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Novel Agents with Len-Dex in Multiple Myeloma

Insights From:Jatin P. Shah, MD, MD Anderson Cancer Center;Ivan Marques Borrello, MD, Johns Hopkins University;James R. Berenson, MD, Institute for Myeloma and Bone Cancer Research
Published: Monday, Aug 22, 2016


Transcript:

Ivan Marques Borrello, MD:
There have been several phase III trials adding novel agents to Revlimid and dexamethasone (RD) that have been published over the last few years. Specifically, there’s been the ASPIRE trial, which compared RD to carfilzomib (KRD; Kyprolis) Revlimid/dexamethasone. There was the TOURMALINE trial, which has compared ixazomib/Revlimid/dexamethasone to RD. And, more recently, there’s the ELOQUENT trial of elotuzumab/Revlimid/dexamethasone versus RD. I think when you look at the Kaplan-Meier curves of these trials, what you see is really what is a fundamental difference between how chemotherapy works versus how immunotherapy works. What you see in general with chemotherapeutic agents is a very early separation of the curves. And, in both of these cases, the ASPIRE and the TOURMALINE trials, we see that the triple regimen appears to show a very early improvement in progression-free survival compared to the doublet. But, eventually with time, these two curves approach each other and basically that difference becomes null. This is in sharp contrast to many immunotherapeutic approaches where what you can see is a tail. And, again, oftentimes a curve starts off tight together, and then, eventually over time, begins to separate.

We see with the elotuzumab/RD data in the ELOQUENT trial that this curve, and therefore, this hazard ratio, does in fact separate. That separation continues although there is now beginning to be some evidence of a reduction in that overall separation, but still that advantage out to 3 years is there. Whereas with ASPIRE and the TOURMALINE trials, the longevity of that separation has not been as pronounced as it has been with the ELOQUENT trial. And, again, I think this speaks to a major difference between what chemotherapy can do compared to immunotherapy.

One of the ways of interpreting these curves, I think, in large part is going to be due to what the primary goal of therapy is. Looking at median progression-free survival is one way of looking at it. The question is, at what point do 50% of the patients have disease that is still in remission compared to disease that has progressed? And depending upon the therapy that’s given, that number can be shorter or longer. In general, we tend to think that a median progression-free survival that is longer is better than a median progression-free survival that isn’t. But, what that doesn’t take into consideration is potentially this curve.

So, if you look at chemotherapy where you may get a bubble where the curve comes back together, you will have a very significant improvement in median progression-free survival, but eventually that disappears. That’s a situation where the hazard ratio may be significantly important. Where the progression-free survival may not be as pronounced, but the fact that there’s this tail that is allowing you to see persistence of progression, a progression-free survival benefit is more important. And I think this really boils down to what the initial role of therapy is. Overall, clearly the goal of all of the therapies that we’re developing in oncology is to improve overall survival. Obviously, and fortunately, in a disease like myeloma where we’re now approaching a decade in terms of the average time that patients can be alive with the disease, that’s an untenable endpoint. Progression-free survival is a much more tenable one, certainly in the relapsed setting. But, what we may not be able to see is the persistence of this. And I think looking at these plateaus at fixed time intervals may be giving us just as important information as looking at progression-free survival alone.

In general, a disease for which we’re looking at long-term control, obviously seeing a tail on the curve is very important. In a disease setting in which short-term control is really what is of interest and an effective therapy may not have as much of a tail may be a more desirable thing. It’s not to say that we can’t eventually, and most likely will be, combining both of these therapeutic approaches to achieve better short-term remission and better long-term remission.

Transcript Edited for Clarity
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Transcript:

Ivan Marques Borrello, MD:
There have been several phase III trials adding novel agents to Revlimid and dexamethasone (RD) that have been published over the last few years. Specifically, there’s been the ASPIRE trial, which compared RD to carfilzomib (KRD; Kyprolis) Revlimid/dexamethasone. There was the TOURMALINE trial, which has compared ixazomib/Revlimid/dexamethasone to RD. And, more recently, there’s the ELOQUENT trial of elotuzumab/Revlimid/dexamethasone versus RD. I think when you look at the Kaplan-Meier curves of these trials, what you see is really what is a fundamental difference between how chemotherapy works versus how immunotherapy works. What you see in general with chemotherapeutic agents is a very early separation of the curves. And, in both of these cases, the ASPIRE and the TOURMALINE trials, we see that the triple regimen appears to show a very early improvement in progression-free survival compared to the doublet. But, eventually with time, these two curves approach each other and basically that difference becomes null. This is in sharp contrast to many immunotherapeutic approaches where what you can see is a tail. And, again, oftentimes a curve starts off tight together, and then, eventually over time, begins to separate.

We see with the elotuzumab/RD data in the ELOQUENT trial that this curve, and therefore, this hazard ratio, does in fact separate. That separation continues although there is now beginning to be some evidence of a reduction in that overall separation, but still that advantage out to 3 years is there. Whereas with ASPIRE and the TOURMALINE trials, the longevity of that separation has not been as pronounced as it has been with the ELOQUENT trial. And, again, I think this speaks to a major difference between what chemotherapy can do compared to immunotherapy.

One of the ways of interpreting these curves, I think, in large part is going to be due to what the primary goal of therapy is. Looking at median progression-free survival is one way of looking at it. The question is, at what point do 50% of the patients have disease that is still in remission compared to disease that has progressed? And depending upon the therapy that’s given, that number can be shorter or longer. In general, we tend to think that a median progression-free survival that is longer is better than a median progression-free survival that isn’t. But, what that doesn’t take into consideration is potentially this curve.

So, if you look at chemotherapy where you may get a bubble where the curve comes back together, you will have a very significant improvement in median progression-free survival, but eventually that disappears. That’s a situation where the hazard ratio may be significantly important. Where the progression-free survival may not be as pronounced, but the fact that there’s this tail that is allowing you to see persistence of progression, a progression-free survival benefit is more important. And I think this really boils down to what the initial role of therapy is. Overall, clearly the goal of all of the therapies that we’re developing in oncology is to improve overall survival. Obviously, and fortunately, in a disease like myeloma where we’re now approaching a decade in terms of the average time that patients can be alive with the disease, that’s an untenable endpoint. Progression-free survival is a much more tenable one, certainly in the relapsed setting. But, what we may not be able to see is the persistence of this. And I think looking at these plateaus at fixed time intervals may be giving us just as important information as looking at progression-free survival alone.

In general, a disease for which we’re looking at long-term control, obviously seeing a tail on the curve is very important. In a disease setting in which short-term control is really what is of interest and an effective therapy may not have as much of a tail may be a more desirable thing. It’s not to say that we can’t eventually, and most likely will be, combining both of these therapeutic approaches to achieve better short-term remission and better long-term remission.

Transcript Edited for Clarity
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