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Relapsed/Refractory Myeloma: Daratumumab-Containing Triplets

Panelists: Keith Stewart, MB, CHB, Mayo Clinic; Sagar Lonial, MD, Winship Cancer Institute; Paul Richardson, MD, Dana-Farber Cancer Institute; Amrita Krishnan, MD, City of Hope Comprehensive Cancer Center; Saad Usmani, MD, Levine Cancer Institute
Published Online: Monday, Feb 13, 2017



Transcript:

Keith Stewart, MB, CHB:
Let’s move on to relapsed/refractory myeloma which is an area in which FDA approval and somewhat paradigm-changing studies of, particularly now, the monoclonal antibodies daratumumab and elotuzumab, seem to be changing our practice. I want to start, then, with really the hottest topic right now, which is daratumumab (the monoclonal antibody against CD38), and what we’ve learned at the ASH 2016 meeting about the use of that drug in combination with existing agents. I’m going to ask you, Paul, to start us off because you were one of the lead investigators on these trials. First of all, let’s talk about the POLLUX clinical trial. Tell us what it is, and what we found?

Paul Richardson, MD: Absolutely. The POLLUX study was a comparison in relapsed and relapsed/refractory disease of 1 to 3 prior lines of the current standard lenalidomide/dexamethasone, versus daratumumab/lenalidomide/dexamethasone in a large international trial. I think the takeaway is very straightforward. There were dramatic results, unprecedented, actually, in terms of hazard ratio, which demonstrated benefit to the 3-drug platform. And I think the progression-free survival estimate hasn’t been reached for the 3-drug arm, but probably is north of 4 years.

Keith Stewart, MB, CHB: How did you get to 4 years? We haven’t even had that much follow-up.

Paul Richardson, MD: If you estimate it and go out, it’s north of about 40 months.

Keith Stewart, MB, CHB: But, right now it’s…

Paul Richardson, MD: Yes, I understand your point. We have to be careful. But, I’m just saying that it’s not reached, and I think that the control arm, of course, lenalidomide/dexamethasone is classical—it’s around 18 months. So, I think at the same time, we’re seeing, essentially, a potential doubling of progression-free survival. And what’s so striking is it’s in the relapsed setting.

Keith Stewart, MB, CHB: Saad, what about response rates and depth of response with this combination of daratumumab/lenalidomide/dexamethasone versus lenalidomide/dexamethasone? What did we learn?

Saad Usmani, MD: Again, I would echo what Paul has already said. We are seeing fairly unprecedented median progression-free survivals and depth of responses. The complete remissions, or better rates of 40-odd percent or above, are very impressive for this kind of setting. And then, in talking about MRD (minimal residual disease)-negativity in this kind of setting, we’re not talking about newly diagnosed, but rather, the relapsed setting. We’re seeing MRD-negativity with this regimen which is also interesting.

Keith Stewart, MB, CHB: It’s 10% to 20%.

Saad Usmani, MD: Yes. It doesn’t matter how you break it down—by lines of therapy, prior exposure, or cytogenetics—there appears to be a benefit across the board.

Keith Stewart, MB, CHB: I was going to ask that question to Sagar because I’ve heard you say that one of the values of these drugs is, perhaps, that they don’t care too much about the genetics of the tumor. What are your thoughts on that?

Sagar Lonial, MD: I think the data are very early in terms of an impact on outcomes. If you’ve had one line, you can do better than if you’ve had more than one line. But, I think, in general, what we’re seeing is the antibodies and daratumumab, in this case specifically, is almost like rituximab. It seems to make everything it works with better.

Keith Stewart, MB, CHB: Very good. We’ve also seen, at the 2016 ASH Annual Meeting, a study called the CASTOR study. Amrita, do you want to tell the audience what that’s about?

Amrita Krishnan, MD: In a similar vein, a randomized phase III trial, the backbone in this case is bortezomib and dexamethasone versus daratumumab/bortezomib/dexamethasone. And we see a similar story—a much higher response rate in the daratumumab arm, MRD-negativity again in the daratumumab arm, and long progression-free survival. And I believe that in that trial, too, we’ve not reached a median progression-free survival for the daratumumab arm. So, I think it suggests that either one of those combinations, daratumumab/bortezomib/dexamethasone or daratumumab/lenalidomide/dexamethasone, are good combinations in the early relapsed setting.

Keith Stewart, MB, CHB: Saad, when I looked at those 2 trials, there was a clear winner in my head. And one of the things I took away from it was the backbone therapy, particularly bortezomib/dexamethasone, just wasn’t that good in our current modern practice. Should anybody get bortezomib/dexamethasone alone? We’ll discuss some other studies in a minute, but should anybody give that alone at relapse, or is that finished?

Saad Usmani, MD: I think you can make the case that the triplet regimens are superior to the doublet regimens. We’ve seen several cases of that in the early lines of settings over the past 2 years. I think you’re probably right.

Paul Richardson, MD: But, in fairness, I think this is something that, in the CASTOR trial, we have to be very clear about. There was a fixed duration of bortezomib exposure, and that resulted in relatively short progression-free survival compared to lenalidomide/dexamethasone—which was continuous. I think we’re just a little bit careful there.

Keith Stewart, MB, CHB: The follow-up of both studies is very short. Do you think it will change over time, or do you think we have our answer already?

Paul Richardson, MD: I think the clinical benefit is so striking that I can’t imagine a situation where it would diminish. We will see whether it will magnify and if there will be a big survival difference emerge. I just think that with a hazard ratio of 0.34, 0.35, those are values that we’ve never seen before in myeloma. Those speak, I think, in volumes.

Amrita Krishnan, MD: I think the other point to make is toxicity-wise, because it’s great to add stuff. I think that was the other striking thing about the combination therapies.

Paul Richardson, MD: Exactly, I agree.

Amrita Krishnan, MD: We did not see a significant increase in toxicities.

Keith Stewart, MB, CHB: So, daratumumab, added to these drugs, looks to be very advantageous. The FDA has just approved for use of these drugs in first relapse. Lenalidomide, we’ve talked about, is widely used in maintenance strategies in North America until time of progression. And this study that we’re all talking about uses lenalidomide, so other alternatives probably have to be considered. What do you do in a patient who’s lenalidomide-refractory if you want to give them daratumumab at relapse?

Sagar Lonial, MD: You’re right. I think the applicability of the POLLUX trial in a group of patients that are lenalidomide-resistant, at least single-agent lenalidomide-resistant, is a little bit hard to extrapolate sometimes. In our situation, when we want to use daratumumab in the first relapse setting, we will likely partner it with pomalidomide based on data presented last year.

Keith Stewart, MB, CHB: Is that pretty much the switch that we’re all making?

Sagar Lonial, MD: Our experience, and we presented some re-treatment data at the 2016 ASH Annual Meeting as well, suggests that it’s highly potent. We have treated 17p-deleted patients, which seem to do well with pomalidomide. This is based on a French trial with pomalidomide/daratumumab, and we have been very happy with the results.

Keith Stewart, MB, CHB: Most people, if they have been on lenalidomide and have progressed on it, would go back to lenalidomide if stopped earlier, like I’ve been doing?

Sagar Lonial, MD: Yes, absolutely. And I think whether or not I abandon lenalidomide depends on the type of relapse, the genetics of that patient, and how far away they live from where they are being treated. I think there are reasons to potentially escalate the lenalidomide, add dexamethasone, add elotuzumab, or add ixazomib, depending upon other options. But, if a patient needs a quick response, our first go-to in that situation is pomalidomide/daratumumab.

Amrita Krishnan, MD: But, I think, also in our experience, sometimes when we add back lenalidomide, we’re doing it not for the lenalidomide, but for its immunomodulatory effects and to make the daratumumab work better. I certainly have done that.

Saad Usmani, MD: And that’s where pomalidomide comes in—at least in my experience. Even a modest dose of pomalidomide appears to augment the effects. I think we have to be careful. I was talking to some of the other Mayo Clinic, Arizona, colleagues, and there is a tolerability issue with a high dose of pomalidomide with daratumumab.

Keith Stewart, MB, CHB: One of my colleagues, in particular, has suggested he’s seen quite a lot of neutropenia when you put those 2 drugs together. Maybe using a lower dose of pomalidomide in the first month or 2 until you’ve sorted things out could help?

Paul Richardson, MD: And weaving in a proteasome inhibitor of whatever variety one wants to choose. Again, I’m struck by the CASTOR data in the sense that it certainly validates the integration of a proteasome inhibitors into the backbone with daratumumab, and I think that’s very promising.

Transcript Edited for Clarity

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Transcript:

Keith Stewart, MB, CHB:
Let’s move on to relapsed/refractory myeloma which is an area in which FDA approval and somewhat paradigm-changing studies of, particularly now, the monoclonal antibodies daratumumab and elotuzumab, seem to be changing our practice. I want to start, then, with really the hottest topic right now, which is daratumumab (the monoclonal antibody against CD38), and what we’ve learned at the ASH 2016 meeting about the use of that drug in combination with existing agents. I’m going to ask you, Paul, to start us off because you were one of the lead investigators on these trials. First of all, let’s talk about the POLLUX clinical trial. Tell us what it is, and what we found?

Paul Richardson, MD: Absolutely. The POLLUX study was a comparison in relapsed and relapsed/refractory disease of 1 to 3 prior lines of the current standard lenalidomide/dexamethasone, versus daratumumab/lenalidomide/dexamethasone in a large international trial. I think the takeaway is very straightforward. There were dramatic results, unprecedented, actually, in terms of hazard ratio, which demonstrated benefit to the 3-drug platform. And I think the progression-free survival estimate hasn’t been reached for the 3-drug arm, but probably is north of 4 years.

Keith Stewart, MB, CHB: How did you get to 4 years? We haven’t even had that much follow-up.

Paul Richardson, MD: If you estimate it and go out, it’s north of about 40 months.

Keith Stewart, MB, CHB: But, right now it’s…

Paul Richardson, MD: Yes, I understand your point. We have to be careful. But, I’m just saying that it’s not reached, and I think that the control arm, of course, lenalidomide/dexamethasone is classical—it’s around 18 months. So, I think at the same time, we’re seeing, essentially, a potential doubling of progression-free survival. And what’s so striking is it’s in the relapsed setting.

Keith Stewart, MB, CHB: Saad, what about response rates and depth of response with this combination of daratumumab/lenalidomide/dexamethasone versus lenalidomide/dexamethasone? What did we learn?

Saad Usmani, MD: Again, I would echo what Paul has already said. We are seeing fairly unprecedented median progression-free survivals and depth of responses. The complete remissions, or better rates of 40-odd percent or above, are very impressive for this kind of setting. And then, in talking about MRD (minimal residual disease)-negativity in this kind of setting, we’re not talking about newly diagnosed, but rather, the relapsed setting. We’re seeing MRD-negativity with this regimen which is also interesting.

Keith Stewart, MB, CHB: It’s 10% to 20%.

Saad Usmani, MD: Yes. It doesn’t matter how you break it down—by lines of therapy, prior exposure, or cytogenetics—there appears to be a benefit across the board.

Keith Stewart, MB, CHB: I was going to ask that question to Sagar because I’ve heard you say that one of the values of these drugs is, perhaps, that they don’t care too much about the genetics of the tumor. What are your thoughts on that?

Sagar Lonial, MD: I think the data are very early in terms of an impact on outcomes. If you’ve had one line, you can do better than if you’ve had more than one line. But, I think, in general, what we’re seeing is the antibodies and daratumumab, in this case specifically, is almost like rituximab. It seems to make everything it works with better.

Keith Stewart, MB, CHB: Very good. We’ve also seen, at the 2016 ASH Annual Meeting, a study called the CASTOR study. Amrita, do you want to tell the audience what that’s about?

Amrita Krishnan, MD: In a similar vein, a randomized phase III trial, the backbone in this case is bortezomib and dexamethasone versus daratumumab/bortezomib/dexamethasone. And we see a similar story—a much higher response rate in the daratumumab arm, MRD-negativity again in the daratumumab arm, and long progression-free survival. And I believe that in that trial, too, we’ve not reached a median progression-free survival for the daratumumab arm. So, I think it suggests that either one of those combinations, daratumumab/bortezomib/dexamethasone or daratumumab/lenalidomide/dexamethasone, are good combinations in the early relapsed setting.

Keith Stewart, MB, CHB: Saad, when I looked at those 2 trials, there was a clear winner in my head. And one of the things I took away from it was the backbone therapy, particularly bortezomib/dexamethasone, just wasn’t that good in our current modern practice. Should anybody get bortezomib/dexamethasone alone? We’ll discuss some other studies in a minute, but should anybody give that alone at relapse, or is that finished?

Saad Usmani, MD: I think you can make the case that the triplet regimens are superior to the doublet regimens. We’ve seen several cases of that in the early lines of settings over the past 2 years. I think you’re probably right.

Paul Richardson, MD: But, in fairness, I think this is something that, in the CASTOR trial, we have to be very clear about. There was a fixed duration of bortezomib exposure, and that resulted in relatively short progression-free survival compared to lenalidomide/dexamethasone—which was continuous. I think we’re just a little bit careful there.

Keith Stewart, MB, CHB: The follow-up of both studies is very short. Do you think it will change over time, or do you think we have our answer already?

Paul Richardson, MD: I think the clinical benefit is so striking that I can’t imagine a situation where it would diminish. We will see whether it will magnify and if there will be a big survival difference emerge. I just think that with a hazard ratio of 0.34, 0.35, those are values that we’ve never seen before in myeloma. Those speak, I think, in volumes.

Amrita Krishnan, MD: I think the other point to make is toxicity-wise, because it’s great to add stuff. I think that was the other striking thing about the combination therapies.

Paul Richardson, MD: Exactly, I agree.

Amrita Krishnan, MD: We did not see a significant increase in toxicities.

Keith Stewart, MB, CHB: So, daratumumab, added to these drugs, looks to be very advantageous. The FDA has just approved for use of these drugs in first relapse. Lenalidomide, we’ve talked about, is widely used in maintenance strategies in North America until time of progression. And this study that we’re all talking about uses lenalidomide, so other alternatives probably have to be considered. What do you do in a patient who’s lenalidomide-refractory if you want to give them daratumumab at relapse?

Sagar Lonial, MD: You’re right. I think the applicability of the POLLUX trial in a group of patients that are lenalidomide-resistant, at least single-agent lenalidomide-resistant, is a little bit hard to extrapolate sometimes. In our situation, when we want to use daratumumab in the first relapse setting, we will likely partner it with pomalidomide based on data presented last year.

Keith Stewart, MB, CHB: Is that pretty much the switch that we’re all making?

Sagar Lonial, MD: Our experience, and we presented some re-treatment data at the 2016 ASH Annual Meeting as well, suggests that it’s highly potent. We have treated 17p-deleted patients, which seem to do well with pomalidomide. This is based on a French trial with pomalidomide/daratumumab, and we have been very happy with the results.

Keith Stewart, MB, CHB: Most people, if they have been on lenalidomide and have progressed on it, would go back to lenalidomide if stopped earlier, like I’ve been doing?

Sagar Lonial, MD: Yes, absolutely. And I think whether or not I abandon lenalidomide depends on the type of relapse, the genetics of that patient, and how far away they live from where they are being treated. I think there are reasons to potentially escalate the lenalidomide, add dexamethasone, add elotuzumab, or add ixazomib, depending upon other options. But, if a patient needs a quick response, our first go-to in that situation is pomalidomide/daratumumab.

Amrita Krishnan, MD: But, I think, also in our experience, sometimes when we add back lenalidomide, we’re doing it not for the lenalidomide, but for its immunomodulatory effects and to make the daratumumab work better. I certainly have done that.

Saad Usmani, MD: And that’s where pomalidomide comes in—at least in my experience. Even a modest dose of pomalidomide appears to augment the effects. I think we have to be careful. I was talking to some of the other Mayo Clinic, Arizona, colleagues, and there is a tolerability issue with a high dose of pomalidomide with daratumumab.

Keith Stewart, MB, CHB: One of my colleagues, in particular, has suggested he’s seen quite a lot of neutropenia when you put those 2 drugs together. Maybe using a lower dose of pomalidomide in the first month or 2 until you’ve sorted things out could help?

Paul Richardson, MD: And weaving in a proteasome inhibitor of whatever variety one wants to choose. Again, I’m struck by the CASTOR data in the sense that it certainly validates the integration of a proteasome inhibitors into the backbone with daratumumab, and I think that’s very promising.

Transcript Edited for Clarity
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