completely reasonable. BCMA loss happens in the minority of patients. If that happens, remember there are other CAR T cell products that we are testing already, specifically against new targets, and this is called the G-protein-coupled receptors 5D, so GPCR5D. Already data with that looks very, very good in the minority of patients who had BCMA loss.
Caller: Excellent. Thank you so much. Namaste to you, Doctor.
Jenny: Thank you so much for your question. Great questions. Okay, we have another caller. Go ahead with your question.
Caller: Hi, thank you so much. Wonderful presentation. Any site for patients who have not failed four lines of therapy but the promise of not being on so many drugs at one time? Are there any centers that are doing any clinical trials prior to failing four lines?
Dr. Raje: Again, a great question. Yes, there's a lot of ongoing research in the earlier space. I think the best way to do this would be go on to clinicaltrials.gov and look at CAR T cells for myeloma. There's trial with Cilta-cel. There's trials with Ide-cel. We're doing it in patients up to one to three lines of treatment, for example, KarMMa-3 allows you to do that. It is a randomized trial and that randomized trial, so you don't have the choice of are you going to get the CAR T cell upfront or not. Having said that, the only reason we have it open at our site is if for whatever -- so it's two is to one randomization. If you have three people, two of you will get CAR T cells, one does not get CAR T cells, and we give them standard of care because earlier in the lines of treatment. But after you relapse after that for whatever line of treatment you're on, you can go -- you will receive CAR T cells. You may not get it up front, and it's almost looking at it as if it's delayed CAR T cells. But that's one way of getting earlier CAR T cells. There are other trials with Cilta-cel also which are doing very similar studies, and those would be trying to get the CAR T cells early.
In the high risk space, we have lots of trials wherein we are doing it even up front instead of a transplant, and that's KarMMa-4, I believe. There's going to be other studies like KarMMa-7 which are going to test some of what Jenny was asking, what are the combinations that we can start thinking about using in the context of CAR T cells?
Caller: Okay. Thank you so much.
Jenny: If I can make a comment too, like clinicaltrials.gov is really hard to navigate in my personal opinion. We created a tool on healthtree.org that you can enter like your prior lines of therapy and some of your lab values and then because all the eligibility criteria is based on that information. Then we have a partnership with SparkCures, so you'll be able to see all the clinical trials you are eligible to join, of all kinds, not just CAR T. But then you can narrow it down and say, okay, I just want to look at the CAR T trials that I'm personally eligible to join or could be soon eligible to join. I did that for myself. Just recently I spent like, I don't know, maybe an hour and a half, two hours kind of just digging into the depths. But I didn't have to look through like 450 openings for myeloma on clinicaltrials.gov. I was looking at maybe 10 or 20. I could kind of really see like, what are the trials? What are they combining? When are they doing it? Do I qualify? So I would make that suggestion.
Well, Dr. Raje, we are at time. I just want to thank you so much for participating on the show. This will not be probably the last time that we invite your participation in a lot of the programs. But your level of expertise in running these studies is so incredible that you were the perfect person to join us for this. Thank you again so much.
Dr. Raje: Thanks so much for having me, and keep doing all the work you're doing, Jenny. I will shout out to HealthTree. I agree completely. It narrows down the clinical trials. Clinicaltrials.gov can be overwhelming for patients. So absolutely. Thank you so much for having me on. Appreciate it.
Jenny: Well, thank you so much. Thank you to our listeners for listening to another episode of Myeloma Crowd Radio. We invite you to join us next time to see how we can help connect with myeloma researchers and also contribute to a potential myeloma cure.
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Feb. 01, 2023
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