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Immunotherapies in Myeloma

Panelists: A. Keith Stewart, MB, ChB, Mayo Clinic; Cristina Gasparetto, MD, Duke University Medical Center; Parameswaran Hari, MD, MRCP, MS, Medical College of Wisconsin; Robert Orlowski, MD, PhD, MD Anderson Cancer Center; Noopur Suresh Raje, MD, Massachusetts General Hospital
Published: Thursday, Mar 08, 2018



Transcript: 

A. Keith Stewart, MB, ChB: Let’s talk about the most exciting area in many heme malignancies but in myeloma as well, which is immunotherapy. We’ve talked about naked antibodies. There are some antibodies out there now, one from GlaxoSmithKline in particular. I haven’t personally used it, but the response rate looked very impressive, about 60%. And this is an anti-BCMA antibody. Anybody have experience using that drug or wants to comment on the abstract? Noopur?

Noopur Suresh Raje, MD: So, I haven’t personally used that, but certainly the response rates are pretty active. I think what we have learned from all of this is BCMA is a good target in myeloma. We have another BCMA-conjugated antibody with DM1 ahead, and again, we’ve seen very similar response rates. So, I think we just have to wait a little bit.

A. Keith Stewart, MB, ChB: Let’s get to the mother of all therapies, which is BCMA CAR T today. Hari, what’s your thinking about CAR T cells in myeloma? Where are we going to end up?

Parameswaran Hari, MD, MRCP, MS: I think CAR T cells are going to be the future in myeloma, but where we end up, we just don’t know yet at this point. We now have competing technologies in terms of the actual backbone of the CAR and the domains of the CAR—which sort of virus is used and how much cells are being given. So, we have a variety of products: The University of Pennsylvania data that are going to be presented by Dr. Cohen, the Bluebird CAR data that are going to be presented by Dr. Berdeja, and then there’s the Chinese data that are going to be presented. And then we have some preclinical data that are being presented with universal CARs and CARs that are bi-targeted, etc.

A. Keith Stewart, MB, ChB: So, Noopur, what do you think? Are you excited? Are you just waiting for more data? You think we need longer follow-up? Where do you sit?

Noopur Suresh Raje, MD: I think the data are very exciting. If you look at part of the Bluebird trial here, what we have is very refractory patients showing amazing responses. In the old days, we never looked at MRD, but we’re seeing MRD-negative disease in multiple relapsed patients who really don’t have other options of treatment. So, it is exciting. The other thing about the Bluebird trial is they have gone out in excess of a year in terms of follow-up, and they’ve seen sustained remissions. I think part of the issue with CAR T cells is it’s not a generalizable treatment. It’s not something that is off the shelf, and it is logistically challenging, and I think that’s something we need to appreciate in terms of expectations.

A. Keith Stewart, MB, ChB: Expensive, too. Bob, you’ve had a little bit of experience. What do you think with CAR T cells?

Robert Orlowski, MD, PhD: Well, the data do look exciting. I think the way you could look at this in the future would be that maybe younger more robust patients could be candidates for the BCMA CAR T. But there may be some older folks who may not be candidates and maybe they would get the BCMA ADCs.

A. Keith Stewart, MB, ChB: Now, you’re alluding to some of the toxicities. What has the experience been at MD Anderson with toxicity of these products?

Robert Orlowski, MD, PhD: Well, the main issues are cytokine release syndrome, which happens relatively early—usually in the first few days. Depending on the severity, it can be treated with IL-6 receptor antibodies or IL-6 cytokine antibodies, and in more severe cases, it may require steroids. And then there’s neurotoxicity, which sometimes comes along with the CRS or sometimes comes separately, and that’s mostly treated with steroids. But before we get too excited about that, it’s worth saying that the number of patients who are out more than a year in complete remission is literally a handful. And there are people who don’t achieve complete remission, and there are folks who achieve and then lose complete remission. So, unfortunately, this is probably not going to be the cure, certainly not for everybody with relapsed/refractory myeloma.

A. Keith Stewart, MB, ChB: Christina, your thoughts on CAR T?

Cristina Gasparetto, MD: Well, I think we need to wait. But I’m also excited. I was actually impressed with the toxicity. I was expecting more toxicity, and, in reality, it was relatively manageable. Bob was talking about the upper age, and there were actually some patients over age 70 who tolerated the therapy. I don’t know where we’re going to niche it. It’s going to be the new allo for the high risk. I don’t know. I think it’s very early but very, very exciting for the myeloma.

A. Keith Stewart, MB, ChB: Bob, do you think people are getting cured or do you think they’ll all relapse eventually?

Robert Orlowski, MD, PhD: Well, if we look at the lymphoma experience, there do seem to be about 20% to 25% of patients who are staying in complete remission. The issue, of course, is with DLBCL. You can go out sometimes up to 5 years and still relapse, and we don’t have that long a follow-up. But there’s reason to be optimistic. As to whether it will be the allotransplant for myeloma, I think that’s a little problematic because you need some tumor cells for the T cells to proliferate and become angry and attack. If our induction therapies are so much better and eliminate myeloma completely down to MRD negativity, I think the question is, is there enough tumor left that the CAR T cell will actually do something other than cost a lot of money?

A. Keith Stewart, MB, ChB: Will it replace transplant, Hari? I’m trying to get you off transplant today.

Parameswaran Hari, MD, MRCP, MS: It might actually replace allotransplant.

A. Keith Stewart, MB, ChB: Allo, nobody does allo anymore except you.

Cristina Gasparetto, MD: We do.

A. Keith Stewart, MB, ChB: You do?

Parameswaran Hari, MD, MRCP, MS: Yes. There’s actually a trial going on. No, I think it could be used in conjunction with transplant, although I have the same worry Bob has: that if you don’t have a target, T cells don’t proliferate. So, if you get to an MRD-negative state with induction and a transplant and then you’re following up with an immuno-oncology approach, then the CAR T may not fit in right there. But maybe it could replace transplant if you could collect for transplant and you could use a portion of the cells to generate CAR T cells and have your stem cells and CAR T cells stored away for the future. That could be the future.

A. Keith Stewart, MB, ChB: Last word on CAR T cells, Noopur.

Noopur Suresh Raje, MD: I think it’s exciting. I think we need to see longer follow-up data, but I do think it has the potential to take the place of an autotransplant. And the problem there is we’re just going to have to use this strategy early, where there is disease on board, for those T cells to work.

A. Keith Stewart, MB, ChB: I never even thought of this point. We’re so good at getting rid of the myeloma, what’s is left to get rid of? Excellent point.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: Let’s talk about the most exciting area in many heme malignancies but in myeloma as well, which is immunotherapy. We’ve talked about naked antibodies. There are some antibodies out there now, one from GlaxoSmithKline in particular. I haven’t personally used it, but the response rate looked very impressive, about 60%. And this is an anti-BCMA antibody. Anybody have experience using that drug or wants to comment on the abstract? Noopur?

Noopur Suresh Raje, MD: So, I haven’t personally used that, but certainly the response rates are pretty active. I think what we have learned from all of this is BCMA is a good target in myeloma. We have another BCMA-conjugated antibody with DM1 ahead, and again, we’ve seen very similar response rates. So, I think we just have to wait a little bit.

A. Keith Stewart, MB, ChB: Let’s get to the mother of all therapies, which is BCMA CAR T today. Hari, what’s your thinking about CAR T cells in myeloma? Where are we going to end up?

Parameswaran Hari, MD, MRCP, MS: I think CAR T cells are going to be the future in myeloma, but where we end up, we just don’t know yet at this point. We now have competing technologies in terms of the actual backbone of the CAR and the domains of the CAR—which sort of virus is used and how much cells are being given. So, we have a variety of products: The University of Pennsylvania data that are going to be presented by Dr. Cohen, the Bluebird CAR data that are going to be presented by Dr. Berdeja, and then there’s the Chinese data that are going to be presented. And then we have some preclinical data that are being presented with universal CARs and CARs that are bi-targeted, etc.

A. Keith Stewart, MB, ChB: So, Noopur, what do you think? Are you excited? Are you just waiting for more data? You think we need longer follow-up? Where do you sit?

Noopur Suresh Raje, MD: I think the data are very exciting. If you look at part of the Bluebird trial here, what we have is very refractory patients showing amazing responses. In the old days, we never looked at MRD, but we’re seeing MRD-negative disease in multiple relapsed patients who really don’t have other options of treatment. So, it is exciting. The other thing about the Bluebird trial is they have gone out in excess of a year in terms of follow-up, and they’ve seen sustained remissions. I think part of the issue with CAR T cells is it’s not a generalizable treatment. It’s not something that is off the shelf, and it is logistically challenging, and I think that’s something we need to appreciate in terms of expectations.

A. Keith Stewart, MB, ChB: Expensive, too. Bob, you’ve had a little bit of experience. What do you think with CAR T cells?

Robert Orlowski, MD, PhD: Well, the data do look exciting. I think the way you could look at this in the future would be that maybe younger more robust patients could be candidates for the BCMA CAR T. But there may be some older folks who may not be candidates and maybe they would get the BCMA ADCs.

A. Keith Stewart, MB, ChB: Now, you’re alluding to some of the toxicities. What has the experience been at MD Anderson with toxicity of these products?

Robert Orlowski, MD, PhD: Well, the main issues are cytokine release syndrome, which happens relatively early—usually in the first few days. Depending on the severity, it can be treated with IL-6 receptor antibodies or IL-6 cytokine antibodies, and in more severe cases, it may require steroids. And then there’s neurotoxicity, which sometimes comes along with the CRS or sometimes comes separately, and that’s mostly treated with steroids. But before we get too excited about that, it’s worth saying that the number of patients who are out more than a year in complete remission is literally a handful. And there are people who don’t achieve complete remission, and there are folks who achieve and then lose complete remission. So, unfortunately, this is probably not going to be the cure, certainly not for everybody with relapsed/refractory myeloma.

A. Keith Stewart, MB, ChB: Christina, your thoughts on CAR T?

Cristina Gasparetto, MD: Well, I think we need to wait. But I’m also excited. I was actually impressed with the toxicity. I was expecting more toxicity, and, in reality, it was relatively manageable. Bob was talking about the upper age, and there were actually some patients over age 70 who tolerated the therapy. I don’t know where we’re going to niche it. It’s going to be the new allo for the high risk. I don’t know. I think it’s very early but very, very exciting for the myeloma.

A. Keith Stewart, MB, ChB: Bob, do you think people are getting cured or do you think they’ll all relapse eventually?

Robert Orlowski, MD, PhD: Well, if we look at the lymphoma experience, there do seem to be about 20% to 25% of patients who are staying in complete remission. The issue, of course, is with DLBCL. You can go out sometimes up to 5 years and still relapse, and we don’t have that long a follow-up. But there’s reason to be optimistic. As to whether it will be the allotransplant for myeloma, I think that’s a little problematic because you need some tumor cells for the T cells to proliferate and become angry and attack. If our induction therapies are so much better and eliminate myeloma completely down to MRD negativity, I think the question is, is there enough tumor left that the CAR T cell will actually do something other than cost a lot of money?

A. Keith Stewart, MB, ChB: Will it replace transplant, Hari? I’m trying to get you off transplant today.

Parameswaran Hari, MD, MRCP, MS: It might actually replace allotransplant.

A. Keith Stewart, MB, ChB: Allo, nobody does allo anymore except you.

Cristina Gasparetto, MD: We do.

A. Keith Stewart, MB, ChB: You do?

Parameswaran Hari, MD, MRCP, MS: Yes. There’s actually a trial going on. No, I think it could be used in conjunction with transplant, although I have the same worry Bob has: that if you don’t have a target, T cells don’t proliferate. So, if you get to an MRD-negative state with induction and a transplant and then you’re following up with an immuno-oncology approach, then the CAR T may not fit in right there. But maybe it could replace transplant if you could collect for transplant and you could use a portion of the cells to generate CAR T cells and have your stem cells and CAR T cells stored away for the future. That could be the future.

A. Keith Stewart, MB, ChB: Last word on CAR T cells, Noopur.

Noopur Suresh Raje, MD: I think it’s exciting. I think we need to see longer follow-up data, but I do think it has the potential to take the place of an autotransplant. And the problem there is we’re just going to have to use this strategy early, where there is disease on board, for those T cells to work.

A. Keith Stewart, MB, ChB: I never even thought of this point. We’re so good at getting rid of the myeloma, what’s is left to get rid of? Excellent point.

Transcript Edited for Clarity 
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