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The Ongoing Role of Transplant in Multiple Myeloma

Panelists:Keith Stewart, MD, CHB, Mayo Clinic;William I. Bensinger, MD, Swedish Cancer Institute;Rafael Fonseca, MD, Mayo Clinic;C. Ola Landgren, MD, PhD, Memorial Sloan Kettering Cancer Center;Jatin P. Shah, MD, MD Anderson Cancer Center
Published: Tuesday, Jul 19, 2016


Transcript:

Keith Stewart, MD, CHB:
Let’s talk about transplant now. So, we started our patient on triplet therapy, Bill, and he comes to see you at the Swedish hospital. What’s your advice to him about transplant, and why do you give that advice, and what have we learned at this meeting that has influenced you?

William I. Bensinger, MD: I tell my patients that transplant is just one component of their initial therapy. It’s a form of consolidation, and it’s useful because it will inevitably improve on the response they get to whatever induction therapy they get. Improve the depth of response, and this can translate into better progression-free survival and overall survival. Now, that’s based on a number of studies. There were early trials in which everyone went to transplant, but they were comparing novel drug combinations to some of the older combinations like that. But in every case, regardless of what was used for induction, after transplant, the percentage of patients that achieved remissions went up. Now we have actually randomized trials. There are four randomized trials that have been done, all of them interestingly from Europe, which is very telling right there.

Keith Stewart, MD, CHB: And it’s important, too. But we’ll come back to that later.

William I. Bensinger, MD: Yes. So, two of the trials used doublets of lenalidomide, dexamethasone and then compared tandem transplants to combinations of melphalan, prednisone, and lenalidomide, or cyclophosphamide, dexamethasone, and lenalidomide. And those trials all showed better progression-free and better overall survival—two of those trials. There was a recent trial presented here from the European Union, which was a very large trial, with nearly 1200 patients, using essentially a CyBorD-type induction regimen and then comparing one or two transplants to a bortezomib, melphalan, and prednisone regimen for four cycles. Actually, I think it might have been six cycles. But that trial showed, again, better response, better progression-free survival; not better overall survival, but there was relatively short follow-up.

The problem is that all three of those trials are not really commonly what we do in the United States. The fourth trial—which was presented by the French group at ASH last year—used a combination of VRD, or bortezomib, lenalidomide, and dexamethasone. Three cycles of induction, stem cell mobilization, and then a randomization to a single transplant, followed by two more cycles of VRD or five cycles of VRD without a transplant. That trial had better overall response rates and a better progression-free survival, favoring the transplant arm. Now, again, there’s no difference in overall survival. We don’t know if that’ll translate to a survival benefit, but the follow-up is still relatively short for that trial. So, we have four trials all showing better PFS. Two of the four trials with sufficient follow-up showed better overall survival. And I think the data speaks for itself at that point.

Keith Stewart, MD, CHB: I just want a very brief answer. At MD Anderson, you send a young patient after four cycles of transplant?

Jatin P. Shah, MD: Yes, absolutely.

Keith Stewart, MD, CHB: Based on these data?

Jatin P. Shah, MD: I think based on the data there are really two things. I think we have these data, and the question keeps coming up in the era of novel therapies—so with lenalidomide and bortezomib, now with carfilzomib, and now with monoclonals. And that question keeps coming up. But, again…

Keith Stewart, MD, CHB: It’s going to come up here in a minute with Ola, too, but I’m leaving him for last.

Jatin P. Shah, MD: This debate keeps coming up. But, again, what I try and stick with—and what we stick with—is we have multiple trials showing a PFS and OS benefit. But I think that the true principle here, in my mind, is that if you have an incurable cancer, or an incurable cancer in the vast majority of patients. I need every therapeutic option. So, until I’ve cured it, until you’ve shown me that we’ve cured a vast majority of patients, then we can start talking about cutting back. But until, as a patient, you’ve cured the disease, then you want every therapeutic option available, regardless if it’s therapy A, B, or C (so transplant)—or X, Y, and Z—that to me is a therapeutic option and means taking advantage of every option for an incurable cancer. And if you stick with that, then I think that makes it easy for us to say that’s an important option for patients.

Keith Stewart, MD, CHB: And now Rafael, before I get to Ola and he tells us we’re all wrong, are we transplanting now?

Rafael Fonseca, MD: Very briefly. 2016 stem cell transplant is a gold standard. It’s incumbent upon combinatorial strategies and people who strategize behind that to show that it’s as good as transplant. In my opinion, there’s many reasons why a patient may or may not want to get a transplant. But, in my opinion, every patient who’s eligible should be steered towards stem cell transplant.

Keith Stewart, MD, CHB: And what if they’re in complete remission before or after the 4 or 6 cycles of induction therapy—and there’s no evidence of disease—do you still think they need a transplant then?

Rafael Fonseca, MD: It depends on how you define that, and if you’re talking about complete remission with next-generation sequencing—negativity that tests genetic-based minimal residual disease. If you have a patient like that, I think you can start the argument. Although I would still say, given what we know today, I would still give the patient the benefit of the doubt because we’re seeing patients in complete responses, both in maintenance trials, as well as on a number of other interventions where the addition of more therapy actually is beneficial. So, I’m curious but I don’t think I’m convinced to withhold transplant at this point.

Keith Stewart, MD, CHB: Ola, you have a different opinion you told me before we started filming here. Tell us your approach to this these days. I guess what I’ve heard so far is at Mayo, MD Anderson in Seattle, people are still transplanting pretty much everybody, but you’ve got a slightly different approach.

C. Ola Landgren, MD, PhD: I think we are looking at the same data, and I think we make a slightly different interpretation of the data. Of course, there is also a component of opinion. And I think the truth of the matter is that there are a lot of questions where we don’t have the formal answers to it. I’m sure we agree on that.

I think looking at all the European studies, they clearly show that transplant has an additive effect. We know that melphalan works very well in myeloma; there is no reason to question that. But I think the question I would like to ask is, when is the right time to give it for each and every patient? Is it at the up-front setting after delivery of very good therapy, where you have also evidence from testing that you actually have no detectible disease with minimal residual disease testing?

So, what we have done is that we have implemented an algorithm at Memorial Sloan Kettering Cancer Center where we give six cycles of carfilzomib, lenalidomide, and dexamethasone. And we do a bone marrow biopsy, and in that biopsy for each and every patient, we check for MRD (minimal residual disease) status. And if you have MRD, we tend to do that six…

Keith Stewart, MD, CHB: You do that by next-generation sequencing or flow cytometry?

C. Ola Landgren, MD, PhD: Yes, sequencing… and; we have both.

Keith Stewart, MD, CHB: You do both?

C. Ola Landgren, MD, PhD: If you’re negative for MRD, we give the patient the option to collect the stem cells and go to maintenance or collect the stem cells and do a transplant. For patients who are MRD-positive, we advocate to go for the transplant. And we say, our readouts from the study from France show that comparing the two arms from the up-front versus delayed transplant; you have deeper responses and longer PFS.

But if you look in the two arms, there are patients that are MRD-negative in both arms, and their progression-free survival is the same. So, there are more patients that reach deep response in the transplant arm, but there are also patients doing it without the transplant. If you don’t check, I think transplant should be done. But if you can do the test, you may not need it. And that’s, I think, an important message.

Jatin P. Shah, MD: I think so, too.

Keith Stewart, MD, CHB: I always tell my patients when they ask me, “When am I getting this therapy? When do you get to transplant? Are you going to give me maintenance?” I always tell them that the goal of therapy is to get you in a complete remission. And all those parts are tools that will get us there—but maybe it’s the complete remission that matters, not the therapy that you have.

C. Ola Landgren, MD, PhD: I think the response is what matters, not how you get there.

Keith Stewart, MD, CHB: Yes, that’s right.

C. Ola Landgren, MD, PhD: And we know myeloma is so heterogeneous. We know that probably 50%, 60% of patients have a much more indolent disease.

Transcript Edited for Clarity
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Transcript:

Keith Stewart, MD, CHB:
Let’s talk about transplant now. So, we started our patient on triplet therapy, Bill, and he comes to see you at the Swedish hospital. What’s your advice to him about transplant, and why do you give that advice, and what have we learned at this meeting that has influenced you?

William I. Bensinger, MD: I tell my patients that transplant is just one component of their initial therapy. It’s a form of consolidation, and it’s useful because it will inevitably improve on the response they get to whatever induction therapy they get. Improve the depth of response, and this can translate into better progression-free survival and overall survival. Now, that’s based on a number of studies. There were early trials in which everyone went to transplant, but they were comparing novel drug combinations to some of the older combinations like that. But in every case, regardless of what was used for induction, after transplant, the percentage of patients that achieved remissions went up. Now we have actually randomized trials. There are four randomized trials that have been done, all of them interestingly from Europe, which is very telling right there.

Keith Stewart, MD, CHB: And it’s important, too. But we’ll come back to that later.

William I. Bensinger, MD: Yes. So, two of the trials used doublets of lenalidomide, dexamethasone and then compared tandem transplants to combinations of melphalan, prednisone, and lenalidomide, or cyclophosphamide, dexamethasone, and lenalidomide. And those trials all showed better progression-free and better overall survival—two of those trials. There was a recent trial presented here from the European Union, which was a very large trial, with nearly 1200 patients, using essentially a CyBorD-type induction regimen and then comparing one or two transplants to a bortezomib, melphalan, and prednisone regimen for four cycles. Actually, I think it might have been six cycles. But that trial showed, again, better response, better progression-free survival; not better overall survival, but there was relatively short follow-up.

The problem is that all three of those trials are not really commonly what we do in the United States. The fourth trial—which was presented by the French group at ASH last year—used a combination of VRD, or bortezomib, lenalidomide, and dexamethasone. Three cycles of induction, stem cell mobilization, and then a randomization to a single transplant, followed by two more cycles of VRD or five cycles of VRD without a transplant. That trial had better overall response rates and a better progression-free survival, favoring the transplant arm. Now, again, there’s no difference in overall survival. We don’t know if that’ll translate to a survival benefit, but the follow-up is still relatively short for that trial. So, we have four trials all showing better PFS. Two of the four trials with sufficient follow-up showed better overall survival. And I think the data speaks for itself at that point.

Keith Stewart, MD, CHB: I just want a very brief answer. At MD Anderson, you send a young patient after four cycles of transplant?

Jatin P. Shah, MD: Yes, absolutely.

Keith Stewart, MD, CHB: Based on these data?

Jatin P. Shah, MD: I think based on the data there are really two things. I think we have these data, and the question keeps coming up in the era of novel therapies—so with lenalidomide and bortezomib, now with carfilzomib, and now with monoclonals. And that question keeps coming up. But, again…

Keith Stewart, MD, CHB: It’s going to come up here in a minute with Ola, too, but I’m leaving him for last.

Jatin P. Shah, MD: This debate keeps coming up. But, again, what I try and stick with—and what we stick with—is we have multiple trials showing a PFS and OS benefit. But I think that the true principle here, in my mind, is that if you have an incurable cancer, or an incurable cancer in the vast majority of patients. I need every therapeutic option. So, until I’ve cured it, until you’ve shown me that we’ve cured a vast majority of patients, then we can start talking about cutting back. But until, as a patient, you’ve cured the disease, then you want every therapeutic option available, regardless if it’s therapy A, B, or C (so transplant)—or X, Y, and Z—that to me is a therapeutic option and means taking advantage of every option for an incurable cancer. And if you stick with that, then I think that makes it easy for us to say that’s an important option for patients.

Keith Stewart, MD, CHB: And now Rafael, before I get to Ola and he tells us we’re all wrong, are we transplanting now?

Rafael Fonseca, MD: Very briefly. 2016 stem cell transplant is a gold standard. It’s incumbent upon combinatorial strategies and people who strategize behind that to show that it’s as good as transplant. In my opinion, there’s many reasons why a patient may or may not want to get a transplant. But, in my opinion, every patient who’s eligible should be steered towards stem cell transplant.

Keith Stewart, MD, CHB: And what if they’re in complete remission before or after the 4 or 6 cycles of induction therapy—and there’s no evidence of disease—do you still think they need a transplant then?

Rafael Fonseca, MD: It depends on how you define that, and if you’re talking about complete remission with next-generation sequencing—negativity that tests genetic-based minimal residual disease. If you have a patient like that, I think you can start the argument. Although I would still say, given what we know today, I would still give the patient the benefit of the doubt because we’re seeing patients in complete responses, both in maintenance trials, as well as on a number of other interventions where the addition of more therapy actually is beneficial. So, I’m curious but I don’t think I’m convinced to withhold transplant at this point.

Keith Stewart, MD, CHB: Ola, you have a different opinion you told me before we started filming here. Tell us your approach to this these days. I guess what I’ve heard so far is at Mayo, MD Anderson in Seattle, people are still transplanting pretty much everybody, but you’ve got a slightly different approach.

C. Ola Landgren, MD, PhD: I think we are looking at the same data, and I think we make a slightly different interpretation of the data. Of course, there is also a component of opinion. And I think the truth of the matter is that there are a lot of questions where we don’t have the formal answers to it. I’m sure we agree on that.

I think looking at all the European studies, they clearly show that transplant has an additive effect. We know that melphalan works very well in myeloma; there is no reason to question that. But I think the question I would like to ask is, when is the right time to give it for each and every patient? Is it at the up-front setting after delivery of very good therapy, where you have also evidence from testing that you actually have no detectible disease with minimal residual disease testing?

So, what we have done is that we have implemented an algorithm at Memorial Sloan Kettering Cancer Center where we give six cycles of carfilzomib, lenalidomide, and dexamethasone. And we do a bone marrow biopsy, and in that biopsy for each and every patient, we check for MRD (minimal residual disease) status. And if you have MRD, we tend to do that six…

Keith Stewart, MD, CHB: You do that by next-generation sequencing or flow cytometry?

C. Ola Landgren, MD, PhD: Yes, sequencing… and; we have both.

Keith Stewart, MD, CHB: You do both?

C. Ola Landgren, MD, PhD: If you’re negative for MRD, we give the patient the option to collect the stem cells and go to maintenance or collect the stem cells and do a transplant. For patients who are MRD-positive, we advocate to go for the transplant. And we say, our readouts from the study from France show that comparing the two arms from the up-front versus delayed transplant; you have deeper responses and longer PFS.

But if you look in the two arms, there are patients that are MRD-negative in both arms, and their progression-free survival is the same. So, there are more patients that reach deep response in the transplant arm, but there are also patients doing it without the transplant. If you don’t check, I think transplant should be done. But if you can do the test, you may not need it. And that’s, I think, an important message.

Jatin P. Shah, MD: I think so, too.

Keith Stewart, MD, CHB: I always tell my patients when they ask me, “When am I getting this therapy? When do you get to transplant? Are you going to give me maintenance?” I always tell them that the goal of therapy is to get you in a complete remission. And all those parts are tools that will get us there—but maybe it’s the complete remission that matters, not the therapy that you have.

C. Ola Landgren, MD, PhD: I think the response is what matters, not how you get there.

Keith Stewart, MD, CHB: Yes, that’s right.

C. Ola Landgren, MD, PhD: And we know myeloma is so heterogeneous. We know that probably 50%, 60% of patients have a much more indolent disease.

Transcript Edited for Clarity
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