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Establishing the Potential of AMG 420 in R/R Multiple Myeloma

Panelists: Sagar Lonial, MD, FACP, Winship Cancer Institute of Emory University; Amrita Y. Krishnan, MD, City of Hope Comprehensive Cancer Center; Thomas G. Martin, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Krina K. Patel, MD, MSc, University of Texas MD Anderson Cancer Center; Saad Z. Usmani, MD, FACP, Levine Cancer Institute
Published: Monday, Jul 29, 2019



Transcript: 

Sagar Lonial, MD, FACP: Let’s talk about the BiTE [bispecific T-cell engager], AMG 420 immune therapy, BCMA [B-cell maturation antigen]. More BCMA all over again. How much BCMA can we take?

Amrita Y. Krishnan, MD: I think you made a good point about BiTE, and this is the one that generated the most buzz because it’s the furthest along. This is the one against BCMA and CD3, but there are many other BiTEs in first-in-human trials that hopefully by ASH [the American Society of Hematology annual meeting] that we will start to see as well. To review the trial, at 42 patients, with dose escalation of the BCMA antibody, it has a very short half-life, there’s continuous infusion. They saw 13 of the 42 patients responded, so that’s the good news.

The other interesting thing I found from it was even when you stop therapy, some of those patients responded for over a year, and given the short half-life of the drug, it’s not from the drug hanging around. To me that’s more a question of, what have you done to the immune environment that’s really been lasting? And so technically you expect that from any of the other BiTEs as well. I think the good news is it works, there are responses. Notes of caution were obviously the neuropathies, but only 2 patients. One of them is having quite severe neuropathy, and I don’t know if anyone else wants to comment, but I found that quite alarming because of no predisposition.

Sagar Lonial, MD, FACP: It was Guillain-Barre syndrome, wasn’t it? It wasn’t just neuropathy.

Thomas G. Martin, MD: It was pretty severe.

Krina K. Patel, MD, MSc: One was Guillain-Barre, and the other patient had issues with walking as well, so the neuropathy was pretty bad.

Amrita Y. Krishnan, MD: Given the unexpectedness of that, I don’t know how to put that into the context of the response rates. But to me it’s, yes, BiTEs are going to come in the future for us in myeloma therapy.

Sagar Lonial, MD, FACP: What about other potential targets? With BCMA, I’m sure each of you guys have treated somebody with a BCMA BiTE, whether it’s this one or the other ones that are out there. What about other targets for BiTEs? I know we’re going to talk maybe in a moment about other CAR [chimeric antigen receptor] T-cell targets, but CS1, CD38, all these other things are potential BiTE targets as well, right?

Saad Z. Usmani, MD, FACP: Yes, GPRC5D [G protein-coupled receptor 5D] is the other one. It’s even being looked at from CAR T-cell development. But I think we have early data and early experience with each of them. It looks like the bispecific monoclonal antibodies do have activity with each of these targets. I think it’s going to be how you deliver them. What kind of safety profile do you get with them, and how do you fit them in? I agree with Sagar. The BCMA as a target is fairly saturated. So I don’t know the value of utilizing a bispecific after a CAR T, or a CAR T after bispecific targeting BCMA. This is a fairly nascent space and you’re going to see a lot of other targets in the same space. CD48A is another one.

Sagar Lonial, MD, FACP:  I think the challenge with CAR T cells is getting them to it, right?

Thomas G. Martin, MD: Right.

Sagar Lonial, MD, FACP: If you could give a BiTE or a bispecific that was a bridge and told you, yes, this target means something in this patient, that might be a way to say, “All right, now I’m going to give them their CAR [T-cell therapy] on the back end.” But that’s a complicated strategy.

Thomas G. Martin, MD: There’s been a lot of talk about how are these going to be employed? How are they going to be deployed? And the truth of the matter is that not everybody can get CAR [T-cell therapy]. It takes a lot of support. Support from family, going to the transplant center, etcetera. It’s like getting an autologous transplant in terms of the logistics that are involved. But in terms of BiTEs, because it’s off the shelf and can be given in the local doctor’s clinic, I think what many patients are going to get BCMA-targeted therapy prior to even being evaluated for a CAR T per se. And it’s going to be interesting about the sequencing. Can we give multiple BCMA-targeted therapies one after another, or do we have to go BCMA and then a different target, SLAMF7? And then can we go back to BCMA? This is going to be the challenge we face in the next 5 to 10 years, it’s going to be great.

Amrita Y. Krishnan, MD: I guess I would have one note of caution, because with AMG, they had a grade 3 CRS [cytokine release syndrome]. We’ve had experience with several of the other BiTEs. We see CRS, and so that’s still not something that’s ready for general use.

Saad Z. Usmani, MD, FACP: Right. I think it’s still going to be at most Centers of Excellence, and then it’s going to be hard managing those kinds of patients. How many community centers are using blinatumomab, for example, in clinical practice? It’s usually the larger centers that are doing it.

Thomas G. Martin, MD: We have the same thing. We did it with daratumumab because there was 50% infusion reactions, and a lot of the local doctors said, “Oh, can you give the first dose, and then we’ll do the next one.” That might what we do for BCMA.

Saad Z. Usmani, MD, FACP: Maybe the first cycle.

Thomas G. Martin, MD: But they got comfortable after a while, and some of them were just putting them in the local hospital for the first dose and then taking them to their clinic. So I do think that that’s going to evolve too. People are going to learn. And they’re seeing that this isn’t just going to be myeloma. BiTEs are coming for breast cancer, prostate cancer. So the doctors are going to get exposed to these things.

Saad Z. Usmani, MD, FACP: Well the same is true for CAR T for that matter. They’re coming in solid tumor types. I do want to highlight the allogeneic CAR T concept where you’re knocking off TCRs [T-cell receptors] from the donor cells. I think that will be a very important off-the-shelf option, essentially a single donor can help make 100 products that are ready for use. I think that will be a game changer.

Transcript Edited for Clarity

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Transcript: 

Sagar Lonial, MD, FACP: Let’s talk about the BiTE [bispecific T-cell engager], AMG 420 immune therapy, BCMA [B-cell maturation antigen]. More BCMA all over again. How much BCMA can we take?

Amrita Y. Krishnan, MD: I think you made a good point about BiTE, and this is the one that generated the most buzz because it’s the furthest along. This is the one against BCMA and CD3, but there are many other BiTEs in first-in-human trials that hopefully by ASH [the American Society of Hematology annual meeting] that we will start to see as well. To review the trial, at 42 patients, with dose escalation of the BCMA antibody, it has a very short half-life, there’s continuous infusion. They saw 13 of the 42 patients responded, so that’s the good news.

The other interesting thing I found from it was even when you stop therapy, some of those patients responded for over a year, and given the short half-life of the drug, it’s not from the drug hanging around. To me that’s more a question of, what have you done to the immune environment that’s really been lasting? And so technically you expect that from any of the other BiTEs as well. I think the good news is it works, there are responses. Notes of caution were obviously the neuropathies, but only 2 patients. One of them is having quite severe neuropathy, and I don’t know if anyone else wants to comment, but I found that quite alarming because of no predisposition.

Sagar Lonial, MD, FACP: It was Guillain-Barre syndrome, wasn’t it? It wasn’t just neuropathy.

Thomas G. Martin, MD: It was pretty severe.

Krina K. Patel, MD, MSc: One was Guillain-Barre, and the other patient had issues with walking as well, so the neuropathy was pretty bad.

Amrita Y. Krishnan, MD: Given the unexpectedness of that, I don’t know how to put that into the context of the response rates. But to me it’s, yes, BiTEs are going to come in the future for us in myeloma therapy.

Sagar Lonial, MD, FACP: What about other potential targets? With BCMA, I’m sure each of you guys have treated somebody with a BCMA BiTE, whether it’s this one or the other ones that are out there. What about other targets for BiTEs? I know we’re going to talk maybe in a moment about other CAR [chimeric antigen receptor] T-cell targets, but CS1, CD38, all these other things are potential BiTE targets as well, right?

Saad Z. Usmani, MD, FACP: Yes, GPRC5D [G protein-coupled receptor 5D] is the other one. It’s even being looked at from CAR T-cell development. But I think we have early data and early experience with each of them. It looks like the bispecific monoclonal antibodies do have activity with each of these targets. I think it’s going to be how you deliver them. What kind of safety profile do you get with them, and how do you fit them in? I agree with Sagar. The BCMA as a target is fairly saturated. So I don’t know the value of utilizing a bispecific after a CAR T, or a CAR T after bispecific targeting BCMA. This is a fairly nascent space and you’re going to see a lot of other targets in the same space. CD48A is another one.

Sagar Lonial, MD, FACP:  I think the challenge with CAR T cells is getting them to it, right?

Thomas G. Martin, MD: Right.

Sagar Lonial, MD, FACP: If you could give a BiTE or a bispecific that was a bridge and told you, yes, this target means something in this patient, that might be a way to say, “All right, now I’m going to give them their CAR [T-cell therapy] on the back end.” But that’s a complicated strategy.

Thomas G. Martin, MD: There’s been a lot of talk about how are these going to be employed? How are they going to be deployed? And the truth of the matter is that not everybody can get CAR [T-cell therapy]. It takes a lot of support. Support from family, going to the transplant center, etcetera. It’s like getting an autologous transplant in terms of the logistics that are involved. But in terms of BiTEs, because it’s off the shelf and can be given in the local doctor’s clinic, I think what many patients are going to get BCMA-targeted therapy prior to even being evaluated for a CAR T per se. And it’s going to be interesting about the sequencing. Can we give multiple BCMA-targeted therapies one after another, or do we have to go BCMA and then a different target, SLAMF7? And then can we go back to BCMA? This is going to be the challenge we face in the next 5 to 10 years, it’s going to be great.

Amrita Y. Krishnan, MD: I guess I would have one note of caution, because with AMG, they had a grade 3 CRS [cytokine release syndrome]. We’ve had experience with several of the other BiTEs. We see CRS, and so that’s still not something that’s ready for general use.

Saad Z. Usmani, MD, FACP: Right. I think it’s still going to be at most Centers of Excellence, and then it’s going to be hard managing those kinds of patients. How many community centers are using blinatumomab, for example, in clinical practice? It’s usually the larger centers that are doing it.

Thomas G. Martin, MD: We have the same thing. We did it with daratumumab because there was 50% infusion reactions, and a lot of the local doctors said, “Oh, can you give the first dose, and then we’ll do the next one.” That might what we do for BCMA.

Saad Z. Usmani, MD, FACP: Maybe the first cycle.

Thomas G. Martin, MD: But they got comfortable after a while, and some of them were just putting them in the local hospital for the first dose and then taking them to their clinic. So I do think that that’s going to evolve too. People are going to learn. And they’re seeing that this isn’t just going to be myeloma. BiTEs are coming for breast cancer, prostate cancer. So the doctors are going to get exposed to these things.

Saad Z. Usmani, MD, FACP: Well the same is true for CAR T for that matter. They’re coming in solid tumor types. I do want to highlight the allogeneic CAR T concept where you’re knocking off TCRs [T-cell receptors] from the donor cells. I think that will be a very important off-the-shelf option, essentially a single donor can help make 100 products that are ready for use. I think that will be a game changer.

Transcript Edited for Clarity
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