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CAR T-Cell Therapy in Myeloma

Insights From: Robert L. Ferris, MD, PhD, UPMC Hillman Cancer Center; Anna C. Pavlick, DO, NYU Langone Hospitals
Published: Thursday, Mar 07, 2019



Transcript:

A. Keith Stewart, MB, ChB:
So we’ll close with the most exciting of all, which is CAR [chimeric antigen receptor] T-cell therapy for myeloma targeting BCMA [B-cell maturation antigen]. There are many abstracts at the meeting looking at different CAR-T structures, different ways of manufacturing. But we’ll focus on the 2 leading targets here which are BB2121 and the Legend L-CAR. There are others too in clinical trials from Juno and other companies. But what do you think?

Thomas Martin, MD: I would say that all of us at this table would say this is the most important thing that’s come through for myeloma in the last 20 years. No doubt about it. With BB2121 in the extremely heavily pretreated population, between 7 and 23 prior lines of therapy, at the appropriate dose, more than 150 million cells, the response rate’s 95% in this population. And the PFS [progression-free survival] is right around a year, so 12 months. These data were presented at ASCO [the American Society of Clinical Oncology annual meeting] by Noopur Raje, MD, and everybody was just blown away with this data in such a heavily pretreated population.

We’re now getting data. Here we’re getting an update from the Legend data. This is the study that was done in China and they’ve enrolled now over 70 patients in China. They’re going to do an update of those data here, but it looks like in the abstract that the response rate is very similar, you know, 88%. And really the benefit is in those people that achieve a CR [complete response]. In those people that achieved a CR, the PFS is 24 months. So this is 2 years of PFS in this….

A. Keith Stewart, MB, ChB: These are really heavily pretreated patients.

Thomas Martin, MD: So, in China, the heavily pretreated….

A. Keith Stewart, MB, ChB: Well, not in China, that’s true.

Thomas Martin, MD: It’s 3 prior lines of therapy. I will say that we have the only US patient that went to China and got this at Legend. And he is a legend for doing this, OK? And this gentleman was penta-refractory and went over there, and we said, “This is your last chance of getting something that’s going to have durable response.” He’s 15 months’ post this therapy now, and he’s in remission and won’t let us do a bone marrow biopsy to prove he’s MRD [minimal residual disease]-negative. Very important.

Adriana Rossi, MD: I was touched by that in the Legend update. The benefit is really for those patients who are able to get to that MRD-negative response with that therapy. So the separation in the curve based on response was striking. For certain patients this is absolutely game changing. But there are some patients that are not going to be reached.

A. Keith Stewart, MB, ChB: There is a relapse rate … there is 50% PFS. So there are people relapsing, which initially we’d hoped we wouldn’t see.

Thomas Martin, MD: Right, correct.

A. Keith Stewart, MB, ChB: But we are seeing those.

Adriana Rossi, MD: But it was like 24 months in the responders, but 6 months if you did not get to that depth of response.

Rafael Fonseca, MD: Well, these are your first trials. You know, 1 dose and then wait. So as we get smarter can you reactivate the immune system? You know, checkpoints, immune modulation with IMiDs [immunomodulatory drugs]? Are we going to refuse? There are all sorts of little permutations that could happen. Plus, it’s a highly competitive field. So I think there’s going to be a lot of incentive to look at various strategies in this area.

A. Keith Stewart, MB, ChB: So toxicity, Faith?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yes, it’s there. There’s no doubt about that. And again, it’s these unusual cytokine release syndromes.

A. Keith Stewart, MB, ChB: It seems to me we sort of figured those out with tocilizumab, but the neurologic complaints we haven’t figured out yet.
Faith Davies, MD, MBBCh, MRCP, FRCPath: Yes. And certainly there seems to be epilepsy and weird things that you’re really not kind of .....

A. Keith Stewart, MB, ChB: Cerebral edema is the big one, right? Did you treat a lot of CAR Ts in San Francisco yet? Are you still in your own days?

Thomas Martin, MD: No, we’ve probably treated 20. And I am actually impressed on 2 things. One, some people don’t respond at all. They have no response whatsoever. And in others, a year later, again, they’re MRD-negative and don’t require any other therapy. They haven’t required any maintenance therapy, which is pretty impressive. I do think that we need biomarkers. We need to know more information about the microenvironment. I think this is where the microenvironment data are going to be so important, of who’s going to respond. And is there a way we can change the microenvironment before they get this therapy to make them a better responder to this?

A. Keith Stewart, MB, ChB: What about timing? This will be my last question for the day here. Where is this going to end up? Right now we’re treating end-stage patients. Where do you think this ends up?

Adriana Rossi, MD: I’m looking forward to learning how to use it better. To Rafael’s point, this is very early on. It’s a huge step, but it’s the first step. I think we need to learn how to manage the toxicities in mass, ideally without steroids. We maybe can toy with the construct a little bit better. It would be great to get sustainability. So there are still some challenges and some room to go; once we get there, moving it upfront would be great.

A. Keith Stewart, MB, ChB: Is it going to replace transplant? Let’s get to the heart of the matter here.

Faith Davies, MD, MBBCh, MRCP, FRCPath: I think it could replace transplant. I’m particularly excited about those high-risk patients, potentially upfront, where we know our current therapies are not good for them.

Thomas Martin, MD: Rafael, I’ll give you the last word. We talked about 4-drug combinations, transplant, consolidation, years and years of maintenance, and millions of dollars worth of therapy. Is this a solution for the economics of this as well?

Rafael Fonseca, MD: Oh, it is. If you think of your best regimen, that you can induce MRD, and potentially you do something like CAR T-cell upfront, and then you do MRD testing and near negative, and we start getting the data, it turns out all this push for all this craziness is going to lead us to better economics. Because you could envision, in the best-case scenario, that we have a future where we treat myeloma like people treat with 2-CdA, you know cladribine, for hairy cell leukemia. So we can’t stop right now because we’re just at the brink of seeing even greater progress. And I’m going to say, I think we are going to see a significant number of myeloma patients being cured quite soon.

A. Keith Stewart, MB, ChB: So when should our community colleagues that may be watching refer a patient for CAR T? Do we wait until they’ve exhausted, or should we send them in earlier?

Adriana Rossi, MD: Well, I think during induction.

A. Keith Stewart, MB, ChB: During induction?

Adriana Rossi, MD: Absolutely. Get them set up so that you can help them dictate their therapy pre-CAR T.

Thomas Martin, MD: Most of the local doctors now treat patients with lenalidomide and bortezomib. And most of the patients eventually become double refractory. So I think when they’re double refractory that’s a time to send them for some of these experimental therapies. And we have hopefully more trials opening up over the next year or 2, and more slots. The problem is that we have plenty of patients for the trials right now but we don’t have enough slots.

A. Keith Stewart, MB, ChB: That’s an ongoing problem

Well thank you everybody. This has been extremely informative. Before we end this discussion, I’d like to get closing thoughts from each of our panelists. So, Dr Martin, closing thoughts?

Thomas Martin, MD: My closing thoughts are that for the treatment of the transplant-ineligible patients, I’m going to start treating them early next year with lenalidomide, dexamethasone, and daratumumab. And when they have first relapse, which is 50 months down the road, they’re going to get either a BiTE [bispecific T-cell engager] or a CAR at that point in time, and that’s going to be at the relapse. In the transplant-eligible they’re going to get a 4-drug combination, a transplant, maintenance. But a year from now, they’re going to get a 4-drug regimen and a CAR. That’s my prediction.

Adriana Rossi, MD: I feel like I’m compelled to go to the other extreme. I look forward to identifying patients and being able to personalize the therapy a little bit better. I think for some patients, absolutely the kitchen sink will be great. But if I could identify the patients that maybe don’t need a quad [4-drug regimen] upfront, maybe don’t need a transplant, or maybe if they have sustained MRD-negativity, I could cut back on therapy. I look forward to that day. I don’t know if it’s quite in the near future.

A. Keith Stewart, MB, ChB: Rafael?

Rafael Fonseca, MD: My closing thought is on something called the value of options. The value of options is a term that the economists use to describe options that open for patients, because they can live to the point that those options become true, which is what happened with AZT [azidothymidine]. Patients who live long enough to see highly active antiretroviral therapy are now living among us. So for any patient who might be seeing this, if you have newly diagnosed myeloma, we have, in many cases, the possibility of controlling the disease for many years. And how we will treat myeloma in 2028, who knows? But I think the push is right there, and there’s a lot of optimism in our field.

A. Keith Stewart, MB, ChB: Faith, last words?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I think that 1 of the good things about this ASH [American Society of Hematology] meeting is that we’ve discovered there’s actually lots of options for patients. And it may be confusing trying to figure out which 1 to use, but, to some extent, I might argue that there may not be a wrong answer. There are actually many correct answers, and we’re now at a point where we talk about patient choice. I think we’re now actually in a position where we can choose the best regimen for the patient.

A. Keith Stewart, MB, ChB: Thank you. Thank you all for your contributions to this discussion. On behalf of our panel we’d like to thank you for joining us. We hope you found this Peer Exchange discussion to be useful and informative.

Transcript edited for clarity.

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Transcript:

A. Keith Stewart, MB, ChB:
So we’ll close with the most exciting of all, which is CAR [chimeric antigen receptor] T-cell therapy for myeloma targeting BCMA [B-cell maturation antigen]. There are many abstracts at the meeting looking at different CAR-T structures, different ways of manufacturing. But we’ll focus on the 2 leading targets here which are BB2121 and the Legend L-CAR. There are others too in clinical trials from Juno and other companies. But what do you think?

Thomas Martin, MD: I would say that all of us at this table would say this is the most important thing that’s come through for myeloma in the last 20 years. No doubt about it. With BB2121 in the extremely heavily pretreated population, between 7 and 23 prior lines of therapy, at the appropriate dose, more than 150 million cells, the response rate’s 95% in this population. And the PFS [progression-free survival] is right around a year, so 12 months. These data were presented at ASCO [the American Society of Clinical Oncology annual meeting] by Noopur Raje, MD, and everybody was just blown away with this data in such a heavily pretreated population.

We’re now getting data. Here we’re getting an update from the Legend data. This is the study that was done in China and they’ve enrolled now over 70 patients in China. They’re going to do an update of those data here, but it looks like in the abstract that the response rate is very similar, you know, 88%. And really the benefit is in those people that achieve a CR [complete response]. In those people that achieved a CR, the PFS is 24 months. So this is 2 years of PFS in this….

A. Keith Stewart, MB, ChB: These are really heavily pretreated patients.

Thomas Martin, MD: So, in China, the heavily pretreated….

A. Keith Stewart, MB, ChB: Well, not in China, that’s true.

Thomas Martin, MD: It’s 3 prior lines of therapy. I will say that we have the only US patient that went to China and got this at Legend. And he is a legend for doing this, OK? And this gentleman was penta-refractory and went over there, and we said, “This is your last chance of getting something that’s going to have durable response.” He’s 15 months’ post this therapy now, and he’s in remission and won’t let us do a bone marrow biopsy to prove he’s MRD [minimal residual disease]-negative. Very important.

Adriana Rossi, MD: I was touched by that in the Legend update. The benefit is really for those patients who are able to get to that MRD-negative response with that therapy. So the separation in the curve based on response was striking. For certain patients this is absolutely game changing. But there are some patients that are not going to be reached.

A. Keith Stewart, MB, ChB: There is a relapse rate … there is 50% PFS. So there are people relapsing, which initially we’d hoped we wouldn’t see.

Thomas Martin, MD: Right, correct.

A. Keith Stewart, MB, ChB: But we are seeing those.

Adriana Rossi, MD: But it was like 24 months in the responders, but 6 months if you did not get to that depth of response.

Rafael Fonseca, MD: Well, these are your first trials. You know, 1 dose and then wait. So as we get smarter can you reactivate the immune system? You know, checkpoints, immune modulation with IMiDs [immunomodulatory drugs]? Are we going to refuse? There are all sorts of little permutations that could happen. Plus, it’s a highly competitive field. So I think there’s going to be a lot of incentive to look at various strategies in this area.

A. Keith Stewart, MB, ChB: So toxicity, Faith?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yes, it’s there. There’s no doubt about that. And again, it’s these unusual cytokine release syndromes.

A. Keith Stewart, MB, ChB: It seems to me we sort of figured those out with tocilizumab, but the neurologic complaints we haven’t figured out yet.
Faith Davies, MD, MBBCh, MRCP, FRCPath: Yes. And certainly there seems to be epilepsy and weird things that you’re really not kind of .....

A. Keith Stewart, MB, ChB: Cerebral edema is the big one, right? Did you treat a lot of CAR Ts in San Francisco yet? Are you still in your own days?

Thomas Martin, MD: No, we’ve probably treated 20. And I am actually impressed on 2 things. One, some people don’t respond at all. They have no response whatsoever. And in others, a year later, again, they’re MRD-negative and don’t require any other therapy. They haven’t required any maintenance therapy, which is pretty impressive. I do think that we need biomarkers. We need to know more information about the microenvironment. I think this is where the microenvironment data are going to be so important, of who’s going to respond. And is there a way we can change the microenvironment before they get this therapy to make them a better responder to this?

A. Keith Stewart, MB, ChB: What about timing? This will be my last question for the day here. Where is this going to end up? Right now we’re treating end-stage patients. Where do you think this ends up?

Adriana Rossi, MD: I’m looking forward to learning how to use it better. To Rafael’s point, this is very early on. It’s a huge step, but it’s the first step. I think we need to learn how to manage the toxicities in mass, ideally without steroids. We maybe can toy with the construct a little bit better. It would be great to get sustainability. So there are still some challenges and some room to go; once we get there, moving it upfront would be great.

A. Keith Stewart, MB, ChB: Is it going to replace transplant? Let’s get to the heart of the matter here.

Faith Davies, MD, MBBCh, MRCP, FRCPath: I think it could replace transplant. I’m particularly excited about those high-risk patients, potentially upfront, where we know our current therapies are not good for them.

Thomas Martin, MD: Rafael, I’ll give you the last word. We talked about 4-drug combinations, transplant, consolidation, years and years of maintenance, and millions of dollars worth of therapy. Is this a solution for the economics of this as well?

Rafael Fonseca, MD: Oh, it is. If you think of your best regimen, that you can induce MRD, and potentially you do something like CAR T-cell upfront, and then you do MRD testing and near negative, and we start getting the data, it turns out all this push for all this craziness is going to lead us to better economics. Because you could envision, in the best-case scenario, that we have a future where we treat myeloma like people treat with 2-CdA, you know cladribine, for hairy cell leukemia. So we can’t stop right now because we’re just at the brink of seeing even greater progress. And I’m going to say, I think we are going to see a significant number of myeloma patients being cured quite soon.

A. Keith Stewart, MB, ChB: So when should our community colleagues that may be watching refer a patient for CAR T? Do we wait until they’ve exhausted, or should we send them in earlier?

Adriana Rossi, MD: Well, I think during induction.

A. Keith Stewart, MB, ChB: During induction?

Adriana Rossi, MD: Absolutely. Get them set up so that you can help them dictate their therapy pre-CAR T.

Thomas Martin, MD: Most of the local doctors now treat patients with lenalidomide and bortezomib. And most of the patients eventually become double refractory. So I think when they’re double refractory that’s a time to send them for some of these experimental therapies. And we have hopefully more trials opening up over the next year or 2, and more slots. The problem is that we have plenty of patients for the trials right now but we don’t have enough slots.

A. Keith Stewart, MB, ChB: That’s an ongoing problem

Well thank you everybody. This has been extremely informative. Before we end this discussion, I’d like to get closing thoughts from each of our panelists. So, Dr Martin, closing thoughts?

Thomas Martin, MD: My closing thoughts are that for the treatment of the transplant-ineligible patients, I’m going to start treating them early next year with lenalidomide, dexamethasone, and daratumumab. And when they have first relapse, which is 50 months down the road, they’re going to get either a BiTE [bispecific T-cell engager] or a CAR at that point in time, and that’s going to be at the relapse. In the transplant-eligible they’re going to get a 4-drug combination, a transplant, maintenance. But a year from now, they’re going to get a 4-drug regimen and a CAR. That’s my prediction.

Adriana Rossi, MD: I feel like I’m compelled to go to the other extreme. I look forward to identifying patients and being able to personalize the therapy a little bit better. I think for some patients, absolutely the kitchen sink will be great. But if I could identify the patients that maybe don’t need a quad [4-drug regimen] upfront, maybe don’t need a transplant, or maybe if they have sustained MRD-negativity, I could cut back on therapy. I look forward to that day. I don’t know if it’s quite in the near future.

A. Keith Stewart, MB, ChB: Rafael?

Rafael Fonseca, MD: My closing thought is on something called the value of options. The value of options is a term that the economists use to describe options that open for patients, because they can live to the point that those options become true, which is what happened with AZT [azidothymidine]. Patients who live long enough to see highly active antiretroviral therapy are now living among us. So for any patient who might be seeing this, if you have newly diagnosed myeloma, we have, in many cases, the possibility of controlling the disease for many years. And how we will treat myeloma in 2028, who knows? But I think the push is right there, and there’s a lot of optimism in our field.

A. Keith Stewart, MB, ChB: Faith, last words?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I think that 1 of the good things about this ASH [American Society of Hematology] meeting is that we’ve discovered there’s actually lots of options for patients. And it may be confusing trying to figure out which 1 to use, but, to some extent, I might argue that there may not be a wrong answer. There are actually many correct answers, and we’re now at a point where we talk about patient choice. I think we’re now actually in a position where we can choose the best regimen for the patient.

A. Keith Stewart, MB, ChB: Thank you. Thank you all for your contributions to this discussion. On behalf of our panel we’d like to thank you for joining us. We hope you found this Peer Exchange discussion to be useful and informative.

Transcript edited for clarity.
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