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BCMA-Targeted Approaches for Relapsed Myeloma

Panelists: Paul Richardson, MD, Harvard Medical School; Ajai Chari, MD, Icahn School of Medicine, Mount Sinai; Amrita Krishan, MD, City of Hope Comprehensive Cancer Center; Sagar Lonial, MD, FACP, Emory University School of Medicine; Nina Shah, MD, UCSF; Kenneth Shain, MD, PhD, Moffitt Cancer Center
Published: Friday, Mar 20, 2020

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Transcript: 

Paul Richardson, MD:
I’m going to ask, Nina, of course, to lead this. When targeting CD38 fails a patient, where do we go? Obviously BCMA [B-cell maturation antigen] has really been the talk of the meeting. Nina, would you like to lead this, please, and talk to us a little bit about what caught your eye for BCMA-targeted approaches?

Nina Shah, MD: BCMA [B-cell maturation antigen] is a great target for cellular therapy for myeloma, and there are 3 modalities to do that. One is the CAR [chimeric antigen receptor] T-cell therapy, for which the CARTITUDE-1 data were presented. That is the US adaptation of the LEGEND data. And so the CARTITUDE data, the first cohort was presented, 100% response rate. That made us feel good because we were worried about the only 3 prior lines in the Chinese data. Actually concomitant with that, the LEGEND-2 data had further follow-up and the PFS [progression-free survival] had improved from 15 to 20 months, which made us think maybe we should be using it in earlier lines. That kind of went with that data. There was an early press release for the KarMMa-1 phase II, in that the overall response rate for all cohorts is around 73%, I believe. For the 450 million cell dose, it’s higher, in the 80% range, and the PFS is 11.3 or 11.4 months for that dose. It pretty much mirrors what I was expecting because they’re going to probably go with the 450 million cell dose, and these patients were sicker than the original Bluebird [Bio Inc], the CRB-401 trial, which was published in the New England Journal of Medicine, meaning these patients were actively progressing when they got on the trial.

Then there were a few other interesting CAR T abstracts. Basically, I don’t think anything is going to make a difference until we have PFS data. For some of these, like the bb21217, where the premise is you want to have the cells live longer, really duration of response. If you respond, do you respond for longer? So those data are pending. The other modality we have is BCMA bispecific T-cell engagers BiTEs. This was my pick abstract for the entire meeting as far as the BCMA goes because it’s a patient friendly, weekly and then every other week, and then monthly schedule for a BCMA BiTE, or bispecific engager. They had 90% response rate at their active dose level, so that was really impressive. The question is in myeloma, do you give drugs forever? I don’t know. A lot of interesting infections. We’ll see.

Then finally there is the BCMA ADC [antibody-drug conjugate], which I thought we were going to see, but we don’t have it at this meeting. I think we’ll probably know more later. The Dreamm-1 study had originally showed a 60% or so response rate, 12 month median PFS. Some issues with the corneal toxicity. I go back and forth about this because I think that ultimately this is going to be manageable if you’re that far into treatment and somebody wants a community friendly treatment that’s effective. I think we’ll figure out how to manage it. There’s been talk of that being a little more elucidated in the Dreamm-2 data that will be published. Those are the things that really are looking at BCMA. I think we need to learn to use it earlier.

One shout-out to the BiTE AMG 701 program, since AMG 420 has been dropped due to continuous infusion, there were preclinical data showing that lenalidomide may enhance that efficacy. I think it’s important because we’re talking about BiTEs. The reality is it’s not going to be single agent in the last line forever. It will probably move up.

Paul Richardson, MD: I must say I was also incredibly impressed by the BiTE data led by Luciano Costa, MD, PhD, and that very exciting platform. That to me was quite remarkable. Sagar, just to build on that, and obviously that is the Celgene BiTE.

Nina Shah, MD: Right, the 269.

Paul Richardson, MD: Exactly, the 269. If I may, Sagar, both you and I have been very involved in the belantamab mafodotin story, GSK-916 or BELA-MAF for short. Thoughts on this? Because obviously we didn’t have a late breaker, but that was for reason simply of selection I suspect up against a phase III, totally understandable. We’ll be making that information more public very soon. Just additional things that we can share.

Sagar Lonial, MD, FACP: I think it’s important. Nina, you mentioned the Dreamm-1 study and the prolonged PFS and response rate in that. If you look at the DARA daratumumab resistant subset of Dreamm-1, the response rate was actually in the mid-30% range, and the PFS was 3 to 4 months. I think we have to be because Dreamm-2 is a pretty resistant group of patients.

Paul Richardson, MD: You had to be daratumumab refractory.

Sagar Lonial, MD, FACP: Yes.

Nina Shah, MD: And they try to mirror it to the CAR T and all that.

Sagar Lonial, MD, FACP: Correct. I think if you’re comparing apples to apples to apples, PFS may be different than what we saw in the Dreamm-1 study.

Nina Shah, MD: Yes, and I would expect that.

Sagar Lonial, MD, FACP: Yes.

Amrita Krishnan, MD: I would make the point that in terms of Luciano’s data with the bispecific T-cell engager, the good part, 88% were daratumumab refractory. We have no idea about durability of responses with those patients.

Nina Shah, MD: We don’t know.

Paul Richardson, MD: Not yet, I agree. What I loved was the convenience of it. It’s a weekly infusion.

Nina Shah, MD: And eventually monthly.

Paul Richardson, MD: Exactly. I think there’s a practical application to it, which could be really game changing. I would echo exactly what Sagar has said. I think the important point about Dreamm-2 is that it embraces this truly penta-refractory population. And we were very pleased with how it performed. I would say in terms of the corneal toxicity, Nina, we really do understand that better. It’s not corneal ulceration and it is not steroid responsive.

Nina Shah, MD: Right, and it’s not necessarily symptomatic. It’s created based on....

Paul Richardson, MD: Quite, well said. I think what we found is it’s very manageable, and if you reduce dose, fascinating, the expanded access program, they’ve been dividing; split dosing has become a thing. I’d love other comments from the panel on the BCMA space because it’s so exciting. If I may, Ken, and then I’ll ask Amrita and Ajai to comment.

Kenneth H. Shain, MD, PhD: I guess the points I would make are 1) it’s very exciting, obviously. But 2) is CAR T and now BiTE. The BiTE data I think were powerful. It tells us, we all thought the immune system was gone at this point, but now you’re engaging a T-cell, and it’s doing a fantastic job. So maybe we’re not so far off in terms of what we can do with the immune system late in therapy. The data are outstanding, but it also teaches us a bit of biology about myeloma later on, maybe educating us, at least changing our mind.

The ADC I think is a fantastic way to go because we’re talking about CAR T, BiTEs; these are things that I still think at this point, these are all academic center, all specialty center kind of drugs. The community really needs something else for these individuals who’ve failed lots of things. BCMA-targeted therapy with an ADC is a fantastic way to go. And again, hopefully we can work on how to help them figure out how to get an ophthalmologist or optometrist involved to help grade these things, what’s the right thing to do, holding, split dosing. Ways to figure things out would be important for getting it truly into the community where they really need it.

Paul Richardson, MD: Fantastic. Amrita, other thoughts?

Amrita Krishnan, MD: I think the thing that excited me a lot about the BCMA bispecific data was the idea that now we have bispecifics in myeloma. And all of us are on many conference calls at strange hours for several other targets. I think this is just the beginning of this story. We’re going to hear the GPRC5 target story in terms of CAR T as well as in bispecifics; FCRL5, so I think this is just tremendous as a whole. As Sagar said, I forget whether it was the platforms or the buckets; I think we’re going to have some new buckets in the future for patients.


Transcript Edited for Clarity

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Transcript: 

Paul Richardson, MD:
I’m going to ask, Nina, of course, to lead this. When targeting CD38 fails a patient, where do we go? Obviously BCMA [B-cell maturation antigen] has really been the talk of the meeting. Nina, would you like to lead this, please, and talk to us a little bit about what caught your eye for BCMA-targeted approaches?

Nina Shah, MD: BCMA [B-cell maturation antigen] is a great target for cellular therapy for myeloma, and there are 3 modalities to do that. One is the CAR [chimeric antigen receptor] T-cell therapy, for which the CARTITUDE-1 data were presented. That is the US adaptation of the LEGEND data. And so the CARTITUDE data, the first cohort was presented, 100% response rate. That made us feel good because we were worried about the only 3 prior lines in the Chinese data. Actually concomitant with that, the LEGEND-2 data had further follow-up and the PFS [progression-free survival] had improved from 15 to 20 months, which made us think maybe we should be using it in earlier lines. That kind of went with that data. There was an early press release for the KarMMa-1 phase II, in that the overall response rate for all cohorts is around 73%, I believe. For the 450 million cell dose, it’s higher, in the 80% range, and the PFS is 11.3 or 11.4 months for that dose. It pretty much mirrors what I was expecting because they’re going to probably go with the 450 million cell dose, and these patients were sicker than the original Bluebird [Bio Inc], the CRB-401 trial, which was published in the New England Journal of Medicine, meaning these patients were actively progressing when they got on the trial.

Then there were a few other interesting CAR T abstracts. Basically, I don’t think anything is going to make a difference until we have PFS data. For some of these, like the bb21217, where the premise is you want to have the cells live longer, really duration of response. If you respond, do you respond for longer? So those data are pending. The other modality we have is BCMA bispecific T-cell engagers BiTEs. This was my pick abstract for the entire meeting as far as the BCMA goes because it’s a patient friendly, weekly and then every other week, and then monthly schedule for a BCMA BiTE, or bispecific engager. They had 90% response rate at their active dose level, so that was really impressive. The question is in myeloma, do you give drugs forever? I don’t know. A lot of interesting infections. We’ll see.

Then finally there is the BCMA ADC [antibody-drug conjugate], which I thought we were going to see, but we don’t have it at this meeting. I think we’ll probably know more later. The Dreamm-1 study had originally showed a 60% or so response rate, 12 month median PFS. Some issues with the corneal toxicity. I go back and forth about this because I think that ultimately this is going to be manageable if you’re that far into treatment and somebody wants a community friendly treatment that’s effective. I think we’ll figure out how to manage it. There’s been talk of that being a little more elucidated in the Dreamm-2 data that will be published. Those are the things that really are looking at BCMA. I think we need to learn to use it earlier.

One shout-out to the BiTE AMG 701 program, since AMG 420 has been dropped due to continuous infusion, there were preclinical data showing that lenalidomide may enhance that efficacy. I think it’s important because we’re talking about BiTEs. The reality is it’s not going to be single agent in the last line forever. It will probably move up.

Paul Richardson, MD: I must say I was also incredibly impressed by the BiTE data led by Luciano Costa, MD, PhD, and that very exciting platform. That to me was quite remarkable. Sagar, just to build on that, and obviously that is the Celgene BiTE.

Nina Shah, MD: Right, the 269.

Paul Richardson, MD: Exactly, the 269. If I may, Sagar, both you and I have been very involved in the belantamab mafodotin story, GSK-916 or BELA-MAF for short. Thoughts on this? Because obviously we didn’t have a late breaker, but that was for reason simply of selection I suspect up against a phase III, totally understandable. We’ll be making that information more public very soon. Just additional things that we can share.

Sagar Lonial, MD, FACP: I think it’s important. Nina, you mentioned the Dreamm-1 study and the prolonged PFS and response rate in that. If you look at the DARA daratumumab resistant subset of Dreamm-1, the response rate was actually in the mid-30% range, and the PFS was 3 to 4 months. I think we have to be because Dreamm-2 is a pretty resistant group of patients.

Paul Richardson, MD: You had to be daratumumab refractory.

Sagar Lonial, MD, FACP: Yes.

Nina Shah, MD: And they try to mirror it to the CAR T and all that.

Sagar Lonial, MD, FACP: Correct. I think if you’re comparing apples to apples to apples, PFS may be different than what we saw in the Dreamm-1 study.

Nina Shah, MD: Yes, and I would expect that.

Sagar Lonial, MD, FACP: Yes.

Amrita Krishnan, MD: I would make the point that in terms of Luciano’s data with the bispecific T-cell engager, the good part, 88% were daratumumab refractory. We have no idea about durability of responses with those patients.

Nina Shah, MD: We don’t know.

Paul Richardson, MD: Not yet, I agree. What I loved was the convenience of it. It’s a weekly infusion.

Nina Shah, MD: And eventually monthly.

Paul Richardson, MD: Exactly. I think there’s a practical application to it, which could be really game changing. I would echo exactly what Sagar has said. I think the important point about Dreamm-2 is that it embraces this truly penta-refractory population. And we were very pleased with how it performed. I would say in terms of the corneal toxicity, Nina, we really do understand that better. It’s not corneal ulceration and it is not steroid responsive.

Nina Shah, MD: Right, and it’s not necessarily symptomatic. It’s created based on....

Paul Richardson, MD: Quite, well said. I think what we found is it’s very manageable, and if you reduce dose, fascinating, the expanded access program, they’ve been dividing; split dosing has become a thing. I’d love other comments from the panel on the BCMA space because it’s so exciting. If I may, Ken, and then I’ll ask Amrita and Ajai to comment.

Kenneth H. Shain, MD, PhD: I guess the points I would make are 1) it’s very exciting, obviously. But 2) is CAR T and now BiTE. The BiTE data I think were powerful. It tells us, we all thought the immune system was gone at this point, but now you’re engaging a T-cell, and it’s doing a fantastic job. So maybe we’re not so far off in terms of what we can do with the immune system late in therapy. The data are outstanding, but it also teaches us a bit of biology about myeloma later on, maybe educating us, at least changing our mind.

The ADC I think is a fantastic way to go because we’re talking about CAR T, BiTEs; these are things that I still think at this point, these are all academic center, all specialty center kind of drugs. The community really needs something else for these individuals who’ve failed lots of things. BCMA-targeted therapy with an ADC is a fantastic way to go. And again, hopefully we can work on how to help them figure out how to get an ophthalmologist or optometrist involved to help grade these things, what’s the right thing to do, holding, split dosing. Ways to figure things out would be important for getting it truly into the community where they really need it.

Paul Richardson, MD: Fantastic. Amrita, other thoughts?

Amrita Krishnan, MD: I think the thing that excited me a lot about the BCMA bispecific data was the idea that now we have bispecifics in myeloma. And all of us are on many conference calls at strange hours for several other targets. I think this is just the beginning of this story. We’re going to hear the GPRC5 target story in terms of CAR T as well as in bispecifics; FCRL5, so I think this is just tremendous as a whole. As Sagar said, I forget whether it was the platforms or the buckets; I think we’re going to have some new buckets in the future for patients.


Transcript Edited for Clarity
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