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Preferred Regimens for Relapsed Myeloma

Panelists: A. Keith Stewart, MB, ChB, The Mayo Clinic in Phoenix Arizona; Thomas Martin, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Faith Davies, MD, MBBCh, MRCP, FRCPath, University of Arkansas for Medical Sciences; Rafael Fonseca, MD, The Mayo Clinic in Phoenix Arizona; Adriana Rossi, MD, Weill Cornell Medical College
Published: Thursday, Feb 21, 2019



Transcript:

A. Keith Stewart, MB, ChB:
Let’s move on and talk about the relapsed setting. Again, we will focus on some of the new data that are coming out at this meeting [the American Society of Hematology Annual Meeting and Exposition]. But before we get into the new abstracts, can you just talk a little bit about your approach to early relapse? Maybe we’ll start with you, Adriana. RVD lite [lenalidomide, bortezomib, and dexamethasone], RVD transplant, maintenance lenalidomide—a lot of our patients are on an IMiD [immunomodulatory drug] at the time that they begin to progress. What’s your approach? I know it has been nuanced by the individual patient. But in general, what’s your approach?

Adriana Rossi, MD: That’s the luxury of nuance, right? If a patient has a biochemical relapse, which I think we now have the luxury of finding much more often, I think you have the option to either re-escalate or add. So if it’s a low dose of lenalidomide, I may add another agent and increase.

A. Keith Stewart, MB, ChB: Such as?

Adriana Rossi, MD: So in the elderly patients, I like elotuzumab. They tend to tolerate it quite well. Carfilzomib is for, I think, a patient who hasn’t gotten it up front. As I’ve mentioned, most of my practice is shifting toward having had exposure to that up front. And dara-pom [daratumumab and pomalidomide] for the clinical relapse is really sort of my most used, I would say, triplet.

A. Keith Stewart, MB, ChB: The triplet?

Adriana Rossi, MD: Yes.

A. Keith Stewart, MB, ChB: Faith, what’s your first relapse regimen of choice?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I really like carfilzomib, pomalidomide and dex [dexamethasone]. Also, if the patient hasn’t been exposed to daratumumab, then I’ll use daratumumab in some.

A. Keith Stewart, MB, ChB: I guess most really haven’t yet.

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yes, most of mine haven’t yet, so I certainly, in the relapsed setting, have good experience with re-exposure. So my assumption would be it would work in the…

A. Keith Stewart, MB, ChB: Using a 4-drug already—KPD [carfilzomib with pomalidomide and dexamethasone] and dara, or just KPD or dara? Is there a choice between carfilzomib and daratumumab?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Unfortunately, I haven’t had the luxury of doing many 4-drug regimens because I can’t get them approved or reimbursed. But you could imagine that if the patient is fit, there’s certainly a possibility. But I think that potentially I’m still using the 3-drug regimen.

A. Keith Stewart, MB, ChB: Adriana, I want to come back to something you said and challenge you on it. Do you continue lenalidomide and escalate the dose, or do you switch?

Adriana Rossi, MD: So in a biochemical relapse, I may maintain the IMiD and just increase the dose and add a new partner.

A. Keith Stewart, MB, ChB: Have you had success with that? Because a lot of people say that hasn’t been very successful.

Adriana Rossi, MD: I have.

A. Keith Stewart, MB, ChB: Tom?

Thomas Martin, MD: I would say in the first relapse I’m going to use a daratumumab-based regimen. I think the POLLUX data, which is len and dex versus daratumumab, len, and dex, or the CASTOR data—bortezomib, dex, plus or minus daratumumab—or your data from ASPIRE. Keith, I would say that those 3 regimens, if you use them first out of the gate for relapse, patients are going to have the longest PFS [progression-free survival] from 1 of those 3 regimens. So usually I’m picking 1 of those 3.

A. Keith Stewart, MB, ChB: If they’re refractory to an IMiD like lenalidomide, why would you keep them on an IMiD? And if so, why wouldn’t you change to pomalidomide, Tom?

Thomas Martin, MD: For me, if somebody is on lenalidomide, continuous lenalidomide, then most of the time I’ll go on daratumumab, bortezomib, and dexamethasone. So I am switching them from an IMiD to a proteasome inhibitor. If it’s somebody who really has aggressive relapse, and we all have those patients, then it is KPD—the KPD, or dara, pom, and dex. I think those regimens work the best in a very aggressive relapse.

A. Keith Stewart, MB, ChB: Just to be slightly controversial, I’ve concluded that bortezomib shouldn’t be used in relapse. I think the results are very weak.

Thomas Martin, MD: So if you take the CASTOR study, and if you look at the PFS at the first relapse, it’s 27 months. It’s a little better than your ASPIRE.

A. Keith Stewart, MB, ChB: Maybe, but that’s not really the question. Rafael, what do you think?

Rafael Fonseca, MD: As I was listening just to the insightful comments here from my colleagues, 1 of the things that just strikes me is…

A. Keith Stewart, MB, ChB: Actually, I have to come back to Thomas. Daratumumab, bortezomib, and dex alone was terrible. It was like 9 months or something.

Thomas Martin, MD: Yeah, I certainly don’t use a doublet.

A. Keith Stewart, MB, ChB: That was about bortezomib.

Thomas Martin, MD: Oh, absolutely. You and I agree.

A. Keith Stewart, MB, ChB: Anyway, back to you, Rafael.

Rafael Fonseca, MD: No, 9 months is not good. So I don’t think that prior exposure should define someone who has been refractory. And I think in myeloma the reach-out is a perfectly legitimate thing. The mechanisms of resistance are quite different. We know with the IMiDs, for instance, that most patients now don’t have certain mutations. And it seems like for most agents, whether it’s PIs [proteasome inhibitors] or IMiDs, I’m going to suggest the same is true for daratumumab. This is just pressure that builds, and if you reach a threshold, you can kill cells, but you induce apoptosis. And rechallenge, I think, is appropriate because sometimes the cells that are left behind will respond. We know that empirically. But someone asked the question yesterday: If you induce a person with dara, KRD, and transplant, then what do you treat that relapse with? The only new card is pom, and you’re hoping they’re t(11;14), so you have venetoclax. But the reality is that there has been a significant period of time of disease control, and I think all those drugs are probably active.

A. Keith Stewart, MB, ChB: There was a trial of a triplet with pomalidomide, bortezomib, and dexamethasone—the OPTIMISMM study. What did you think of that, Faith?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I think it was positive. It showed that the triplet was better than the doublet. But for me, assuming my patient has already used bortezomib, I would be wanting to move to 1 of the other proteasome inhibitors, being carfilzomib, or if the patient wanted an oral agent, maybe ixazomib.

A. Keith Stewart, MB, ChB: Yeah, I must say in my own practice, for the longest time I was switching from bortezomib to carfilzomib, and from lenalidomide to pomalidomide. The question then becomes, how do you build daratumumab into that? Do you do 4 drugs, or do you drop the proteasome inhibitor? Any thoughts on that, Adriana?

Adriana Rossi, MD: Having sort of lived through the addition and the expansion of our armamentarium, I used to switch only 1 at a time, if I was able to, if it wasn’t done in an aggressive relapse. So say from a CyBorD [cyclophosphamide, bortezomib, and dexamethasone] to an RVD to a KRD [carfilzomib, lenalidomide, and dexamethasone] to pom, and so just switch 1 partner at a time. So I would still consider doing something like that. I don’t feel that I would need to add all of them at once in a nonaggressive case.

Thomas Martin, MD: We do a lot of the ping-pong approach. They’re on an IMiD base, we switch to a proteasome inhibitor base, and back and forth. For me with pomalidomide, the good partners that we have now are monoclonal antibodies in carfilzomib. But the monoclonal antibodies—we now have elotuzumab, pomalidomide, and dexamethasone, which showed impressive results from the ELOQUENT-3 study, in which the overall response rate was 56%, or 53% versus 26%, and a PFS of 11 months versus 5 months. And that was actually pretty amazing.

I do think the POMALYST [pomalidomide] in the IL-2 [interleukin-2] locally produced enhances the NK [natural killer] cell effect. And it works really well, much better than I expected with elotuzumab.

Transcript edited for clarity.

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Transcript:

A. Keith Stewart, MB, ChB:
Let’s move on and talk about the relapsed setting. Again, we will focus on some of the new data that are coming out at this meeting [the American Society of Hematology Annual Meeting and Exposition]. But before we get into the new abstracts, can you just talk a little bit about your approach to early relapse? Maybe we’ll start with you, Adriana. RVD lite [lenalidomide, bortezomib, and dexamethasone], RVD transplant, maintenance lenalidomide—a lot of our patients are on an IMiD [immunomodulatory drug] at the time that they begin to progress. What’s your approach? I know it has been nuanced by the individual patient. But in general, what’s your approach?

Adriana Rossi, MD: That’s the luxury of nuance, right? If a patient has a biochemical relapse, which I think we now have the luxury of finding much more often, I think you have the option to either re-escalate or add. So if it’s a low dose of lenalidomide, I may add another agent and increase.

A. Keith Stewart, MB, ChB: Such as?

Adriana Rossi, MD: So in the elderly patients, I like elotuzumab. They tend to tolerate it quite well. Carfilzomib is for, I think, a patient who hasn’t gotten it up front. As I’ve mentioned, most of my practice is shifting toward having had exposure to that up front. And dara-pom [daratumumab and pomalidomide] for the clinical relapse is really sort of my most used, I would say, triplet.

A. Keith Stewart, MB, ChB: The triplet?

Adriana Rossi, MD: Yes.

A. Keith Stewart, MB, ChB: Faith, what’s your first relapse regimen of choice?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I really like carfilzomib, pomalidomide and dex [dexamethasone]. Also, if the patient hasn’t been exposed to daratumumab, then I’ll use daratumumab in some.

A. Keith Stewart, MB, ChB: I guess most really haven’t yet.

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yes, most of mine haven’t yet, so I certainly, in the relapsed setting, have good experience with re-exposure. So my assumption would be it would work in the…

A. Keith Stewart, MB, ChB: Using a 4-drug already—KPD [carfilzomib with pomalidomide and dexamethasone] and dara, or just KPD or dara? Is there a choice between carfilzomib and daratumumab?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Unfortunately, I haven’t had the luxury of doing many 4-drug regimens because I can’t get them approved or reimbursed. But you could imagine that if the patient is fit, there’s certainly a possibility. But I think that potentially I’m still using the 3-drug regimen.

A. Keith Stewart, MB, ChB: Adriana, I want to come back to something you said and challenge you on it. Do you continue lenalidomide and escalate the dose, or do you switch?

Adriana Rossi, MD: So in a biochemical relapse, I may maintain the IMiD and just increase the dose and add a new partner.

A. Keith Stewart, MB, ChB: Have you had success with that? Because a lot of people say that hasn’t been very successful.

Adriana Rossi, MD: I have.

A. Keith Stewart, MB, ChB: Tom?

Thomas Martin, MD: I would say in the first relapse I’m going to use a daratumumab-based regimen. I think the POLLUX data, which is len and dex versus daratumumab, len, and dex, or the CASTOR data—bortezomib, dex, plus or minus daratumumab—or your data from ASPIRE. Keith, I would say that those 3 regimens, if you use them first out of the gate for relapse, patients are going to have the longest PFS [progression-free survival] from 1 of those 3 regimens. So usually I’m picking 1 of those 3.

A. Keith Stewart, MB, ChB: If they’re refractory to an IMiD like lenalidomide, why would you keep them on an IMiD? And if so, why wouldn’t you change to pomalidomide, Tom?

Thomas Martin, MD: For me, if somebody is on lenalidomide, continuous lenalidomide, then most of the time I’ll go on daratumumab, bortezomib, and dexamethasone. So I am switching them from an IMiD to a proteasome inhibitor. If it’s somebody who really has aggressive relapse, and we all have those patients, then it is KPD—the KPD, or dara, pom, and dex. I think those regimens work the best in a very aggressive relapse.

A. Keith Stewart, MB, ChB: Just to be slightly controversial, I’ve concluded that bortezomib shouldn’t be used in relapse. I think the results are very weak.

Thomas Martin, MD: So if you take the CASTOR study, and if you look at the PFS at the first relapse, it’s 27 months. It’s a little better than your ASPIRE.

A. Keith Stewart, MB, ChB: Maybe, but that’s not really the question. Rafael, what do you think?

Rafael Fonseca, MD: As I was listening just to the insightful comments here from my colleagues, 1 of the things that just strikes me is…

A. Keith Stewart, MB, ChB: Actually, I have to come back to Thomas. Daratumumab, bortezomib, and dex alone was terrible. It was like 9 months or something.

Thomas Martin, MD: Yeah, I certainly don’t use a doublet.

A. Keith Stewart, MB, ChB: That was about bortezomib.

Thomas Martin, MD: Oh, absolutely. You and I agree.

A. Keith Stewart, MB, ChB: Anyway, back to you, Rafael.

Rafael Fonseca, MD: No, 9 months is not good. So I don’t think that prior exposure should define someone who has been refractory. And I think in myeloma the reach-out is a perfectly legitimate thing. The mechanisms of resistance are quite different. We know with the IMiDs, for instance, that most patients now don’t have certain mutations. And it seems like for most agents, whether it’s PIs [proteasome inhibitors] or IMiDs, I’m going to suggest the same is true for daratumumab. This is just pressure that builds, and if you reach a threshold, you can kill cells, but you induce apoptosis. And rechallenge, I think, is appropriate because sometimes the cells that are left behind will respond. We know that empirically. But someone asked the question yesterday: If you induce a person with dara, KRD, and transplant, then what do you treat that relapse with? The only new card is pom, and you’re hoping they’re t(11;14), so you have venetoclax. But the reality is that there has been a significant period of time of disease control, and I think all those drugs are probably active.

A. Keith Stewart, MB, ChB: There was a trial of a triplet with pomalidomide, bortezomib, and dexamethasone—the OPTIMISMM study. What did you think of that, Faith?

Faith Davies, MD, MBBCh, MRCP, FRCPath: I think it was positive. It showed that the triplet was better than the doublet. But for me, assuming my patient has already used bortezomib, I would be wanting to move to 1 of the other proteasome inhibitors, being carfilzomib, or if the patient wanted an oral agent, maybe ixazomib.

A. Keith Stewart, MB, ChB: Yeah, I must say in my own practice, for the longest time I was switching from bortezomib to carfilzomib, and from lenalidomide to pomalidomide. The question then becomes, how do you build daratumumab into that? Do you do 4 drugs, or do you drop the proteasome inhibitor? Any thoughts on that, Adriana?

Adriana Rossi, MD: Having sort of lived through the addition and the expansion of our armamentarium, I used to switch only 1 at a time, if I was able to, if it wasn’t done in an aggressive relapse. So say from a CyBorD [cyclophosphamide, bortezomib, and dexamethasone] to an RVD to a KRD [carfilzomib, lenalidomide, and dexamethasone] to pom, and so just switch 1 partner at a time. So I would still consider doing something like that. I don’t feel that I would need to add all of them at once in a nonaggressive case.

Thomas Martin, MD: We do a lot of the ping-pong approach. They’re on an IMiD base, we switch to a proteasome inhibitor base, and back and forth. For me with pomalidomide, the good partners that we have now are monoclonal antibodies in carfilzomib. But the monoclonal antibodies—we now have elotuzumab, pomalidomide, and dexamethasone, which showed impressive results from the ELOQUENT-3 study, in which the overall response rate was 56%, or 53% versus 26%, and a PFS of 11 months versus 5 months. And that was actually pretty amazing.

I do think the POMALYST [pomalidomide] in the IL-2 [interleukin-2] locally produced enhances the NK [natural killer] cell effect. And it works really well, much better than I expected with elotuzumab.

Transcript edited for clarity.
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