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Optimizing the Use of Anti-BCMA Therapy in MM

Panelists: A. Keith Stewart, MB, ChB, Mayo Clinic; Sagar Lonial, MD, FACP, Emory University School of Medicine; Thomas Martin, MD, UCSF Helen Diller Family; Edward A. Stadtmauer, MD, University of Pennsylvania; Ajai Chari, MD, Mount Sinai Hospital; Amrita Krishnan, MD, FACP, City of Hope Cancer Center
Published: Friday, Aug 31, 2018



Transcript: 

A. Keith Stewart, MB, ChB: So, what about the toxicity? We’ve all been educated already to be a little scared of these products. The U Penn folks did a good job of getting us frightened. It’s basically cerebral edema, high fevers, confusion, and there have been some deaths on some of the studies. What do you take away from the presentation yesterday about that particular CAR T product?

Amrita Krishnan, MD, FACP: Well, so they had a 60% incidence of CRS…

A. Keith Stewart, MB, ChB: CRS is cytokine release syndrome, yes.

Amrita Krishnan, MD, FACP: And only 2% had grade 3 cytokine release, and only about 4% of patients needed to use tocilizumab, the anti–IL-6 antibody. So, what I took home from it though more was these therapies evolve and you get better. I’m not sure it’s just the product, but it’s also your management of the toxicity.

Edward A. Stadtmauer, MD: It’s a learning curve in all of these treatments.

Amrita Krishnan, MD, FACP: Exactly.

A. Keith Stewart, MB, ChB: I was sort of impressed it was not very toxic, so that’s what I thought you were going to see. Sagar, what did you think?

Sagar Lonial, MD, FACP: To me, there are 2 issues: there’s CRS and there’s neurotoxicity. CRS, to me, is like tumor lysis syndrome. You’ve just got to figure out how to deal with it and there’s a certain amount of experience that comes with it. But, certainly, it’s not a reason not to use the therapy. The neurotoxicity is a different story, and I think the mechanism on that is not quite as clear. The management is a little bit more challenging, but, fortunately, that’s a rare event. It doesn’t mean it doesn’t happen, but it is a rare event. What struck me about the presentation yesterday, despite all of these, it wasn’t this, it wasn’t that, the median PFS was 4 times longer than it was for CD19 in large cell lymphoma. Four times longer. That’s pretty good, I think.

A. Keith Stewart, MB, ChB: Ed, should we be using this much earlier in the treatment course? How early are you going to go with CAR T therapy?

Edward A. Stadtmauer, MD: That goes along with the engineering issue. Currently, the vast majority of these patients are very heavily pretreated and in their last legs of their life. And the immune system, the T cells in particular, can be very damaged, and that may account for manufacturing failures for these things, lack of persistence. There seems to be a real association with the persistence and expansion of these cells. And so, I think these results are promising enough. But think of the results of the study that was presented in the relapsed/refractory setting. So, just like when we first were studying daratumumab or bortezomib, in that setting, we saw very exciting responses, but they were potentially not as durable or as curative. And then we started moving these treatments earlier and earlier, and we’re seeing better and better responses.

A. Keith Stewart, MB, ChB: Atezolizumab and daratumumab don’t cost $400,000.

Edward A. Stadtmauer, MD: Well, if we can give one spritz it may be worth it. So, yes, I think there are a number of studies that are moving earlier and earlier in the course of the disease. There are also different targets that CD19-directed CAR T cells have been approved for in acute lymphocytic leukemia and non-Hodgkin lymphoma. And that seems to be a wonderful target in that setting. In multiple myeloma, BCMA seems like a very rational target since it is expressed very frequently. But perhaps there are other targets like CD38. CD19 perhaps is in the group of the cells that are the most resistant. Maybe combinations of these cells, maybe combining other immunotherapies with these cells. So, I think we still have a lot of work to do, but certainly the initial results are very promising.

A. Keith Stewart, MB, ChB: So, my take on listening to some of the lymphoma people talk about this is we’re still in the very early days of understanding how to manage this and improve on, which we will. Sagar, there are other drugs that target BCMA that have been talked about. What’s getting you interested in the non-CAR T BCMA space?

Sagar Lonial, MD, FACP: Yes, I think BCMA is the ideal target and I’m going to stay away from Ed’s reference to the CD19 stem cell, which he snuck in there. But BCMA, I think, is really exciting, and there’s an antibody-drug conjugate. The DREAM study was presented at ASH and looks really good, and a larger phase II study is now being done to just…

A. Keith Stewart, MB, ChB: Yes, they had about a 60% response rate, pretty heavily pretreated patients.

Sagar Lonial, MD, FACP: Sixty percent across the board, yes. If you look at daratumumab-resistant, it was about 50%.

A. Keith Stewart, MB, ChB: And what about eye toxicity? That came out as an issue. Are you worried about that?

Sagar Lonial, MD, FACP: Well, I think it’s a learning curve in terms of how to manage it. It’s a known side effect of the immunotoxin that’s associated with the antibody. So, I think we’ll just have to see, with the mitigation strategy in the current phase II trial, whether that’s sufficient to reduce the severity of the corneal toxicity. It is reversible in almost all the patients.

A. Keith Stewart, MB, ChB: BCMA BiTEs, or bi-specifics, has anybody had any experience with those yet or excited to try?

Ajai Chari, MD: We have some other bi-specifics with very encouraging activity. I think to kind of compare it to the CAR T, it goes back to the patient selection. Here, it’s an off-the-shelf product, so I think that’s important when you’re picking the right patient. And this is going to be, again, a sequencing issue because if you do give these BCMA drugs currently the way the CAR T studies are written…

A. Keith Stewart, MB, ChB: The BiTEs…

Ajai Chari, MD: They’re excluded, so I think we have another sequencing issue, so you want to make sure that you’re doing the right thing for the patient.

A. Keith Stewart, MB, ChB: All right. Well, thanks very much. CAR T, I think we’ll be talking about that for a long time to come.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: So, what about the toxicity? We’ve all been educated already to be a little scared of these products. The U Penn folks did a good job of getting us frightened. It’s basically cerebral edema, high fevers, confusion, and there have been some deaths on some of the studies. What do you take away from the presentation yesterday about that particular CAR T product?

Amrita Krishnan, MD, FACP: Well, so they had a 60% incidence of CRS…

A. Keith Stewart, MB, ChB: CRS is cytokine release syndrome, yes.

Amrita Krishnan, MD, FACP: And only 2% had grade 3 cytokine release, and only about 4% of patients needed to use tocilizumab, the anti–IL-6 antibody. So, what I took home from it though more was these therapies evolve and you get better. I’m not sure it’s just the product, but it’s also your management of the toxicity.

Edward A. Stadtmauer, MD: It’s a learning curve in all of these treatments.

Amrita Krishnan, MD, FACP: Exactly.

A. Keith Stewart, MB, ChB: I was sort of impressed it was not very toxic, so that’s what I thought you were going to see. Sagar, what did you think?

Sagar Lonial, MD, FACP: To me, there are 2 issues: there’s CRS and there’s neurotoxicity. CRS, to me, is like tumor lysis syndrome. You’ve just got to figure out how to deal with it and there’s a certain amount of experience that comes with it. But, certainly, it’s not a reason not to use the therapy. The neurotoxicity is a different story, and I think the mechanism on that is not quite as clear. The management is a little bit more challenging, but, fortunately, that’s a rare event. It doesn’t mean it doesn’t happen, but it is a rare event. What struck me about the presentation yesterday, despite all of these, it wasn’t this, it wasn’t that, the median PFS was 4 times longer than it was for CD19 in large cell lymphoma. Four times longer. That’s pretty good, I think.

A. Keith Stewart, MB, ChB: Ed, should we be using this much earlier in the treatment course? How early are you going to go with CAR T therapy?

Edward A. Stadtmauer, MD: That goes along with the engineering issue. Currently, the vast majority of these patients are very heavily pretreated and in their last legs of their life. And the immune system, the T cells in particular, can be very damaged, and that may account for manufacturing failures for these things, lack of persistence. There seems to be a real association with the persistence and expansion of these cells. And so, I think these results are promising enough. But think of the results of the study that was presented in the relapsed/refractory setting. So, just like when we first were studying daratumumab or bortezomib, in that setting, we saw very exciting responses, but they were potentially not as durable or as curative. And then we started moving these treatments earlier and earlier, and we’re seeing better and better responses.

A. Keith Stewart, MB, ChB: Atezolizumab and daratumumab don’t cost $400,000.

Edward A. Stadtmauer, MD: Well, if we can give one spritz it may be worth it. So, yes, I think there are a number of studies that are moving earlier and earlier in the course of the disease. There are also different targets that CD19-directed CAR T cells have been approved for in acute lymphocytic leukemia and non-Hodgkin lymphoma. And that seems to be a wonderful target in that setting. In multiple myeloma, BCMA seems like a very rational target since it is expressed very frequently. But perhaps there are other targets like CD38. CD19 perhaps is in the group of the cells that are the most resistant. Maybe combinations of these cells, maybe combining other immunotherapies with these cells. So, I think we still have a lot of work to do, but certainly the initial results are very promising.

A. Keith Stewart, MB, ChB: So, my take on listening to some of the lymphoma people talk about this is we’re still in the very early days of understanding how to manage this and improve on, which we will. Sagar, there are other drugs that target BCMA that have been talked about. What’s getting you interested in the non-CAR T BCMA space?

Sagar Lonial, MD, FACP: Yes, I think BCMA is the ideal target and I’m going to stay away from Ed’s reference to the CD19 stem cell, which he snuck in there. But BCMA, I think, is really exciting, and there’s an antibody-drug conjugate. The DREAM study was presented at ASH and looks really good, and a larger phase II study is now being done to just…

A. Keith Stewart, MB, ChB: Yes, they had about a 60% response rate, pretty heavily pretreated patients.

Sagar Lonial, MD, FACP: Sixty percent across the board, yes. If you look at daratumumab-resistant, it was about 50%.

A. Keith Stewart, MB, ChB: And what about eye toxicity? That came out as an issue. Are you worried about that?

Sagar Lonial, MD, FACP: Well, I think it’s a learning curve in terms of how to manage it. It’s a known side effect of the immunotoxin that’s associated with the antibody. So, I think we’ll just have to see, with the mitigation strategy in the current phase II trial, whether that’s sufficient to reduce the severity of the corneal toxicity. It is reversible in almost all the patients.

A. Keith Stewart, MB, ChB: BCMA BiTEs, or bi-specifics, has anybody had any experience with those yet or excited to try?

Ajai Chari, MD: We have some other bi-specifics with very encouraging activity. I think to kind of compare it to the CAR T, it goes back to the patient selection. Here, it’s an off-the-shelf product, so I think that’s important when you’re picking the right patient. And this is going to be, again, a sequencing issue because if you do give these BCMA drugs currently the way the CAR T studies are written…

A. Keith Stewart, MB, ChB: The BiTEs…

Ajai Chari, MD: They’re excluded, so I think we have another sequencing issue, so you want to make sure that you’re doing the right thing for the patient.

A. Keith Stewart, MB, ChB: All right. Well, thanks very much. CAR T, I think we’ll be talking about that for a long time to come.

Transcript Edited for Clarity 
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