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BCMA-Targeted CAR T-Cell Therapy for Myeloma

Panelists: Krishna V. Komanduri, MD, Sylvester Comprehensive Cancer Center; David Maloney, MD, PhD, Fred Hutchinson Cancer Research Center; Sattva S. Neelapu, MD, University of Texas MD Anderson Cancer Center; Michael Pulsipher, MD, Children
Published: Thursday, Mar 01, 2018



Transcript: 

Krishna V. Komanduri, MD: I want to talk about some other diseases beyond the approved indications, and we have some very exciting, I think, preliminary data that we hope to see more about this weekend in the setting of myeloma and AML. And I think I’d like to talk about future directions. So, David, do you want to talk about targeting of BCMA, the B-cell maturation antigen, which is very exciting?

David Maloney, MD, PhD: Yes, so BCMA is a target that is expressed on plasma cells in many cases of multiple myeloma. And we’re starting to see exciting results from several direct companies and groups targeting this. And I think there are 4 or 5 abstracts at the meeting using these approaches which, in some cases, can do stringent CRs in patients with quite refractory multiple myeloma. Obviously, multiple myeloma is a disease where we have a lot of drugs, but none of them are really curative and we’re starting to see that when people run out of options, they don’t have many other places to go. It’s very exciting to see this. I’m actually fascinated by the fact that we still see cytokine release syndrome and neurotoxicity now with a totally different CAR target. So, it’s not just CD19 or CD20 that’s resulting in this, there seems to be a specific toxicity, and especially a neurotoxicity, that’s related to the encounter with the antigen. We’re just beginning our BCMA trials and I know many groups have experienced this, and it seems to be quite varied. The follow-up is short thus far, but we’ve seen response rates in the 50% to 100% range, but we really need to see real data on that in terms of stringency of those complete remissions. Are they really immuno-fixation negative? But it’s really, really encouraging.

Krishna V. Komanduri, MD: Steve, in some ways, if you look at older adults with, for example, low-grade lymphomas and myeloma—median age of myeloma diagnosis is 68—many patients will respond, for example, with follicular lymphoma, but it’s not a durable response. So, there are some parallels here.

Stephen J. Schuster, MD: There’s clearly bad actors with follicular lymphoma. Many patients don’t even need to be treated, but there’s a subset of patients who are bad at the get-go and then there’s a subset of patients who are bad at the end of their disease. And we’ve studied a group of patients like that using the same CD19-directed CAR, tisagenlecleucel, that we used for diffuse large B-cell lymphoma. And there, we actually got a 71% CR rate with a duration of remission the same as we got with large-cell patients. We haven’t reached the median around 2.5 years of follow-up.

Krishna V. Komanduri, MD: So, it’s a challenge, I think, with those low-grade lymphoma patients. Lots of things work, lots of things result in response. They’re not curative. And in myeloma, we have a phenomenal number of agents, proteasome inhibitors and daratumumab have obviously had phenomenal results being moved up earlier. We have quadruplets now rather than just triplets that were the standard a short while ago. And now we have CARs with remarkable efficacy but unknown durability of response in an older population. So, how do we put all these data together and how are trials going to get done?

Stephen J. Schuster, MD: With regard to low-grade lymphoma, I think the most important thing to remember is not everybody needs to be treated.

Krishna V. Komanduri, MD: What about myeloma?

Stephen J. Schuster, MD: And you’ll get the best results treating patients who don’t need treatment.

Krishna V. Komanduri, MD: So, in myeloma, they do need to be treated.

Stephen J. Schuster, MD: Yes, they do need to be treated.

Krishna V. Komanduri, MD: But how do you put a CAR in a setting of a wonderful range of up-front therapies?

Stephen J. Schuster, MD: I think the thing about myeloma.

David Maloney, MD, PhD: It’s just like lymphoma, right? You start off in a population that is kind of end of the road. We’ve used up all their options and then you show the safety, you show some activity, and then you start moving it up based on those results. There are some challenges with BCMA. The antigen is shed. It’s cleaved and comes off of the cell surface. We’re already starting to see in the reports that in resistance cells, the BCMA level is lower. So, there’s probably shedding and loss of the antigen that’s going to be a problem, but that also then opens up avenues to prevent the cleavage of the BCMA from the cells. And there are already plans for combination studies to try to do that. And so, I think there’s a lot of ways to go forward. Obviously, we’re probably not going to be treating 90-year-olds with myeloma, so this will very likely start off in the younger population who have the most severe disease that’s resistant to all treatments. But once you get some proof of concept, which we’re now seeing, then it opens the avenues to move this up…

Stephen J. Schuster, MD: I agree exactly with what David is saying because you may have a plethora of drugs that are active in myeloma, and the average life span is now about 8 years from diagnosis. These people have to live continuously on medicines that have a lot of side effects. The myeloma agents have a lot of side effects, so if I think if you give them a single treatment that even buys you a remission of a significant duration where you’re not on one drug after another, that’s a benefit in terms of quality of life.

Krishna V. Komanduri, MD: I agree, and I think the other thing I would add is that in myeloma in terms of approval, we looked at overall survival first and we moved now to standard being progression-free survival. And I think a lot of people are now talking about the ability to achieve a stringent CR. I think if we have an early endpoint that’s a surrogate for that long-term survival, it could be that we’re going to be looking at whether quadruplet or whether CAR T-cell therapy results in that stringent CR at a measured earlier time point. We haven’t proven that yet but…

David Maloney, MD, PhD: But I think initially we’re going to have to study it in these really refractory patients, and the comparisons are obviously very difficult; what do you compare to? I think no one will disagree that in this population, that’s really, really bad to have failed all of those agents, that this is an advantage.

Krishna V. Komanduri, MD: I think Jim Kochenderfer at the NCI developed a first BCMA-targeted CAR, and Bluebird and then a Chinese company have had some pretty impressive results that have been reported at this meeting.

David Maloney, MD, PhD: The results appear almost too good to be true. Really exciting.

Krishna V. Komanduri, MD: I have to tell you that I was in a hospital in China, that institution had treated 40 patients actually with CD19 CARs for lymphoma. The Chinese experience actually is impressive in some areas, and I think that we have to look at what those results will be, especially at this meeting where there will be more results with longer endpoints.

David Maloney, MD, PhD: I think Steve said it. The costs of these other drugs are not cheap. And if you’re on lenalidomide and on all these drugs for years and years at a tremendous cost, it might be cheaper to get a sample of CAR T-cell therapy.

Stephen J. Schuster, MD: Financial toxicity as well as side effects.

David Maloney, MD, PhD: But who knows, maybe the future will be to just give a CAR early on.

Krishna V. Komanduri, MD: It’s certainly possible or we could end up in the autotransplant situation for myeloma where we have combination induction and then some consolidative therapy, whether it be an autotransplant or a CAR and then some maintenance. It may be that we don’t replace things but we place something in sequence, which might increase costs, not decrease them. We’ll have to see.

Transcript Edited for Clarity 

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Transcript: 

Krishna V. Komanduri, MD: I want to talk about some other diseases beyond the approved indications, and we have some very exciting, I think, preliminary data that we hope to see more about this weekend in the setting of myeloma and AML. And I think I’d like to talk about future directions. So, David, do you want to talk about targeting of BCMA, the B-cell maturation antigen, which is very exciting?

David Maloney, MD, PhD: Yes, so BCMA is a target that is expressed on plasma cells in many cases of multiple myeloma. And we’re starting to see exciting results from several direct companies and groups targeting this. And I think there are 4 or 5 abstracts at the meeting using these approaches which, in some cases, can do stringent CRs in patients with quite refractory multiple myeloma. Obviously, multiple myeloma is a disease where we have a lot of drugs, but none of them are really curative and we’re starting to see that when people run out of options, they don’t have many other places to go. It’s very exciting to see this. I’m actually fascinated by the fact that we still see cytokine release syndrome and neurotoxicity now with a totally different CAR target. So, it’s not just CD19 or CD20 that’s resulting in this, there seems to be a specific toxicity, and especially a neurotoxicity, that’s related to the encounter with the antigen. We’re just beginning our BCMA trials and I know many groups have experienced this, and it seems to be quite varied. The follow-up is short thus far, but we’ve seen response rates in the 50% to 100% range, but we really need to see real data on that in terms of stringency of those complete remissions. Are they really immuno-fixation negative? But it’s really, really encouraging.

Krishna V. Komanduri, MD: Steve, in some ways, if you look at older adults with, for example, low-grade lymphomas and myeloma—median age of myeloma diagnosis is 68—many patients will respond, for example, with follicular lymphoma, but it’s not a durable response. So, there are some parallels here.

Stephen J. Schuster, MD: There’s clearly bad actors with follicular lymphoma. Many patients don’t even need to be treated, but there’s a subset of patients who are bad at the get-go and then there’s a subset of patients who are bad at the end of their disease. And we’ve studied a group of patients like that using the same CD19-directed CAR, tisagenlecleucel, that we used for diffuse large B-cell lymphoma. And there, we actually got a 71% CR rate with a duration of remission the same as we got with large-cell patients. We haven’t reached the median around 2.5 years of follow-up.

Krishna V. Komanduri, MD: So, it’s a challenge, I think, with those low-grade lymphoma patients. Lots of things work, lots of things result in response. They’re not curative. And in myeloma, we have a phenomenal number of agents, proteasome inhibitors and daratumumab have obviously had phenomenal results being moved up earlier. We have quadruplets now rather than just triplets that were the standard a short while ago. And now we have CARs with remarkable efficacy but unknown durability of response in an older population. So, how do we put all these data together and how are trials going to get done?

Stephen J. Schuster, MD: With regard to low-grade lymphoma, I think the most important thing to remember is not everybody needs to be treated.

Krishna V. Komanduri, MD: What about myeloma?

Stephen J. Schuster, MD: And you’ll get the best results treating patients who don’t need treatment.

Krishna V. Komanduri, MD: So, in myeloma, they do need to be treated.

Stephen J. Schuster, MD: Yes, they do need to be treated.

Krishna V. Komanduri, MD: But how do you put a CAR in a setting of a wonderful range of up-front therapies?

Stephen J. Schuster, MD: I think the thing about myeloma.

David Maloney, MD, PhD: It’s just like lymphoma, right? You start off in a population that is kind of end of the road. We’ve used up all their options and then you show the safety, you show some activity, and then you start moving it up based on those results. There are some challenges with BCMA. The antigen is shed. It’s cleaved and comes off of the cell surface. We’re already starting to see in the reports that in resistance cells, the BCMA level is lower. So, there’s probably shedding and loss of the antigen that’s going to be a problem, but that also then opens up avenues to prevent the cleavage of the BCMA from the cells. And there are already plans for combination studies to try to do that. And so, I think there’s a lot of ways to go forward. Obviously, we’re probably not going to be treating 90-year-olds with myeloma, so this will very likely start off in the younger population who have the most severe disease that’s resistant to all treatments. But once you get some proof of concept, which we’re now seeing, then it opens the avenues to move this up…

Stephen J. Schuster, MD: I agree exactly with what David is saying because you may have a plethora of drugs that are active in myeloma, and the average life span is now about 8 years from diagnosis. These people have to live continuously on medicines that have a lot of side effects. The myeloma agents have a lot of side effects, so if I think if you give them a single treatment that even buys you a remission of a significant duration where you’re not on one drug after another, that’s a benefit in terms of quality of life.

Krishna V. Komanduri, MD: I agree, and I think the other thing I would add is that in myeloma in terms of approval, we looked at overall survival first and we moved now to standard being progression-free survival. And I think a lot of people are now talking about the ability to achieve a stringent CR. I think if we have an early endpoint that’s a surrogate for that long-term survival, it could be that we’re going to be looking at whether quadruplet or whether CAR T-cell therapy results in that stringent CR at a measured earlier time point. We haven’t proven that yet but…

David Maloney, MD, PhD: But I think initially we’re going to have to study it in these really refractory patients, and the comparisons are obviously very difficult; what do you compare to? I think no one will disagree that in this population, that’s really, really bad to have failed all of those agents, that this is an advantage.

Krishna V. Komanduri, MD: I think Jim Kochenderfer at the NCI developed a first BCMA-targeted CAR, and Bluebird and then a Chinese company have had some pretty impressive results that have been reported at this meeting.

David Maloney, MD, PhD: The results appear almost too good to be true. Really exciting.

Krishna V. Komanduri, MD: I have to tell you that I was in a hospital in China, that institution had treated 40 patients actually with CD19 CARs for lymphoma. The Chinese experience actually is impressive in some areas, and I think that we have to look at what those results will be, especially at this meeting where there will be more results with longer endpoints.

David Maloney, MD, PhD: I think Steve said it. The costs of these other drugs are not cheap. And if you’re on lenalidomide and on all these drugs for years and years at a tremendous cost, it might be cheaper to get a sample of CAR T-cell therapy.

Stephen J. Schuster, MD: Financial toxicity as well as side effects.

David Maloney, MD, PhD: But who knows, maybe the future will be to just give a CAR early on.

Krishna V. Komanduri, MD: It’s certainly possible or we could end up in the autotransplant situation for myeloma where we have combination induction and then some consolidative therapy, whether it be an autotransplant or a CAR and then some maintenance. It may be that we don’t replace things but we place something in sequence, which might increase costs, not decrease them. We’ll have to see.

Transcript Edited for Clarity 
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