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Significance of the ENDEAVOR Trial in Multiple Myeloma

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: Friday, Feb 26, 2016


Transcript:

Keith Stewart, MB, CHB: Big question. Triplets or doublets at relapse?

Ajai Chari, MD: Triplets.

Keith Stewart, MB, CHB: Anybody for, against that?

Paul G. Richardson, MD: Nope.

Keith Stewart, MB, CHB: Always triplets. How about the ENDEAVOR clinic, the ENDEAVOR Clinical Trial.

Jatin J. Shah, MD: So, I don't know if triplets apply uniformly in first or second relapse. I think that the data looks great with the ASPIRE.

Keith Stewart, MB, CHB: So ASPIRE, for those who don't know, is triplet carfilzomib with lenalidomide-dexamethasone.

Paul G. Richardson, MD: Yes.

Keith Stewart, MB, CHB: Let me just spend a minute, Jatin. I don't know if you have the figures at your fingertips here, but can you explain to the audience the ENDEAVOR Clinical Trial? I think it's an important trial that we discuss.

Jatin J. Shah, MD: Yes. I think the ENDEAVOR trial is actually a very important trial. And in that trial they randomized patients to either carfilzomib and dexamethasone versus bortezomib and dexamethasone in one to three lines of therapy.

Keith Stewart, MB, CHB: I know the carfilzomib dose was not what's on the label currently for FDA approval.

Jatin J. Shah, MD: That's correct. So the carfilzomib there was given 56 mg metered squared on days one, two.

Keith Stewart, MB, CHB: Which is twice the label dose, right?

Jatin J. Shah, MD: It's twice the label dose, but I don't think that's quote/unquote high dose. That may in fact be full dose therapy, and the label dose is actually sub-optimal or a sub-therapeutic dosing. So I think it's important when you frame that and discuss it, it's not necessarily a high dose, it's maybe potentially full-dose therapy, and everything we've been doing so far has been sub-therapeutic.

Keith Stewart, MB, CHB: Right.

Jatin J. Shah, MD: And this is actually an important trial because this is one of the first trials in myeloma that's actually compared head-to-head two drugs versus two drugs, which I think is really practice informing. I mean I think we expect to see improvements with three versus two drugs. But from a practicing perspective, when you have a head-to-head comparison, I think this is rather powerful. And what they showed there was a significant improvement in progression-free survival from approximately 9 months to 18 months, almost a near doubling in the progression-free survival, which I think is really unheard of when you compare it.

Keith Stewart, MB, CHB: Any overall survival change?

Jatin J. Shah, MD: So I don't know if we've seen overall survival changes at this point in time, but I think that's pretty important because now it starts letting us get away from three drugs. Because when you talk about progression-free survivals in the 18-, 19-, 20-month range, all that's been previously done with three drugs. So now, potentially, I can get that year and a half, to two-year progression-free survival with just two drugs.

Keith Stewart, MB, CHB: So we also voted, I would put my hand up too, for triplet therapy.

Jatin J. Shah, MD: But this changes.

Keith Stewart, MB, CHB: Why, who would get a doublet therapy? And we could throw in maybe pomalidomide and dexamethasone, as well. Like, who would get a doublet instead of a triplet therapy, so if anyone?

Jatin J. Shah, MD: It's a great question. So I think it's a little bit different because I think the three-drug regimens with ASPIRE and TOURMALINE are very helpful. But I'm not sure if they apply to patients right now that are getting continuous Revlimid in front-line therapy, or after transplant and getting Revlimid maintenance, that those three-drug regimens and that data applies to that setting. So I think that's where the ENDEAVOR data with carfilzomib/dexamethasone becomes very powerful because it does apply to patients who are progressing on lenalidomide from first-line therapy. So I think that's where you can get some nice responses.

Keith Stewart, MB, CHB: The trials of carfilzomib-dexamethasone almost double progression-free survival. We don't know if overall survival increases response rate. But it is twice a week versus once a week. So does it change your practice at all here in the United States?

Ajai Chari, MD: There is some.

Keith Stewart, MB, CHB: Your group actually defined that 56 was a terrible blow, so.

Ajai Chari, MD: Yeah, and we even found that for patients who progressed on 27, you can recapture their response by escalating 56. And the advantage of doing that is you minimize cost as well as the toxicity. So for those few patients who may have idiosyncratic side effects from a cardiopulmonary point of view at 20/27, you've saved the 56 for the future. But I think to Jatin's point, it is one of the first times that we're seeing this kind of efficacy with a two-drug regimen. But, I think one other thing I think we have to think about now with the approval of Empliciti, or elotuzumab, is sequencing. Because elotuzumab doesn't have a single agent activity and it's going to combine with lenalidomide/dexamethasone.

Keith Stewart, MB, CHB: So because we jumped on to elotuzumab, we're talking a monoclonal antibody here that's targeting myeloma cells, right?

Ajai Chari, MD: Right, correct. And because this is an early relapse setting, which is where this was studied, the eloquent Dr. Lonial should speak about it.

Keith Stewart, MB, CHB: We will in a minute. I just want to finish up with this ENDEAVOR trial.

Ajai Chari, MD: I think the point is lenalidomide/dexamethasone with the addition of elotuzumab improved PFS. Particularly also in high-risk patients there was a benefit. And I think if you don't use the elotuzumab when a patient has not progressed on full-dose lenalidomide, we don't know what its role might be. And there were some significant PFS benefits that are not to be minimized. So in other words, what I'm saying is, if you do RDLO, you could always go back to all of the other drugs that you've heard about, including high-dose carfilzomib.

Keith Stewart, MB, CHB: So my question was really about whether ENDEAVOR is significant within the US.

Sagar Lonial, MD: I think, from my perspective, what ENDEAVOR tells me is that if somebody is proteasome-inhibitor resistant, going to the higher dose of carfilzomib can salvage those patients. It doesn't mean that I'm going to use the higher dose earlier in the course, it just means that I know I've got a PI I can go to, that for the most part, is well tolerated at the higher dose.

Jatin J. Shah, MD: That's interesting because we talk about using our most effective therapy. So if you have an effective therapy, you try and move that earlier. Here you're partnering it. Sagar Lonial, MD: If you can't partner it. That's my issue.

Keith Stewart, MB, CHB: What are you on?

Sagar Lonial, MD: 56. If you can't partner it.

Jatin J. Shah, MD: But do you need to partner it though if you're already giving such ...

Keith Stewart, MB, CHB: I don't know that anybody's tested the hypothesis yet.

Sagar Lonial, MD: Well, most of the combination trials have an MTD of 36. So you know you can't go higher. I mean if you believe that there are multiple subclones in the disease at any given time, we're going to combination therapy, why do you want to give a dose so high you can't combine it?

Paul G. Richardson, MD: Jatin, if I may, I so agree with Sagar. I totally take your point, and I think what's so impressive about this is it tells you, in practice, that you've got more potent proteasome inhibitors, that in the properly selected patient who has been prior proteasome inhibitor exposed, you can salvage them. But I completely agree, Sagar. I think three drug regimens and four, I mean your data support that, your own work with RVD.

Jatin J. Shah, MD: For newly-diagnosed, yeah.

Paul G. Richardson, MD: I understood. But even in relapse. I mean arguably, relapse is more important.

Keith Stewart, MB, CHB: I would say there are some patients who can't take IMiDs. I mean not everybody can tolerate them.

Paul G. Richardson, MD: That's true.

Keith Stewart, MB, CHB: They'll get rash, people have renal failure. So there is probably a market for doublet therapy in certain indications. Maybe in older patients too.

Paul G. Richardson, MD: That's fair.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Keith Stewart, MB, CHB: Big question. Triplets or doublets at relapse?

Ajai Chari, MD: Triplets.

Keith Stewart, MB, CHB: Anybody for, against that?

Paul G. Richardson, MD: Nope.

Keith Stewart, MB, CHB: Always triplets. How about the ENDEAVOR clinic, the ENDEAVOR Clinical Trial.

Jatin J. Shah, MD: So, I don't know if triplets apply uniformly in first or second relapse. I think that the data looks great with the ASPIRE.

Keith Stewart, MB, CHB: So ASPIRE, for those who don't know, is triplet carfilzomib with lenalidomide-dexamethasone.

Paul G. Richardson, MD: Yes.

Keith Stewart, MB, CHB: Let me just spend a minute, Jatin. I don't know if you have the figures at your fingertips here, but can you explain to the audience the ENDEAVOR Clinical Trial? I think it's an important trial that we discuss.

Jatin J. Shah, MD: Yes. I think the ENDEAVOR trial is actually a very important trial. And in that trial they randomized patients to either carfilzomib and dexamethasone versus bortezomib and dexamethasone in one to three lines of therapy.

Keith Stewart, MB, CHB: I know the carfilzomib dose was not what's on the label currently for FDA approval.

Jatin J. Shah, MD: That's correct. So the carfilzomib there was given 56 mg metered squared on days one, two.

Keith Stewart, MB, CHB: Which is twice the label dose, right?

Jatin J. Shah, MD: It's twice the label dose, but I don't think that's quote/unquote high dose. That may in fact be full dose therapy, and the label dose is actually sub-optimal or a sub-therapeutic dosing. So I think it's important when you frame that and discuss it, it's not necessarily a high dose, it's maybe potentially full-dose therapy, and everything we've been doing so far has been sub-therapeutic.

Keith Stewart, MB, CHB: Right.

Jatin J. Shah, MD: And this is actually an important trial because this is one of the first trials in myeloma that's actually compared head-to-head two drugs versus two drugs, which I think is really practice informing. I mean I think we expect to see improvements with three versus two drugs. But from a practicing perspective, when you have a head-to-head comparison, I think this is rather powerful. And what they showed there was a significant improvement in progression-free survival from approximately 9 months to 18 months, almost a near doubling in the progression-free survival, which I think is really unheard of when you compare it.

Keith Stewart, MB, CHB: Any overall survival change?

Jatin J. Shah, MD: So I don't know if we've seen overall survival changes at this point in time, but I think that's pretty important because now it starts letting us get away from three drugs. Because when you talk about progression-free survivals in the 18-, 19-, 20-month range, all that's been previously done with three drugs. So now, potentially, I can get that year and a half, to two-year progression-free survival with just two drugs.

Keith Stewart, MB, CHB: So we also voted, I would put my hand up too, for triplet therapy.

Jatin J. Shah, MD: But this changes.

Keith Stewart, MB, CHB: Why, who would get a doublet therapy? And we could throw in maybe pomalidomide and dexamethasone, as well. Like, who would get a doublet instead of a triplet therapy, so if anyone?

Jatin J. Shah, MD: It's a great question. So I think it's a little bit different because I think the three-drug regimens with ASPIRE and TOURMALINE are very helpful. But I'm not sure if they apply to patients right now that are getting continuous Revlimid in front-line therapy, or after transplant and getting Revlimid maintenance, that those three-drug regimens and that data applies to that setting. So I think that's where the ENDEAVOR data with carfilzomib/dexamethasone becomes very powerful because it does apply to patients who are progressing on lenalidomide from first-line therapy. So I think that's where you can get some nice responses.

Keith Stewart, MB, CHB: The trials of carfilzomib-dexamethasone almost double progression-free survival. We don't know if overall survival increases response rate. But it is twice a week versus once a week. So does it change your practice at all here in the United States?

Ajai Chari, MD: There is some.

Keith Stewart, MB, CHB: Your group actually defined that 56 was a terrible blow, so.

Ajai Chari, MD: Yeah, and we even found that for patients who progressed on 27, you can recapture their response by escalating 56. And the advantage of doing that is you minimize cost as well as the toxicity. So for those few patients who may have idiosyncratic side effects from a cardiopulmonary point of view at 20/27, you've saved the 56 for the future. But I think to Jatin's point, it is one of the first times that we're seeing this kind of efficacy with a two-drug regimen. But, I think one other thing I think we have to think about now with the approval of Empliciti, or elotuzumab, is sequencing. Because elotuzumab doesn't have a single agent activity and it's going to combine with lenalidomide/dexamethasone.

Keith Stewart, MB, CHB: So because we jumped on to elotuzumab, we're talking a monoclonal antibody here that's targeting myeloma cells, right?

Ajai Chari, MD: Right, correct. And because this is an early relapse setting, which is where this was studied, the eloquent Dr. Lonial should speak about it.

Keith Stewart, MB, CHB: We will in a minute. I just want to finish up with this ENDEAVOR trial.

Ajai Chari, MD: I think the point is lenalidomide/dexamethasone with the addition of elotuzumab improved PFS. Particularly also in high-risk patients there was a benefit. And I think if you don't use the elotuzumab when a patient has not progressed on full-dose lenalidomide, we don't know what its role might be. And there were some significant PFS benefits that are not to be minimized. So in other words, what I'm saying is, if you do RDLO, you could always go back to all of the other drugs that you've heard about, including high-dose carfilzomib.

Keith Stewart, MB, CHB: So my question was really about whether ENDEAVOR is significant within the US.

Sagar Lonial, MD: I think, from my perspective, what ENDEAVOR tells me is that if somebody is proteasome-inhibitor resistant, going to the higher dose of carfilzomib can salvage those patients. It doesn't mean that I'm going to use the higher dose earlier in the course, it just means that I know I've got a PI I can go to, that for the most part, is well tolerated at the higher dose.

Jatin J. Shah, MD: That's interesting because we talk about using our most effective therapy. So if you have an effective therapy, you try and move that earlier. Here you're partnering it. Sagar Lonial, MD: If you can't partner it. That's my issue.

Keith Stewart, MB, CHB: What are you on?

Sagar Lonial, MD: 56. If you can't partner it.

Jatin J. Shah, MD: But do you need to partner it though if you're already giving such ...

Keith Stewart, MB, CHB: I don't know that anybody's tested the hypothesis yet.

Sagar Lonial, MD: Well, most of the combination trials have an MTD of 36. So you know you can't go higher. I mean if you believe that there are multiple subclones in the disease at any given time, we're going to combination therapy, why do you want to give a dose so high you can't combine it?

Paul G. Richardson, MD: Jatin, if I may, I so agree with Sagar. I totally take your point, and I think what's so impressive about this is it tells you, in practice, that you've got more potent proteasome inhibitors, that in the properly selected patient who has been prior proteasome inhibitor exposed, you can salvage them. But I completely agree, Sagar. I think three drug regimens and four, I mean your data support that, your own work with RVD.

Jatin J. Shah, MD: For newly-diagnosed, yeah.

Paul G. Richardson, MD: I understood. But even in relapse. I mean arguably, relapse is more important.

Keith Stewart, MB, CHB: I would say there are some patients who can't take IMiDs. I mean not everybody can tolerate them.

Paul G. Richardson, MD: That's true.

Keith Stewart, MB, CHB: They'll get rash, people have renal failure. So there is probably a market for doublet therapy in certain indications. Maybe in older patients too.

Paul G. Richardson, MD: That's fair.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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