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Extrapolating from Clinical Trials: Daratumumab in MM

Panelists: A. Keith Stewart, MB, ChB, Mayo Clinic; Sagar Lonial, MD, FACP, Emory University School of Medicine; Thomas Martin, MD, UCSF Helen Diller Family; Edward A. Stadtmauer, MD, University of Pennsylvania; Ajai Chari, MD, Mount Sinai Hospital; Amrita Krishnan, MD, FACP, City of Hope Cancer Center
Published: Friday, Jul 27, 2018



Transcript: 

A. Keith Stewart, MB, ChB: We just saw the FDA approve the drug daratumumab for elderly patients. We talked about lenalidomide/dexamethasone or RVd-lite is pretty much how we treat those patients today. Familiarity with a study for the audience, Tom, do you want to just quickly describe the results of the ALCYONE trial?

Thomas Martin, MD: Yes. The ALCYONE trial involved 700 patients and they were randomly assigned to 2 regimens. It was really a European-based regimen. Their standard induction of bortezomib/melphalan/prednisone—so VMP. And so, it’s VMP plus or minus daratumumab. They got 9 cycles of VMP with daratumumab. It was weekly for 6 weeks and then it was every 3 weeks for 9 cycles. And then after that, the arm that got daratumumab/VMP continued on daratumumab maintenance. The arm that got VMP just stopped therapy after 9 months. And this is the first study really that showed a quadruplet is better than a triplet. It was a nice study.

The problem in the United States is we don’t really use VMP so I don’t know how translatable it is to us. But that said, it was an advantage of daratumumab/VMP versus VMP. But the overall response rate was over 90% versus low 70%. And PFS adds 18 months; it was 74% versus 50%. Very different in terms of the 4-drug arm.

Now what I really liked about this study is if you look at the PFS curve, there was initial separation of the curve in the first 9 cycles, but then when they got to after 9 cycles to maintenance, the curve actually even separated out more. And daratumumab used as a single agent maintenance therapy looked extremely well tolerated. That’s what I really like, especially in the older population. Some of the other drugs that we use for maintenance—bortezomib, lenalidomide, etc.—there are toxicities, especially cumulative toxicities, in the older patients. I don’t think you have the same cumulative toxicities.

A. Keith Stewart, MB, ChB: Let’s come back to maintenance later. In the FDA approval, I understand that turning MRD-negativity was 1 of the things highlighted. Does that influence your choice of therapy, Sagar?

Sagar Lonial, MD, FACP: I think MRD negativity, certainly in the context of induction therapy, is a feather in the cap of the regimen. But for now, I still think of it as a prognostic tool. It tells you who’s going to do well. It doesn’t necessarily tell you that what you’ve done has influenced who’s going to do well. So, I think it’s certainly nice to see. We’ve not seen that in the older patient population like we did in the ALCYONE trial. But that alone is not sufficient for me to make a decision.

A. Keith Stewart, MB, ChB: Amrita, what are the practical implications of this for you? We don’t use melphalan here in the United States, but how do you think this is going to impact your clinical practice in the transplant-ineligible patients?

Amrita Krishnan, MD, FACP: That’s a good question because I don’t think any of us have written a VMP prescription. I think for me, it allows me to feel comfortable using a quadruplet regimen even in an elderly frail population. Maybe will that be RVd-lite plus daratumumab? Probably, I think. I think the other thing that was nice is that, yes, in an elderly frail population, if you look at MRD into the prognostic factors, you can get MRD negativity with a quadruplet regimen. So, hopefully, you can have outcomes similar to your transplant-eligible population downstream.

A. Keith Stewart, MB, ChB: Ajai, are we going to use daratumumab in the United States now with other combinations do you think, or is it not ready for that yet?

Ajai Chari, MD: I think the easiest extrapolation now is even if we’re not so fond of using melphalan in newly diagnosed patients, you could do daratumumab/VMP and just not give the “M”. And that daratumumab/VD essentially is what that would be. And the people who are using that in the relapsed setting, you could easily do that in the frontline setting.

In terms of going off-label, we know United States oncologists do that. We didn’t have the SWOG S0777 study comparing VRD to RD for many years, and yet people were using VRD based on a phase II regimen. So, I think in the United States, physicians are going to be comfortable extrapolating from the daratumumab/VMP to get frontline daratumumab, but then substituting in the drugs that they really like to use as a backbone.

And I think the other point is that, to Tom’s point, we shouldn’t lump all quadruplets in the same category. So, RVd plus cyclophosphamide added neutropenia without benefit, but VMP with melphalan/daratumumab does significant add to toxicities, other than a slightly higher rate of infection. But I think that’s probably the patient population.

A. Keith Stewart, MB, ChB: I think, for sure, we have to understand toxicity before we leap wholeheartedly into 4-drug cocktails.

Edward A. Stadtmauer, MD: It does feel right for oncologists in that we assume that there will be a R-CHOP for multiple myeloma, and it’s starting to look like a monoclonal antibody plus the backbone, right?

A. Keith Stewart, MB, ChB: We’re waiting for the results of the MAIA study, which is a combination of lenalidomide, dexamethasone, and daratumumab versus lenalidomide/dexamethasone. We’re kind of expecting that later this year. What do you need to see from Rd/daratumumab to use it instead of RVd-lite, for example, Amrita?

Amrita Krishnan, MD, FACP: Well, I mean just…

A. Keith Stewart, MB, ChB: What were you waiting for that’s going to be, “Yup, that’s it, I’m going to do that”?

Amrita Krishnan, MD, FACP: Well, I think, again, if I could see MRD negativity, I’d be happy. Or if I can see similar PFS, which is pretty good with RVd-lite. So, I think if I could get both of those, 80% at 2 years, I think I’d be very happy. And I’d be surprised, quite frankly, if they don’t meet that.

A. Keith Stewart, MB, ChB: Any other thoughts on that, Sagar?

Sagar Lonial, MD, FACP: I think if you look at POLLUX, the median PFS for POLLUX for the lenalidomide/daratumumab/dexamethasone arm is probably somewhere between 40 and 48 months. So, if the upfront trial gives you something in that same ballpark, you’re looking at sort of the same benefit for a transplant-ineligible patient that we saw from the IFM transplant arm, right? Forty-eight months was the median PFS. So, that’s pretty powerful.

Thomas Martin, MD: And the SWOG S0777 study, too, had a PFS of 43 months.

A. Keith Stewart, MB, ChB: And for those people who don’t know what that is, tell them.

Thomas Martin, MD: So, those were transplant-ineligible patients. Or actually was transplant-eligible and transplant-ineligible, but those patients mostly did not undergo transplantation.

A. Keith Stewart, MB, ChB: And it was RVd versus what?

Thomas Martin, MD: RVd versus Rd, and the PFS was 43 months in the RVd arm. So, if we surpass that—if I was to guess in terms of safety, because you asked about safety, too—I think the tolerability and the safety with DRd is going to be at least equivalent if not better than RVd. There will be little or no neuropathy, which will be great.

Amrita Krishnan, MD, FACP: Would equivalence be enough? It would be enough for me.

Thomas Martin, MD: I think it would actually. Yes.

Sagar Lonial, MD, FACP: The equivalence between?

Thomas Martin, MD: The 2 arms. With a safer triplet, less toxicity.

A. Keith Stewart, MB, ChB: Will bortezomib go away as a frontline drug to get combinations with no neuropathy that are just as good?

Ajai Chari, MD: The studies were not identical, right? So, it was without an intent to transplant. The number of patients who were over 65 is relatively small, and they were given twice-weekly bortezomib intravenously. So, it’s not a really fair comparison, but I think we all agree that DRd is going to be very easy to give, even in an elderly population.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: We just saw the FDA approve the drug daratumumab for elderly patients. We talked about lenalidomide/dexamethasone or RVd-lite is pretty much how we treat those patients today. Familiarity with a study for the audience, Tom, do you want to just quickly describe the results of the ALCYONE trial?

Thomas Martin, MD: Yes. The ALCYONE trial involved 700 patients and they were randomly assigned to 2 regimens. It was really a European-based regimen. Their standard induction of bortezomib/melphalan/prednisone—so VMP. And so, it’s VMP plus or minus daratumumab. They got 9 cycles of VMP with daratumumab. It was weekly for 6 weeks and then it was every 3 weeks for 9 cycles. And then after that, the arm that got daratumumab/VMP continued on daratumumab maintenance. The arm that got VMP just stopped therapy after 9 months. And this is the first study really that showed a quadruplet is better than a triplet. It was a nice study.

The problem in the United States is we don’t really use VMP so I don’t know how translatable it is to us. But that said, it was an advantage of daratumumab/VMP versus VMP. But the overall response rate was over 90% versus low 70%. And PFS adds 18 months; it was 74% versus 50%. Very different in terms of the 4-drug arm.

Now what I really liked about this study is if you look at the PFS curve, there was initial separation of the curve in the first 9 cycles, but then when they got to after 9 cycles to maintenance, the curve actually even separated out more. And daratumumab used as a single agent maintenance therapy looked extremely well tolerated. That’s what I really like, especially in the older population. Some of the other drugs that we use for maintenance—bortezomib, lenalidomide, etc.—there are toxicities, especially cumulative toxicities, in the older patients. I don’t think you have the same cumulative toxicities.

A. Keith Stewart, MB, ChB: Let’s come back to maintenance later. In the FDA approval, I understand that turning MRD-negativity was 1 of the things highlighted. Does that influence your choice of therapy, Sagar?

Sagar Lonial, MD, FACP: I think MRD negativity, certainly in the context of induction therapy, is a feather in the cap of the regimen. But for now, I still think of it as a prognostic tool. It tells you who’s going to do well. It doesn’t necessarily tell you that what you’ve done has influenced who’s going to do well. So, I think it’s certainly nice to see. We’ve not seen that in the older patient population like we did in the ALCYONE trial. But that alone is not sufficient for me to make a decision.

A. Keith Stewart, MB, ChB: Amrita, what are the practical implications of this for you? We don’t use melphalan here in the United States, but how do you think this is going to impact your clinical practice in the transplant-ineligible patients?

Amrita Krishnan, MD, FACP: That’s a good question because I don’t think any of us have written a VMP prescription. I think for me, it allows me to feel comfortable using a quadruplet regimen even in an elderly frail population. Maybe will that be RVd-lite plus daratumumab? Probably, I think. I think the other thing that was nice is that, yes, in an elderly frail population, if you look at MRD into the prognostic factors, you can get MRD negativity with a quadruplet regimen. So, hopefully, you can have outcomes similar to your transplant-eligible population downstream.

A. Keith Stewart, MB, ChB: Ajai, are we going to use daratumumab in the United States now with other combinations do you think, or is it not ready for that yet?

Ajai Chari, MD: I think the easiest extrapolation now is even if we’re not so fond of using melphalan in newly diagnosed patients, you could do daratumumab/VMP and just not give the “M”. And that daratumumab/VD essentially is what that would be. And the people who are using that in the relapsed setting, you could easily do that in the frontline setting.

In terms of going off-label, we know United States oncologists do that. We didn’t have the SWOG S0777 study comparing VRD to RD for many years, and yet people were using VRD based on a phase II regimen. So, I think in the United States, physicians are going to be comfortable extrapolating from the daratumumab/VMP to get frontline daratumumab, but then substituting in the drugs that they really like to use as a backbone.

And I think the other point is that, to Tom’s point, we shouldn’t lump all quadruplets in the same category. So, RVd plus cyclophosphamide added neutropenia without benefit, but VMP with melphalan/daratumumab does significant add to toxicities, other than a slightly higher rate of infection. But I think that’s probably the patient population.

A. Keith Stewart, MB, ChB: I think, for sure, we have to understand toxicity before we leap wholeheartedly into 4-drug cocktails.

Edward A. Stadtmauer, MD: It does feel right for oncologists in that we assume that there will be a R-CHOP for multiple myeloma, and it’s starting to look like a monoclonal antibody plus the backbone, right?

A. Keith Stewart, MB, ChB: We’re waiting for the results of the MAIA study, which is a combination of lenalidomide, dexamethasone, and daratumumab versus lenalidomide/dexamethasone. We’re kind of expecting that later this year. What do you need to see from Rd/daratumumab to use it instead of RVd-lite, for example, Amrita?

Amrita Krishnan, MD, FACP: Well, I mean just…

A. Keith Stewart, MB, ChB: What were you waiting for that’s going to be, “Yup, that’s it, I’m going to do that”?

Amrita Krishnan, MD, FACP: Well, I think, again, if I could see MRD negativity, I’d be happy. Or if I can see similar PFS, which is pretty good with RVd-lite. So, I think if I could get both of those, 80% at 2 years, I think I’d be very happy. And I’d be surprised, quite frankly, if they don’t meet that.

A. Keith Stewart, MB, ChB: Any other thoughts on that, Sagar?

Sagar Lonial, MD, FACP: I think if you look at POLLUX, the median PFS for POLLUX for the lenalidomide/daratumumab/dexamethasone arm is probably somewhere between 40 and 48 months. So, if the upfront trial gives you something in that same ballpark, you’re looking at sort of the same benefit for a transplant-ineligible patient that we saw from the IFM transplant arm, right? Forty-eight months was the median PFS. So, that’s pretty powerful.

Thomas Martin, MD: And the SWOG S0777 study, too, had a PFS of 43 months.

A. Keith Stewart, MB, ChB: And for those people who don’t know what that is, tell them.

Thomas Martin, MD: So, those were transplant-ineligible patients. Or actually was transplant-eligible and transplant-ineligible, but those patients mostly did not undergo transplantation.

A. Keith Stewart, MB, ChB: And it was RVd versus what?

Thomas Martin, MD: RVd versus Rd, and the PFS was 43 months in the RVd arm. So, if we surpass that—if I was to guess in terms of safety, because you asked about safety, too—I think the tolerability and the safety with DRd is going to be at least equivalent if not better than RVd. There will be little or no neuropathy, which will be great.

Amrita Krishnan, MD, FACP: Would equivalence be enough? It would be enough for me.

Thomas Martin, MD: I think it would actually. Yes.

Sagar Lonial, MD, FACP: The equivalence between?

Thomas Martin, MD: The 2 arms. With a safer triplet, less toxicity.

A. Keith Stewart, MB, ChB: Will bortezomib go away as a frontline drug to get combinations with no neuropathy that are just as good?

Ajai Chari, MD: The studies were not identical, right? So, it was without an intent to transplant. The number of patients who were over 65 is relatively small, and they were given twice-weekly bortezomib intravenously. So, it’s not a really fair comparison, but I think we all agree that DRd is going to be very easy to give, even in an elderly population.

Transcript Edited for Clarity 
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