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Emerging Therapies for Myeloma

Panelists:Keith Stewart, MD, CHB, Mayo Clinic;William I. Bensinger, MD, Swedish Cancer Institute;Rafael Fonseca, MD, Mayo Clinic;C. Ola Landgren, MD, PhD, Memorial Sloan Kettering Cancer Center;Jatin P. Shah, MD, MD Anderson Cancer Center
Published Online: Tuesday, Sep 13, 2016



Transcript:

Keith Stewart, MD, CHB:
There are still patients who progress and relapse multiple times despite all these therapies, and we’re left looking for new options that are coming. I’d just like to spend the last few minutes talking about what’s out there that’s got you excited about what’s coming.

William I. Bensinger, MD: Well, one drug class that I think is quite interesting is the checkpoint inhibitors, the PD-1 inhibitors. And, while the data on initial therapy with monotherapy were pretty disappointing, there weren’t any real partial responses among a study with one of the checkpoint inhibitors. There were data presented at ASH combining it with lenalidomide and dexamethasone and they saw very impressive response rates, about 50%, even among patients who were known to be refractory to lenalidomide. So, the idea that you could recapture sensitivity by adding in a PD-1 inhibitor to me is very intriguing.

Keith Stewart, MD, CHB: I think there’s an update at this meeting.

William I. Bensinger, MD: Yes, I think there will be. But I think that’s very exciting.

Keith Stewart, MD, CHB: What do the others think? Do you think checkpoint inhibitors are going to work in myeloma? They work in Hodgkin’s disease; they work in some solid tumors.

Jatin P. Shah, MD: I think they will. The principle here is that immunotherapy is not disease specific or tumor specific, and so I think we’ve seen globally that immunotherapy is going to be important in all cancers. Now, how do you use immunotherapy is going to be the question. Things like prostate cancer—which are not immunogenic, and we saw no responses with a single agent with a PD-1 inhibitor—when you combine it with a CTLA inhibitor, there’s actually some very nice robust activity that we see there. I think, similarly, in myeloma, it’s not the most immunogenic tumor like melanoma that we can expect to see single-agent activity with a checkpoint inhibitor or a PD-1 inhibitor, but I think clearly as we move forward now, there are some very intriguing data with IMiDs, and we have to generate the data with proteasome inhibitors. We have to combine it with other checkpoint inhibitors. And so we’re going to be doing a trial at MD Anderson now where, similar to melanoma, they combined a PD-1 plus a CTLA, we’re going to be doing that in myeloma, as well. So, I think that’s very exciting as we move forward now that immunotherapy globally is going to be an important part of myeloma.

Keith Stewart, MD, CHB: I guess I’m a little more on the fence about checkpoint inhibitors personally, but what do you think guys?

Rafael Fonseca, MD: I think when you look at checkpoints, they’re the only other agents that are going to give us a flat curve with what we’re seeing in other tumor types. The fact that it rescues lenalidomide sensitivity, I think, is interesting. Almost all the agents we have talked about before, they have had a duration, even if that’s in years. So, maybe I’m too optimistic, but I do think the checkpoint inhibitors do hold a lot of promise for myeloma.

Keith Stewart, MD, CHB: Ola, you’ve got some trials at your center.

C. Ola Landgren, MD, PhD: We have interest in immunology across different diseases at our institution, and I think there are a lot of preclinical data that would strongly encourage doing it. But then at the same time, there is no single drug activity. So, combining that with which drugs—should it be with IMiD? Should it be with daratumumab? Should it be with other types of cell-based therapies? Could it be CAR-T cell therapy?

Keith Stewart, MD, CHB: Yes, talk about them for a minute because I must admit I’m on the phone now with NIH in Pennsylvania trying to find slots for CAR-T cell therapy. What do you think of those treatments?

C. Ola Landgren, MD, PhD: We are opening our first trial. We’re going to put the first patient on a CAR-T cell for BCMA (B-cell maturation antigen) March 1st of 2017. That’s when we’re going to open our CAR-T cell program for myeloma. This is going to be next year, so we are very enthusiastic about it. We have followed closely the other groups and our institution has a track record in acute leukemias, and other diseases as well. So, myeloma will be our next disease where we’re going after with CAR-T cells. We intend to do armored CAR-T cells where we’re going to clone in interleukins into the T cells. And we also are planning on doing more than one target in the CAR-T cells. You don’t only have BCMA, you have two or three other targets, as well.

Keith Stewart, MD, CHB: Okay, what other drugs are out there? Rafael, what else has caught your attention? What about venetoclax or selinexor?

Rafael Fonseca, MD: You know, I’m particularly keen on venetoclax. I’d like to see a lot more work being done.

Keith Stewart, MD, CHB: Tell us what that drug is.

Rafael Fonseca, MD: It’s a new compound which is a BCL-2 inhibitor, but it’s interesting because we have seen on a preliminary fashion that patients with a translocation of chromosome 14 or with lymphoid morphology seem to respond very well. I’m actually eager to start using it on some of my patients that have exhausted all other options. Their response rates have been very high, including complete responses. There are several trials going on so I think it’s been played out. I’m not sure what the best use or what combination is best used. But I’m going to venture out to say that, particularly for patients with a lymphoid of variant myeloid t(11:14) this seems to be a very promising agent.

Keith Stewart, MD, CHB: Anybody else had experience with venetoclax? I must admit, I guess we’ve had a trial, and I’ve had a great deal of success with it but mainly in (11:14) patients, as you pointed out. So, a real targeted therapy, approved for CLL now but worth trying in your myeloma patients off-label. What about others? The selinexor maybe is one we should mention and talk about.

Jatin P. Shah, MD: I think continuing with actually the CLL drugs, just briefly, we see ibrutinib, which has also approved in CLL.

Keith Stewart, MD, CHB: You think that’s got activity in myeloma or…?

Jatin P. Shah, MD: I think as a single agent we didn’t see much activity and, biologically, we’re not sure why it would, but the clinical data from Ajay that were presented at ASH were compelling where we’ve seen some nice response rates with carfilzomib. So, I think that’s some interesting data there that we need to follow, as well. The selinexor data also is very interesting, as well.

Keith Stewart, MD, CHB: What is selinexor, Jatin?

Jatin P. Shah, MD: Selinexor is a SINE (selective inhibitors of nuclear export) protein inhibitor. So, basically…

Keith Stewart, MD, CHB: It blocks exportin.

Jatin P. Shah, MD: Exactly. I think that’s a very different mechanism of action that we see with selinexor, but the challenge is going to be trying to find the right dose, the right schedule, and the right combination because it has a fair number of side effects that we see from fatigue, asthenia, and GI toxicity as well.

Keith Stewart, MD, CHB: Okay. Any other thoughts on selinexor? It’s got some promise. It’s got some single-agent activity it looks like.

C. Ola Landgren, MD, PhD: I think it’s a promising agent like Jatin said. We are opening a trial now in the relapse setting together with ixazomib, where we are decreasing the dose of selinexor in combination with ixazomib. And, it’s too early, so I don’t really have any data to share today.

Keith Stewart, MD, CHB: Any other drugs out there that we haven’t talked about that people would like to mention? Plitidepsin got some coverage yesterday and I think what’s your fancy there?

William I. Bensinger, MD: I have no experience with that drug.

Jatin P. Shah, MD: I think the other exciting target, as well, is BCMA. I think that there are not too much clinical data quite yet, but that’s an important other target on the surface of plasma cells, that for community physicians to be aware of that we’re seeing some trials now with the naked antibody, as drug conjugate, and as BiTE technology targeting BCMA. We’re using CAR-T cells to target BCMA, so I think that’s an important target. The way we attack it, either by naked or other antibody, is going to be explored in the next few years, but BCMA is a target and important to keep in mind for a community physician. I think that’s high promise.

Transcript Edited for Clarity

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Transcript:

Keith Stewart, MD, CHB:
There are still patients who progress and relapse multiple times despite all these therapies, and we’re left looking for new options that are coming. I’d just like to spend the last few minutes talking about what’s out there that’s got you excited about what’s coming.

William I. Bensinger, MD: Well, one drug class that I think is quite interesting is the checkpoint inhibitors, the PD-1 inhibitors. And, while the data on initial therapy with monotherapy were pretty disappointing, there weren’t any real partial responses among a study with one of the checkpoint inhibitors. There were data presented at ASH combining it with lenalidomide and dexamethasone and they saw very impressive response rates, about 50%, even among patients who were known to be refractory to lenalidomide. So, the idea that you could recapture sensitivity by adding in a PD-1 inhibitor to me is very intriguing.

Keith Stewart, MD, CHB: I think there’s an update at this meeting.

William I. Bensinger, MD: Yes, I think there will be. But I think that’s very exciting.

Keith Stewart, MD, CHB: What do the others think? Do you think checkpoint inhibitors are going to work in myeloma? They work in Hodgkin’s disease; they work in some solid tumors.

Jatin P. Shah, MD: I think they will. The principle here is that immunotherapy is not disease specific or tumor specific, and so I think we’ve seen globally that immunotherapy is going to be important in all cancers. Now, how do you use immunotherapy is going to be the question. Things like prostate cancer—which are not immunogenic, and we saw no responses with a single agent with a PD-1 inhibitor—when you combine it with a CTLA inhibitor, there’s actually some very nice robust activity that we see there. I think, similarly, in myeloma, it’s not the most immunogenic tumor like melanoma that we can expect to see single-agent activity with a checkpoint inhibitor or a PD-1 inhibitor, but I think clearly as we move forward now, there are some very intriguing data with IMiDs, and we have to generate the data with proteasome inhibitors. We have to combine it with other checkpoint inhibitors. And so we’re going to be doing a trial at MD Anderson now where, similar to melanoma, they combined a PD-1 plus a CTLA, we’re going to be doing that in myeloma, as well. So, I think that’s very exciting as we move forward now that immunotherapy globally is going to be an important part of myeloma.

Keith Stewart, MD, CHB: I guess I’m a little more on the fence about checkpoint inhibitors personally, but what do you think guys?

Rafael Fonseca, MD: I think when you look at checkpoints, they’re the only other agents that are going to give us a flat curve with what we’re seeing in other tumor types. The fact that it rescues lenalidomide sensitivity, I think, is interesting. Almost all the agents we have talked about before, they have had a duration, even if that’s in years. So, maybe I’m too optimistic, but I do think the checkpoint inhibitors do hold a lot of promise for myeloma.

Keith Stewart, MD, CHB: Ola, you’ve got some trials at your center.

C. Ola Landgren, MD, PhD: We have interest in immunology across different diseases at our institution, and I think there are a lot of preclinical data that would strongly encourage doing it. But then at the same time, there is no single drug activity. So, combining that with which drugs—should it be with IMiD? Should it be with daratumumab? Should it be with other types of cell-based therapies? Could it be CAR-T cell therapy?

Keith Stewart, MD, CHB: Yes, talk about them for a minute because I must admit I’m on the phone now with NIH in Pennsylvania trying to find slots for CAR-T cell therapy. What do you think of those treatments?

C. Ola Landgren, MD, PhD: We are opening our first trial. We’re going to put the first patient on a CAR-T cell for BCMA (B-cell maturation antigen) March 1st of 2017. That’s when we’re going to open our CAR-T cell program for myeloma. This is going to be next year, so we are very enthusiastic about it. We have followed closely the other groups and our institution has a track record in acute leukemias, and other diseases as well. So, myeloma will be our next disease where we’re going after with CAR-T cells. We intend to do armored CAR-T cells where we’re going to clone in interleukins into the T cells. And we also are planning on doing more than one target in the CAR-T cells. You don’t only have BCMA, you have two or three other targets, as well.

Keith Stewart, MD, CHB: Okay, what other drugs are out there? Rafael, what else has caught your attention? What about venetoclax or selinexor?

Rafael Fonseca, MD: You know, I’m particularly keen on venetoclax. I’d like to see a lot more work being done.

Keith Stewart, MD, CHB: Tell us what that drug is.

Rafael Fonseca, MD: It’s a new compound which is a BCL-2 inhibitor, but it’s interesting because we have seen on a preliminary fashion that patients with a translocation of chromosome 14 or with lymphoid morphology seem to respond very well. I’m actually eager to start using it on some of my patients that have exhausted all other options. Their response rates have been very high, including complete responses. There are several trials going on so I think it’s been played out. I’m not sure what the best use or what combination is best used. But I’m going to venture out to say that, particularly for patients with a lymphoid of variant myeloid t(11:14) this seems to be a very promising agent.

Keith Stewart, MD, CHB: Anybody else had experience with venetoclax? I must admit, I guess we’ve had a trial, and I’ve had a great deal of success with it but mainly in (11:14) patients, as you pointed out. So, a real targeted therapy, approved for CLL now but worth trying in your myeloma patients off-label. What about others? The selinexor maybe is one we should mention and talk about.

Jatin P. Shah, MD: I think continuing with actually the CLL drugs, just briefly, we see ibrutinib, which has also approved in CLL.

Keith Stewart, MD, CHB: You think that’s got activity in myeloma or…?

Jatin P. Shah, MD: I think as a single agent we didn’t see much activity and, biologically, we’re not sure why it would, but the clinical data from Ajay that were presented at ASH were compelling where we’ve seen some nice response rates with carfilzomib. So, I think that’s some interesting data there that we need to follow, as well. The selinexor data also is very interesting, as well.

Keith Stewart, MD, CHB: What is selinexor, Jatin?

Jatin P. Shah, MD: Selinexor is a SINE (selective inhibitors of nuclear export) protein inhibitor. So, basically…

Keith Stewart, MD, CHB: It blocks exportin.

Jatin P. Shah, MD: Exactly. I think that’s a very different mechanism of action that we see with selinexor, but the challenge is going to be trying to find the right dose, the right schedule, and the right combination because it has a fair number of side effects that we see from fatigue, asthenia, and GI toxicity as well.

Keith Stewart, MD, CHB: Okay. Any other thoughts on selinexor? It’s got some promise. It’s got some single-agent activity it looks like.

C. Ola Landgren, MD, PhD: I think it’s a promising agent like Jatin said. We are opening a trial now in the relapse setting together with ixazomib, where we are decreasing the dose of selinexor in combination with ixazomib. And, it’s too early, so I don’t really have any data to share today.

Keith Stewart, MD, CHB: Any other drugs out there that we haven’t talked about that people would like to mention? Plitidepsin got some coverage yesterday and I think what’s your fancy there?

William I. Bensinger, MD: I have no experience with that drug.

Jatin P. Shah, MD: I think the other exciting target, as well, is BCMA. I think that there are not too much clinical data quite yet, but that’s an important other target on the surface of plasma cells, that for community physicians to be aware of that we’re seeing some trials now with the naked antibody, as drug conjugate, and as BiTE technology targeting BCMA. We’re using CAR-T cells to target BCMA, so I think that’s an important target. The way we attack it, either by naked or other antibody, is going to be explored in the next few years, but BCMA is a target and important to keep in mind for a community physician. I think that’s high promise.

Transcript Edited for Clarity
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