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Applying New Multiple Myeloma Agents to Practice

Panelists:Ajai Chari, MD, Mount Sinai Hospital; Sagar Lonial, MD, Emory University School of Medicine; Paul G. Richardson, MD, Harvard Medical School; Jatin J. Shah, MD, MD Anderson Cancer Center; Keith Stewart, MD, CHB, Mayo Clinic
Published: Thursday, Mar 17, 2016


Transcript:

Keith Stewart, MB, CHB:
So we have these three trials now where we have very similar populations entering the trial all showing improvements in progression-free survival (PFS), all using lenalidomide, dexamethasone as a backbone. I'm going to move to the fact that we've had a lot of Revlimid in the past in the US and talk about pomalidomide in one second. But, Jatin, how are you going to decide which of these three drugs to use when the backbone is essentially the same?

Jatin J. Shah, MD: You're talking about the oral proteasome inhibitor (PI).

Keith Stewart, MB, CHB: Oral ixazomib, carfilzomib, and the monoclonal antibody elotuzumab, which targets myeloma cells.

Jatin J. Shah, MD: So I think that all three of them are great drugs, and they really made significant advances. I think they're all highly active. The question that you asked is, how are you going to clinically use all these? And I think that's the key: how do you leverage each and every one of these? The challenge is that elotuzumab I think has some great data with lenalidomide and also some data with bortezomib in a phase 2 study with a similar hazard ratio. So you can potentially combine with bortezomib, even though it's not part of the label; that's not how it's FDA-approved.

But I worry that if that's going to be my best partner drug right now, I want to leverage that because I don't have single-agent activity with elotuzumab with other drugs or by itself. So if I use lenalidomide and dexamethasone with something else, then I'm losing the opportunity, potentially, to get the best benefit from elotuzumab. And number two, I think there's really an immune stimulatory component to elotuzumab where it requires NK cells in part and stimulates those. So I think it's very different. I think the earlier in the disease course that you use it to attack the immune system, you may be able to get more benefit from that biologically. So for me, that makes sense to combine it in that setting.

Ajai Chari, MD: I think it's also important to clarify a little bit. You kind of alluded to these three studies and the patient populations, but I don't think they're exactly the same.

Keith Stewart, MB, CHB: I didn't say that, I said they were similar. And just to be clear, they all had one to three prior therapies as the main eligibility.....

Ajai Chari, MD: Correct. I think the devil's in the details. Which is, for example, the ASPIRE and the TOURMALINE study did not allow bortezomib or PI-refractory patients, whereas the ELOQUENT study did. And I think that's one example. So I could imagine as a community oncologist you have these three phase III studies and one to three lines of therapy—and then if you add to that the ENDEAVOR study and also the PANORAMA study.

Keith Stewart, MB, CHB: Which we're going to talk about it in a second.

Ajai Chari, MD: But the point is we have now five phase III studies in one to three lines of prior therapy. As a community oncologist, what do you do with that information?

Keith Stewart, MB, CHB: Well, that's why I just asked you.

Ajai Chari, MD: And one of the things I would say is that we can't say that these subtle differences are going to make significant impacts in outcomes that we see, particularly in PI-- or lenalidomide-refractory patients, whether that's allowed; and not to forget one of the challenges of applying these studies to US populations, given the extent of lenalidomide exposure.

Keith Stewart, MB, CHB: That was going to be my next question. But to get to the one I asked you, which of the three and why?

Ajai Chari, MD: But I think the point is that we should also look at the hazard ratios. Because 50, we're looking at PFS, and it looks like one study has dramatically improved PFS. And as Jatin had mentioned, not that the hazard ratios make it better; you know you shouldn't compare across these studies, but at least it mitigates. It's telling you what the novel agent is adding relative to the control arm to standardize it. And the point is that those hazard ratios are really stacking up in this 0.5-to-0.7 range. And at the end of the day, it's going to come back to being an oncologist and a doctor: what does this patient need? Can they tolerate a PI? Do they have high-risk disease? Are they able to come for parenteral administration?

Keith Stewart, MB, CHB: I guess that's why I would. To me, it’s very patient-dependent.

Sagar Lonial, MD: Yeah, right.

Keith Stewart, MB, CHB: For a high-risk patient with rapidly progressive disease who is interested in aggressive therapy, probably carfilzomib is probably still your choice.

Sagar Lonial, MD: Right.

Keith Stewart, MB, CHB: For somebody who perhaps wants to keep working or maybe lives further away from the clinic: let's put carfilzomib aside for a second and say it's a little bit of an older patient or somebody who just doesn't want to come in twice a week. How are you going to balance elotuzumab versus ixazomib, or are they not mutually exclusive which is the other option?

Sagar Lonial, MD: I think that's a good point, and, again, to put all of those trials in one basket, I think if you got a rapidly progressing patient or a high-risk patient, then I think the carfilzomib combination makes a lot of sense. If you've got somebody who's got a little bit more of an indolent relapse, then adding an antibody where you've got a little bit of time to see the response probably makes sense. Carfilzomib is clearly the more potent proteasome inhibitor. And I suspect that that applies to ixazomib as well. Keith Stewart, MB, CHB: The ability to give ixazomib over a long time is quite attractive too, right?

Sagar Lonial, MD: Right. I mean, so I think there are a lot of factors that weigh in there. And we don't have biomarkers that tell us this patient needs one drug, this patient needs another. Yet, to be able to parse that out…

Keith Stewart, MB, CHB: So we're still figuring it out. That's the short answer, right?

Paul G. Richardson, MD: I think so, but I'd build on the point Sagar is making. I mean, I think your domain will have biomarkers classically, but we certainly have clinical clues. And I think the great news is that we have choices. And I would see it as the pot is truly half full versus half empty, that's for sure. And I think that ixazomib clearly would be an ideal choice for someone who, you know, coming into the clinic twice a week would be a challenge. Completely agree that [in] a high-risk patient with explosive relapse, a very potent inhibitor like carfilzomib makes great sense with the usual caveats. And I think that the elotuzumab data are very provocative, particularly given its tolerability and this idea that it's a true immune oncologic. But I think one thing, Keith, we need to touch on is pomalidomide.

Keith Stewart, MB, CHB: We're getting there. Got to ask the man, the man here is the pomalidomide guy right next to you. Well, you both are, but for the purpose I want.

Paul G. Richardson, MD: Yeah.

Keith Stewart, MB, CHB: Thank you Paul. Just to summarize this discussion: we're very lucky. We've got four randomized trials, we've got new drugs, we're still trying to figure out who gets what, but it's probably going to be quite individualized, I think, at the end of day.

Paul G. Richardson, MD: Yes, absolutely.

Keith Stewart, MB, CHB: And maybe there will be other factors, economic factors, that play in eventually.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Keith Stewart, MB, CHB:
So we have these three trials now where we have very similar populations entering the trial all showing improvements in progression-free survival (PFS), all using lenalidomide, dexamethasone as a backbone. I'm going to move to the fact that we've had a lot of Revlimid in the past in the US and talk about pomalidomide in one second. But, Jatin, how are you going to decide which of these three drugs to use when the backbone is essentially the same?

Jatin J. Shah, MD: You're talking about the oral proteasome inhibitor (PI).

Keith Stewart, MB, CHB: Oral ixazomib, carfilzomib, and the monoclonal antibody elotuzumab, which targets myeloma cells.

Jatin J. Shah, MD: So I think that all three of them are great drugs, and they really made significant advances. I think they're all highly active. The question that you asked is, how are you going to clinically use all these? And I think that's the key: how do you leverage each and every one of these? The challenge is that elotuzumab I think has some great data with lenalidomide and also some data with bortezomib in a phase 2 study with a similar hazard ratio. So you can potentially combine with bortezomib, even though it's not part of the label; that's not how it's FDA-approved.

But I worry that if that's going to be my best partner drug right now, I want to leverage that because I don't have single-agent activity with elotuzumab with other drugs or by itself. So if I use lenalidomide and dexamethasone with something else, then I'm losing the opportunity, potentially, to get the best benefit from elotuzumab. And number two, I think there's really an immune stimulatory component to elotuzumab where it requires NK cells in part and stimulates those. So I think it's very different. I think the earlier in the disease course that you use it to attack the immune system, you may be able to get more benefit from that biologically. So for me, that makes sense to combine it in that setting.

Ajai Chari, MD: I think it's also important to clarify a little bit. You kind of alluded to these three studies and the patient populations, but I don't think they're exactly the same.

Keith Stewart, MB, CHB: I didn't say that, I said they were similar. And just to be clear, they all had one to three prior therapies as the main eligibility.....

Ajai Chari, MD: Correct. I think the devil's in the details. Which is, for example, the ASPIRE and the TOURMALINE study did not allow bortezomib or PI-refractory patients, whereas the ELOQUENT study did. And I think that's one example. So I could imagine as a community oncologist you have these three phase III studies and one to three lines of therapy—and then if you add to that the ENDEAVOR study and also the PANORAMA study.

Keith Stewart, MB, CHB: Which we're going to talk about it in a second.

Ajai Chari, MD: But the point is we have now five phase III studies in one to three lines of prior therapy. As a community oncologist, what do you do with that information?

Keith Stewart, MB, CHB: Well, that's why I just asked you.

Ajai Chari, MD: And one of the things I would say is that we can't say that these subtle differences are going to make significant impacts in outcomes that we see, particularly in PI-- or lenalidomide-refractory patients, whether that's allowed; and not to forget one of the challenges of applying these studies to US populations, given the extent of lenalidomide exposure.

Keith Stewart, MB, CHB: That was going to be my next question. But to get to the one I asked you, which of the three and why?

Ajai Chari, MD: But I think the point is that we should also look at the hazard ratios. Because 50, we're looking at PFS, and it looks like one study has dramatically improved PFS. And as Jatin had mentioned, not that the hazard ratios make it better; you know you shouldn't compare across these studies, but at least it mitigates. It's telling you what the novel agent is adding relative to the control arm to standardize it. And the point is that those hazard ratios are really stacking up in this 0.5-to-0.7 range. And at the end of the day, it's going to come back to being an oncologist and a doctor: what does this patient need? Can they tolerate a PI? Do they have high-risk disease? Are they able to come for parenteral administration?

Keith Stewart, MB, CHB: I guess that's why I would. To me, it’s very patient-dependent.

Sagar Lonial, MD: Yeah, right.

Keith Stewart, MB, CHB: For a high-risk patient with rapidly progressive disease who is interested in aggressive therapy, probably carfilzomib is probably still your choice.

Sagar Lonial, MD: Right.

Keith Stewart, MB, CHB: For somebody who perhaps wants to keep working or maybe lives further away from the clinic: let's put carfilzomib aside for a second and say it's a little bit of an older patient or somebody who just doesn't want to come in twice a week. How are you going to balance elotuzumab versus ixazomib, or are they not mutually exclusive which is the other option?

Sagar Lonial, MD: I think that's a good point, and, again, to put all of those trials in one basket, I think if you got a rapidly progressing patient or a high-risk patient, then I think the carfilzomib combination makes a lot of sense. If you've got somebody who's got a little bit more of an indolent relapse, then adding an antibody where you've got a little bit of time to see the response probably makes sense. Carfilzomib is clearly the more potent proteasome inhibitor. And I suspect that that applies to ixazomib as well. Keith Stewart, MB, CHB: The ability to give ixazomib over a long time is quite attractive too, right?

Sagar Lonial, MD: Right. I mean, so I think there are a lot of factors that weigh in there. And we don't have biomarkers that tell us this patient needs one drug, this patient needs another. Yet, to be able to parse that out…

Keith Stewart, MB, CHB: So we're still figuring it out. That's the short answer, right?

Paul G. Richardson, MD: I think so, but I'd build on the point Sagar is making. I mean, I think your domain will have biomarkers classically, but we certainly have clinical clues. And I think the great news is that we have choices. And I would see it as the pot is truly half full versus half empty, that's for sure. And I think that ixazomib clearly would be an ideal choice for someone who, you know, coming into the clinic twice a week would be a challenge. Completely agree that [in] a high-risk patient with explosive relapse, a very potent inhibitor like carfilzomib makes great sense with the usual caveats. And I think that the elotuzumab data are very provocative, particularly given its tolerability and this idea that it's a true immune oncologic. But I think one thing, Keith, we need to touch on is pomalidomide.

Keith Stewart, MB, CHB: We're getting there. Got to ask the man, the man here is the pomalidomide guy right next to you. Well, you both are, but for the purpose I want.

Paul G. Richardson, MD: Yeah.

Keith Stewart, MB, CHB: Thank you Paul. Just to summarize this discussion: we're very lucky. We've got four randomized trials, we've got new drugs, we're still trying to figure out who gets what, but it's probably going to be quite individualized, I think, at the end of day.

Paul G. Richardson, MD: Yes, absolutely.

Keith Stewart, MB, CHB: And maybe there will be other factors, economic factors, that play in eventually.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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