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Optimizing Therapy for High-Risk Newly Diagnosed 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: Wednesday, Jul 25, 2018



Transcript: 

A. Keith Stewart, MB, ChB: You talked, Amrita, about restricting carfilzomib to higher-risk patients. How do you define high-risk disease?

Amrita Krishnan, MD, FACP: Well, some of it’s easier. We have high-risk cytogenetics, high-risk gene expression profiling, R-ISS staging, so that’s all easy. But there are other patients who you’re surprised if you do their R-ISS staging, they don’t fit category 3, but you know they have bad disease, they have huge tumor burden, they have lytic lesions, and they look sick when they come in. So, I think clinically high risk is also important to consider. And again, younger patients I tend to think of as also high risk just because obviously if you’re 30 and you have myeloma, you’re very different than someone who is 70 with myeloma as well.

A. Keith Stewart, MB, ChB: Some people would push back on this and ask, “If you’re going to treat everybody with the same drugs anyway, why bother either measuring it?” What changes in your thinking if you find somebody who has got high-risk genetics?

Ajai Chari, MD: I think just to get those 2 issues, which is, there’s a baseline risk and then there’s the kinetic risk, which is, especially in resource…

A. Keith Stewart, MB, ChB: Sort of fancy talk. Kinetic risk, what is that?

Ajai Chari, MD: Well, I think if you’re, for example, one of the poor-resource countries where you don’t have access to the appropriate FISH testing, which it should be CD1 for the selected or plasma-cell specific FISH. But you could argue that is what’s more important than a short PFS on induction, or failure to respond. So, I think that that’s another element of clinical risk. But I think, again, outside of clinical trials, you can start with the regimen VRd. And if you don’t have the response that you would like, you can either switch to “K” [KRd] and give more cycles, as Ed was alluding to. So, we’re not pinned down to one thing.

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

Thomas Martin, MD: Yes. So, I think for the majority of people, I do start them RVd as the initial therapy. And sometimes we don’t get the cytogenetic tests back by the time we’ve already started their therapy. And then it comes back and they’re high-risk. And so, then what do you do at that point in time? And if somebody had a 17p deletion, I would actually at that time switch them to carfilzomib/lenalidomide/dexamethasone. And it also affects what I do in the transplant eligible, they’ll get a transplant posttransplant. So, I tend to be very aggressive posttransplant with maintenance-based therapy when they’re high risk.

A. Keith Stewart, MB, ChB: Yes, me too. So, that’s just becoming a trend, I think, to mop up after the transplant as opposed to the…

Sagar Lonial, MD, FACP: I think one of the caveats, or one of the things associated with high-risk, is not just the ability to achieve a CR, but it’s the ability to maintain that CR. So, I’ll push back a little bit and say that we don’t switch to carfilzomib for people who have 17p if they’re responding nicely to RVd, but we do use RVd-based consolidation in maintenance. And we’ve shown pretty good survival for those patients. It doesn’t cure or give the kinds of remissions you in get in non-17p, but it can be very effective.

A. Keith Stewart, MB, ChB: Ed, I’ll ask you this question. If your patient obtains a complete remission after induction therapy—so you’ve given them 5 cycles of RVd and there’s no evidence of disease—do you still transplant them?

Edward A. Stadtmauer, MD: Yes, I do. I think that so far, if anything, the patients who have the best responses are the patients who do the best with high-dose melphalan and stem cell transplant. Until we’re certain that we have an initial therapy that is curative and that really destroys every last myeloma cell, then I’m just assuming that whatever is left is somewhat resistant to the therapies that the patient has already received. And in every study, it seems like adding a dose of high-dose melphalan will improve duration of response and maybe survival.

A. Keith Stewart, MB, ChB: Does anyone disagree with that? Is anyone acting differently?

Thomas Martin, MD: I think in some circumstances I disagree with that. And in fact, I think that is one of the most important discussions with a patient. They’ve achieved a stringent CR, and now we’re testing—I think we’ll talk about it a little later on—MRD status.

A. Keith Stewart, MB, ChB: Minimal residual disease.

Thomas Martin, MD: Minimal residual disease. If we check it and they’re MRD-negative at the pretransplant point, then it goes to a longer discussion with a patient. Because there’s no survival difference between upfront transplant in, you say, delayed transplant. That we’re going to collect now, but we’re going to do the transplant down the road and we’re going to follow their MRD status. Now that is off the cuff. There’s no trial that has done that. But for some patients they say, “No, I want to do it now.” And I say, “Perfect, let’s do it now and let’s get it over with.” And others that say, “You know what, I’ll wait and we’ll see how, how we do with this MRD negativity.”

A. Keith Stewart, MB, ChB: California versus the rough East Coast people.

Amrita Krishnan, MD, FACP: If I could disagree with one thing…if you look at the trial you’re alluding to, the early versus delayed transplant after RVd, 20% of people were not able to get to transplants. I think that’s an important discussion to have with them, too, and whether that was disease progression or other comorbidities.

A. Keith Stewart, MB, ChB: All right. Amrita, just let’s move on here. So, Amrita, would you go in the opposite direction of doing 2 transplants? You did the large StaMINA trial, and we heard from the Europeans recently on their version of no single or double consolidation. Summarize quickly for us where we’re at with that.

Amrita Krishnan, MD, FACP: We have 2 huge trials that showed 2 different results, but they really are different trials. The European trial had sideboard induction first of all, which I think is the key.

A. Keith Stewart, MB, ChB: That’s cyclophosphamide/bortezomib/dexamethasone.

Amrita Krishnan, MD, FACP: And they did show a benefit to tandem transplant in the especially high-risk cytogenetic population, which is what sort of generated a lot of buzz; is tandem transplant coming back? But in contrast, the StaMINA trial, first of all, over 50% of the patients had RVd.

A. Keith Stewart, MB, ChB: Most of our viewers might not know what the StaMINA trial is, so why don’t you explain quickly what it was.

Amrita Krishnan, MD, FACP: The StaMINA trial was trying to answer the question, “What’s the best thing to do after your autologous transplant to improve PFS?” Is it tandem transplant? Is it just standalone maintenance? Or is it RVd consolidation? And then there’s lenalidomide maintenance.

A. Keith Stewart, MB, ChB: And what did it show?

Amrita Krishnan, MD, FACP: That lenalidomide maintenance was equivalent in terms of PFS to doing either a tandem transplant or to doing RVd consolidation.

A. Keith Stewart, MB, ChB: A lot of us were surprised by that result. We had in our heads that consolidation was good, and maybe for some patients even today, a tandem transplant might be helpful. Were you surprised by the result?

Amrita Krishnan, MD, FACP: I was surprised, too, and I think, Ed, as the co-chair on this trial, probably was equally surprised.

A. Keith Stewart, MB, ChB: Ed, I’m sorry, I knew that was going to get to you, but were you surprised, Ed?

Edward A. Stadtmauer, MD: Well, we designed the study because we were hopeful that we could make incremental improvements in the care of patients undergoing stem cell transplant. So, we were hopeful that one of these arms would be an incremental benefit. I think the results of the StaMINA study are really interesting and really make us think about the postremission therapy and what the best approaches for patients who undergo transplant are. I think comparing the StaMINA study, which is a United States study, with European studies is very difficult. If you really look into the weeds, you see that there’s a different group of patients really. In the StaMINA study, these are patients who had already received therapy and then they went to their transplant, as opposed to in Europe where the patients start right from the beginning on a clinical trial. And so, they’re really asking little different questions in a different group of patients.

A. Keith Stewart, MB, ChB: So, let’s just cut to the chase. Sagar, do you do tandem transplants?

Sagar Lonial, MD, FACP: No.

A. Keith Stewart, MB, ChB: Tom, do you do tandem transplants?

Thomas Martin, MD: No.

A. Keith Stewart, MB, ChB: Ajai?

Ajai Chari, MD: No.

Amrita Krishnan, MD, FACP: He should ask both of us, though.

A. Keith Stewart, MB, ChB: My own experience is rarely. Started to use MRD and if I can’t get rid of it, I sometimes consider a certain transplant. But what if you change your practice based on StaMINA or the European study?

Edward A. Stadtmauer, MD: The only group of patients who I really think about are patients who have a poor response to initial therapy, then have a nice response and tolerate the first transplant, but it still looks like it can go deeper. That’s the one subset of patients where I think about it. Obviously all of these clinical trials, in practice we don’t do 1 arm versus another arm. In practice, what we do is an adapted strategy based on what’s happening with the patient.

Transcript Edited for Clarity

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Transcript: 

A. Keith Stewart, MB, ChB: You talked, Amrita, about restricting carfilzomib to higher-risk patients. How do you define high-risk disease?

Amrita Krishnan, MD, FACP: Well, some of it’s easier. We have high-risk cytogenetics, high-risk gene expression profiling, R-ISS staging, so that’s all easy. But there are other patients who you’re surprised if you do their R-ISS staging, they don’t fit category 3, but you know they have bad disease, they have huge tumor burden, they have lytic lesions, and they look sick when they come in. So, I think clinically high risk is also important to consider. And again, younger patients I tend to think of as also high risk just because obviously if you’re 30 and you have myeloma, you’re very different than someone who is 70 with myeloma as well.

A. Keith Stewart, MB, ChB: Some people would push back on this and ask, “If you’re going to treat everybody with the same drugs anyway, why bother either measuring it?” What changes in your thinking if you find somebody who has got high-risk genetics?

Ajai Chari, MD: I think just to get those 2 issues, which is, there’s a baseline risk and then there’s the kinetic risk, which is, especially in resource…

A. Keith Stewart, MB, ChB: Sort of fancy talk. Kinetic risk, what is that?

Ajai Chari, MD: Well, I think if you’re, for example, one of the poor-resource countries where you don’t have access to the appropriate FISH testing, which it should be CD1 for the selected or plasma-cell specific FISH. But you could argue that is what’s more important than a short PFS on induction, or failure to respond. So, I think that that’s another element of clinical risk. But I think, again, outside of clinical trials, you can start with the regimen VRd. And if you don’t have the response that you would like, you can either switch to “K” [KRd] and give more cycles, as Ed was alluding to. So, we’re not pinned down to one thing.

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

Thomas Martin, MD: Yes. So, I think for the majority of people, I do start them RVd as the initial therapy. And sometimes we don’t get the cytogenetic tests back by the time we’ve already started their therapy. And then it comes back and they’re high-risk. And so, then what do you do at that point in time? And if somebody had a 17p deletion, I would actually at that time switch them to carfilzomib/lenalidomide/dexamethasone. And it also affects what I do in the transplant eligible, they’ll get a transplant posttransplant. So, I tend to be very aggressive posttransplant with maintenance-based therapy when they’re high risk.

A. Keith Stewart, MB, ChB: Yes, me too. So, that’s just becoming a trend, I think, to mop up after the transplant as opposed to the…

Sagar Lonial, MD, FACP: I think one of the caveats, or one of the things associated with high-risk, is not just the ability to achieve a CR, but it’s the ability to maintain that CR. So, I’ll push back a little bit and say that we don’t switch to carfilzomib for people who have 17p if they’re responding nicely to RVd, but we do use RVd-based consolidation in maintenance. And we’ve shown pretty good survival for those patients. It doesn’t cure or give the kinds of remissions you in get in non-17p, but it can be very effective.

A. Keith Stewart, MB, ChB: Ed, I’ll ask you this question. If your patient obtains a complete remission after induction therapy—so you’ve given them 5 cycles of RVd and there’s no evidence of disease—do you still transplant them?

Edward A. Stadtmauer, MD: Yes, I do. I think that so far, if anything, the patients who have the best responses are the patients who do the best with high-dose melphalan and stem cell transplant. Until we’re certain that we have an initial therapy that is curative and that really destroys every last myeloma cell, then I’m just assuming that whatever is left is somewhat resistant to the therapies that the patient has already received. And in every study, it seems like adding a dose of high-dose melphalan will improve duration of response and maybe survival.

A. Keith Stewart, MB, ChB: Does anyone disagree with that? Is anyone acting differently?

Thomas Martin, MD: I think in some circumstances I disagree with that. And in fact, I think that is one of the most important discussions with a patient. They’ve achieved a stringent CR, and now we’re testing—I think we’ll talk about it a little later on—MRD status.

A. Keith Stewart, MB, ChB: Minimal residual disease.

Thomas Martin, MD: Minimal residual disease. If we check it and they’re MRD-negative at the pretransplant point, then it goes to a longer discussion with a patient. Because there’s no survival difference between upfront transplant in, you say, delayed transplant. That we’re going to collect now, but we’re going to do the transplant down the road and we’re going to follow their MRD status. Now that is off the cuff. There’s no trial that has done that. But for some patients they say, “No, I want to do it now.” And I say, “Perfect, let’s do it now and let’s get it over with.” And others that say, “You know what, I’ll wait and we’ll see how, how we do with this MRD negativity.”

A. Keith Stewart, MB, ChB: California versus the rough East Coast people.

Amrita Krishnan, MD, FACP: If I could disagree with one thing…if you look at the trial you’re alluding to, the early versus delayed transplant after RVd, 20% of people were not able to get to transplants. I think that’s an important discussion to have with them, too, and whether that was disease progression or other comorbidities.

A. Keith Stewart, MB, ChB: All right. Amrita, just let’s move on here. So, Amrita, would you go in the opposite direction of doing 2 transplants? You did the large StaMINA trial, and we heard from the Europeans recently on their version of no single or double consolidation. Summarize quickly for us where we’re at with that.

Amrita Krishnan, MD, FACP: We have 2 huge trials that showed 2 different results, but they really are different trials. The European trial had sideboard induction first of all, which I think is the key.

A. Keith Stewart, MB, ChB: That’s cyclophosphamide/bortezomib/dexamethasone.

Amrita Krishnan, MD, FACP: And they did show a benefit to tandem transplant in the especially high-risk cytogenetic population, which is what sort of generated a lot of buzz; is tandem transplant coming back? But in contrast, the StaMINA trial, first of all, over 50% of the patients had RVd.

A. Keith Stewart, MB, ChB: Most of our viewers might not know what the StaMINA trial is, so why don’t you explain quickly what it was.

Amrita Krishnan, MD, FACP: The StaMINA trial was trying to answer the question, “What’s the best thing to do after your autologous transplant to improve PFS?” Is it tandem transplant? Is it just standalone maintenance? Or is it RVd consolidation? And then there’s lenalidomide maintenance.

A. Keith Stewart, MB, ChB: And what did it show?

Amrita Krishnan, MD, FACP: That lenalidomide maintenance was equivalent in terms of PFS to doing either a tandem transplant or to doing RVd consolidation.

A. Keith Stewart, MB, ChB: A lot of us were surprised by that result. We had in our heads that consolidation was good, and maybe for some patients even today, a tandem transplant might be helpful. Were you surprised by the result?

Amrita Krishnan, MD, FACP: I was surprised, too, and I think, Ed, as the co-chair on this trial, probably was equally surprised.

A. Keith Stewart, MB, ChB: Ed, I’m sorry, I knew that was going to get to you, but were you surprised, Ed?

Edward A. Stadtmauer, MD: Well, we designed the study because we were hopeful that we could make incremental improvements in the care of patients undergoing stem cell transplant. So, we were hopeful that one of these arms would be an incremental benefit. I think the results of the StaMINA study are really interesting and really make us think about the postremission therapy and what the best approaches for patients who undergo transplant are. I think comparing the StaMINA study, which is a United States study, with European studies is very difficult. If you really look into the weeds, you see that there’s a different group of patients really. In the StaMINA study, these are patients who had already received therapy and then they went to their transplant, as opposed to in Europe where the patients start right from the beginning on a clinical trial. And so, they’re really asking little different questions in a different group of patients.

A. Keith Stewart, MB, ChB: So, let’s just cut to the chase. Sagar, do you do tandem transplants?

Sagar Lonial, MD, FACP: No.

A. Keith Stewart, MB, ChB: Tom, do you do tandem transplants?

Thomas Martin, MD: No.

A. Keith Stewart, MB, ChB: Ajai?

Ajai Chari, MD: No.

Amrita Krishnan, MD, FACP: He should ask both of us, though.

A. Keith Stewart, MB, ChB: My own experience is rarely. Started to use MRD and if I can’t get rid of it, I sometimes consider a certain transplant. But what if you change your practice based on StaMINA or the European study?

Edward A. Stadtmauer, MD: The only group of patients who I really think about are patients who have a poor response to initial therapy, then have a nice response and tolerate the first transplant, but it still looks like it can go deeper. That’s the one subset of patients where I think about it. Obviously all of these clinical trials, in practice we don’t do 1 arm versus another arm. In practice, what we do is an adapted strategy based on what’s happening with the patient.

Transcript Edited for Clarity
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