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Transplant in Multiple Myeloma

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: Thursday, Feb 02, 2017



Transcript:

Keith Stewart, MB, CHB:
Let’s talk about transplant. Is transplant the goal of all eligible patients? I know there will be a difference of opinion here, so I’m going to start with a transplant fan. Tell us why you think everybody needs a transplant, and more specifically, tell us what the data at this meeting are that leads you to support that conclusion?

Amrita Krishnan, MD: I would touch upon 2 major trials. One of them is actually Paul’s trial that was presented at last year’s meeting, which looked at what I would consider standard of care—induction—in the United States with RVD (Revlimid/Velcade/dexamethasone). One arm received continued RVD, the other arm had early transplant followed by RVD consolidation, and both arms received lenalidomide maintenance therapy for 1 year. There was a significant progression-free survival benefit to the early RVD arm.

I know Paul is going to jump in and say, “But, there’s no overall survival benefit.” But, again, this is with the length of follow-up that we have. And I think that if you continue to follow it, and if we look at depth of responses, we may ultimately see that benefit.

The other thing I would say is we have data at this meeting looking at CyBorD (cyclophosphamide, bortezomib, and dexamethasone) followed by single or tandem transplant from the European groups as compared to a VMP (bortezomib, melphalan, and prednisone) arm. That’s much more reflective then of the real world in Europe, and also shows a progression-free survival benefit to early transplant. And then the last point I want to make is if you look at the United States, only 20% of patients who are eligible for transplant are actually referred for transplant. So, I think, at the very least, it’s important that patients are allowed to have that discussion about transplant.

Keith Stewart, MB, CHB: I was struck. We did a meeting yesterday, and we asked the audience about a case. We asked about a transplant-eligible patient. We asked how many would send them to transplant, and 97% of the audience, Paul, said they would send them for transplant. I think you’ve got an uphill battle in convincing people to delay transplant. But, tell us why you think we should maybe delay?

Paul Richardson, MD: I think Amrita touched on it. The United States outcomes in myeloma are the best in the world. So, if we were failing our patients by not transplanting everyone, why do we have the best outcomes in the world with the data that you just shared?

I attend on the transplant service, so I’m very comfortable offering transplant to the appropriate patient. My position is simply that one size does not fit all. And I think in this meeting we’re hearing more and more information that in Europe, certainly, where salvage strategies are different, practice patterns are different. And obviously, all your good approaches need to be used relatively early to ensure better outcome. In the United States, we’re blessed with great salvage options. And in that context, for certain patients, it may be reasonable to collect, store, and wait. I think our French study shows, clearly, the progression-free survival benefit. And I think Amrita is quite right—it’s striking. What is equally striking, though, is, given the depth of that progression-free survival difference, there isn’t an OS difference.

Keith Stewart, MB, CHB: OS being overall survival benefit?

Paul Richardson, MD: Exactly. And so I think what it tells our patients is that they may have a choice. So I think we’re actually much closer than what weimplied by sitting here because, in fact, what I would say is it’s clearly a standard option—it’s an option. And the issue for a patient is “collect and wait” may be reasonable, or it may be better to “go straight.” I think that until we actually have more information on subgroups of patients who benefit versus not, the current trials are going to be so important in addressing that question. And it’s great, actually, because everyone at this table is participating in various studies that are looking at this. I think, critically, we’re going to learn that, particularly, with the advent of antibodies and other strategies, this philosophy of tailoring treatment and sparing patients toxicity, both acute and long-term, may be very important.

Keith Stewart, MB, CHB: I just want to dig a little bit into the new data at this meeting. In particular, I want to talk about, first, the 3 major groups—European, English, and the StaMINA trial from the US—that looked to the issue not just of transplant, but also at consolidation and second transplant. I’m going to pick on you again, Amrita, because you’re actually one of the lead investigators on the StaMINA trial. Do you want to tell the audience what that is, and what the conclusions of that trial are?

Amrita Krishnan, MD: This is a tremendous trial in the US. It’s 700 patients, so it’s a real testament to all of us working together. It’s a 3-arm trial. We did not mandate the induction regimen, so I think that’s a very important point in contrast to the European trials. Patients got a standard autologous transplant with high-dose melphalan, and then one arm got lenalidomide maintenance therapy, one arm got a second transplant followed by lenalidomide maintenance therapy, and one arm got RVD consolidation followed by lenalidomide maintenance therapy. And with our follow-up, now at about 38 months, we did not see a significant difference between any of those arms. I think you can interpret that in a matter of ways. My interpretation of that is if you have a good induction regimen, then doing a single transplant followed by lenalidomide maintenance therapy is very good.

Keith Stewart, MB, CHB: Now, who wants to take on the European trial? It was somewhat contradictory with your trial? Sagar, do you want to take on the HOVON, or the German study?

Sagar Lonial, MD: In summary, because it’s a very complicated trial with multiple different areas of randomization, one of the take-home messages from the European presenters is that tandem transplant offers benefit, particularly for the high-risk subsets of patients.

Keith Stewart, MB, CHB: Which your trial did not show, right?

Amrita Krishnan, MD: Yes, our trial, even in high-risk patients, did not show benefit to tandem.

Sagar Lonial, MD: I think one of the real differences between these 2 trials is the efficacy of the induction therapy. In the European regimen, they used VCD (bortezomib-cyclophosphamide-dexamethasone), which I think is not the optimal induction regimen. We don’t know what the United States investigators got, but I suspect a significant fraction got RVD because that is part of the practice pattern in the United States. I think a lot of this discussion over transplant early versus transplant late really speaks to the quality of the induction regimen you’re giving. That probably influences your CR rate, and that influences the post-transplant outcomes.

Saad Usmani, MD: It might simply be the quality of induction. These patients are coming in with different burdens of disease and different disease biology. So, there are patients that we are going to overtreat with induction, transplant, consolidation and/or maintenance. We haven’t figured out which ones those are. And this leads into what Paul was saying about personalizing therapies, and not approaching things in a one-size-fits-all way.

Keith Stewart, MB, CHB: Is anybody doing tandem transplant routinely? I think the answer is probably no.

Amrita Krishnan, MD: No, but we’re all collecting for 2.

Keith Stewart, MB, CHB: That’s more for delayed transplant.

Paul Richardson, MD: That is true.

Transcript Edited for Clarity

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Transcript:

Keith Stewart, MB, CHB:
Let’s talk about transplant. Is transplant the goal of all eligible patients? I know there will be a difference of opinion here, so I’m going to start with a transplant fan. Tell us why you think everybody needs a transplant, and more specifically, tell us what the data at this meeting are that leads you to support that conclusion?

Amrita Krishnan, MD: I would touch upon 2 major trials. One of them is actually Paul’s trial that was presented at last year’s meeting, which looked at what I would consider standard of care—induction—in the United States with RVD (Revlimid/Velcade/dexamethasone). One arm received continued RVD, the other arm had early transplant followed by RVD consolidation, and both arms received lenalidomide maintenance therapy for 1 year. There was a significant progression-free survival benefit to the early RVD arm.

I know Paul is going to jump in and say, “But, there’s no overall survival benefit.” But, again, this is with the length of follow-up that we have. And I think that if you continue to follow it, and if we look at depth of responses, we may ultimately see that benefit.

The other thing I would say is we have data at this meeting looking at CyBorD (cyclophosphamide, bortezomib, and dexamethasone) followed by single or tandem transplant from the European groups as compared to a VMP (bortezomib, melphalan, and prednisone) arm. That’s much more reflective then of the real world in Europe, and also shows a progression-free survival benefit to early transplant. And then the last point I want to make is if you look at the United States, only 20% of patients who are eligible for transplant are actually referred for transplant. So, I think, at the very least, it’s important that patients are allowed to have that discussion about transplant.

Keith Stewart, MB, CHB: I was struck. We did a meeting yesterday, and we asked the audience about a case. We asked about a transplant-eligible patient. We asked how many would send them to transplant, and 97% of the audience, Paul, said they would send them for transplant. I think you’ve got an uphill battle in convincing people to delay transplant. But, tell us why you think we should maybe delay?

Paul Richardson, MD: I think Amrita touched on it. The United States outcomes in myeloma are the best in the world. So, if we were failing our patients by not transplanting everyone, why do we have the best outcomes in the world with the data that you just shared?

I attend on the transplant service, so I’m very comfortable offering transplant to the appropriate patient. My position is simply that one size does not fit all. And I think in this meeting we’re hearing more and more information that in Europe, certainly, where salvage strategies are different, practice patterns are different. And obviously, all your good approaches need to be used relatively early to ensure better outcome. In the United States, we’re blessed with great salvage options. And in that context, for certain patients, it may be reasonable to collect, store, and wait. I think our French study shows, clearly, the progression-free survival benefit. And I think Amrita is quite right—it’s striking. What is equally striking, though, is, given the depth of that progression-free survival difference, there isn’t an OS difference.

Keith Stewart, MB, CHB: OS being overall survival benefit?

Paul Richardson, MD: Exactly. And so I think what it tells our patients is that they may have a choice. So I think we’re actually much closer than what weimplied by sitting here because, in fact, what I would say is it’s clearly a standard option—it’s an option. And the issue for a patient is “collect and wait” may be reasonable, or it may be better to “go straight.” I think that until we actually have more information on subgroups of patients who benefit versus not, the current trials are going to be so important in addressing that question. And it’s great, actually, because everyone at this table is participating in various studies that are looking at this. I think, critically, we’re going to learn that, particularly, with the advent of antibodies and other strategies, this philosophy of tailoring treatment and sparing patients toxicity, both acute and long-term, may be very important.

Keith Stewart, MB, CHB: I just want to dig a little bit into the new data at this meeting. In particular, I want to talk about, first, the 3 major groups—European, English, and the StaMINA trial from the US—that looked to the issue not just of transplant, but also at consolidation and second transplant. I’m going to pick on you again, Amrita, because you’re actually one of the lead investigators on the StaMINA trial. Do you want to tell the audience what that is, and what the conclusions of that trial are?

Amrita Krishnan, MD: This is a tremendous trial in the US. It’s 700 patients, so it’s a real testament to all of us working together. It’s a 3-arm trial. We did not mandate the induction regimen, so I think that’s a very important point in contrast to the European trials. Patients got a standard autologous transplant with high-dose melphalan, and then one arm got lenalidomide maintenance therapy, one arm got a second transplant followed by lenalidomide maintenance therapy, and one arm got RVD consolidation followed by lenalidomide maintenance therapy. And with our follow-up, now at about 38 months, we did not see a significant difference between any of those arms. I think you can interpret that in a matter of ways. My interpretation of that is if you have a good induction regimen, then doing a single transplant followed by lenalidomide maintenance therapy is very good.

Keith Stewart, MB, CHB: Now, who wants to take on the European trial? It was somewhat contradictory with your trial? Sagar, do you want to take on the HOVON, or the German study?

Sagar Lonial, MD: In summary, because it’s a very complicated trial with multiple different areas of randomization, one of the take-home messages from the European presenters is that tandem transplant offers benefit, particularly for the high-risk subsets of patients.

Keith Stewart, MB, CHB: Which your trial did not show, right?

Amrita Krishnan, MD: Yes, our trial, even in high-risk patients, did not show benefit to tandem.

Sagar Lonial, MD: I think one of the real differences between these 2 trials is the efficacy of the induction therapy. In the European regimen, they used VCD (bortezomib-cyclophosphamide-dexamethasone), which I think is not the optimal induction regimen. We don’t know what the United States investigators got, but I suspect a significant fraction got RVD because that is part of the practice pattern in the United States. I think a lot of this discussion over transplant early versus transplant late really speaks to the quality of the induction regimen you’re giving. That probably influences your CR rate, and that influences the post-transplant outcomes.

Saad Usmani, MD: It might simply be the quality of induction. These patients are coming in with different burdens of disease and different disease biology. So, there are patients that we are going to overtreat with induction, transplant, consolidation and/or maintenance. We haven’t figured out which ones those are. And this leads into what Paul was saying about personalizing therapies, and not approaching things in a one-size-fits-all way.

Keith Stewart, MB, CHB: Is anybody doing tandem transplant routinely? I think the answer is probably no.

Amrita Krishnan, MD: No, but we’re all collecting for 2.

Keith Stewart, MB, CHB: That’s more for delayed transplant.

Paul Richardson, MD: That is true.

Transcript Edited for Clarity
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