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Treatment Approaches in Relapsed Multiple Myeloma

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, Aug 10, 2018



Transcript: 

A. Keith Stewart, MB, ChB: So, let’s talk about relapsed myeloma. In the old days, we used to wait until people were exhibiting symptoms before we treated them. I sense there has been a move to intervene more quickly because we have new drugs to use. You’re nodding, Ed, you agree with that? Your numbers are going up, do you wait or do you just get in there and start?

Edward A. Stadtmauer, MD: Well, I think that’s the key to the whole discussion, that in the old days we didn’t have as good tests.

A. Keith Stewart, MB, ChB: By the way, we were all part of the old days.

Edward A. Stadtmauer, MD: We didn’t have great tests to monitor patients and so we had to wait for them to have a broken bone or bad anemia. Now with the light chain analyses, with our serum protein electrophoresis sensitivities, and our close monitoring of patients, we will detect most of the patients before some catastrophic event that their disease is progressing. My first intervention tends to be to watch them more closely rather than to initiate any therapy, if it’s just a number that’s going up.

And then we start typing to get the tempo. But a lot of it depends on how sick the patient was when they were initially presenting. Because if their disease was really nasty, I don’t want to watch someone going through renal failure. I don’t want to watch someone have worsening neuropathy. And so, it’s a very patient-specific sort of approach.

Sagar Lonial, MD, FACP: My caveat to that would be that if we know that they had a high-risk disease at the beginning, I’m less comfortable watching those patients.

Edward A. Stadtmauer, MD: Correct.

Sagar Lonial, MD, FACP: And I’m doing more PET scans at the time of biochemical relapse, because that’s where you find out stuff that you didn’t anticipate.

A. Keith Stewart, MB, ChB: I must say I’ve been disinclined to watch and wait any more. I’ve almost had the sense that if you use CyBorD and a transplant and 18 months of lenalidomide maintenance, you were undertreated and we should start again from scratch and try and get you back into MRD negativity. But maybe that’s just me, I don’t know.

So, let’s assume we’ve done what we said we would do in the last session. You’ve had RVd, you’ve had transplants and consolidation, lenalidomide maintenance, and you’re not progressing. I’d kind of like to hear from the group, understanding there’s no one-size-fits-all regimen, what kind of regimens are you using at first relapse? Maybe we’ll go this way. Tom, you can tell us.

Thomas Martin, MD: So, I think in 3 of the studies in the 1 to 3 prior lines of therapy, the daratumumab/bortezomib index—so DVd versus daratumumab/lenalidomide/dexamethasone, or DRd—and in your study, the carfilzomib/lenalidomide/dexamethasone, or KRd, both have shown, or all 3 of them have shown, significant advantage to starting one of those 3 regimens in people who have first relapse.

So, like you were just saying, I try to be pretty aggressive in the first relapse, especially in the young patients, especially in patients who can tolerate really aggressive therapy from the start. I will usually give them KRd, DRd, or DVd at the time of first progression. If they’re truly lenalidomide-refractory, then probably I’m going to do DVd as the regimen.

A. Keith Stewart, MB, ChB: You wouldn’t switch to pomalidomide instead of lenalidomide?

Thomas Martin, MD: I think it depends. For some people, if their counts are not a problem, I will do DPd. Often, I’ll actually not do it as the second regimen. I’d save pomalidomide for the next regimen.

A. Keith Stewart, MB, ChB: Ajai, what do you think? Do you class switch or do you just give the next generation of the same drugs?

Ajai Chari, MD: If you’re going to practice some evidence-based medicine, if you include the 4 lenalidomide-based backbones and the 3 bortezomib backbones, you really have 7 studies to choose from. But the reality of how many of those patients are actually applicable is who’s sitting in front of you in clinic, which is who is progressing on lenalidomide maintenance. Because then you essentially exclude those 4 studies that require lenalidomide-naïve. And then you end up with the 3 Vd backbone regimens. But I think daratumumab has shown in this first relapse consistently to really have a better reduction in the risk of progression relative to the control arm. I would favor a daratumumab-based regimen, and then the partner drug depends on the patient. So, I would favor daratumumab with pomalidomide if they have no history of thrombotic events and good blood counts. If they’re t(4;14), maybe either DKd with carfilzomib or with bortezomib. Luckily, we have so many combinations’ abilities to pick from.

A. Keith Stewart, MB, ChB: Right. I suspect we’re going to hear the same from all of you. Is that pretty much consistent with your approach?

Amrita Krishnan, MD, FACP: Yes. I think Ajai presented some interesting data with the daratumumab/Kd in terms of using carfilzomib weekly and then splitting the dose of daratumumab. So, making it a little bit more user-friendly, because that used to be a little bit of a roadblock to putting patients on that choice.

A. Keith Stewart, MB, ChB: So, carfilzomib is a bit more attractive. I think we’re going to probably talk through that study in a minute.

Sagar Lonial, MD, FACP: I think what’s really interesting is that the efficacy of pomalidomide in t(4;14) as a partner and in 17p is probably undervalued. In 17p, it actually looks as good as any other drug that’s out there. So, daratumumab/pomalidomide/dexamethasone for that reason is our go-to in the first salvage. And I’ve been really struck by the t(4;14)s and how well they’ve responded after having short responses to either K or B.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: So, let’s talk about relapsed myeloma. In the old days, we used to wait until people were exhibiting symptoms before we treated them. I sense there has been a move to intervene more quickly because we have new drugs to use. You’re nodding, Ed, you agree with that? Your numbers are going up, do you wait or do you just get in there and start?

Edward A. Stadtmauer, MD: Well, I think that’s the key to the whole discussion, that in the old days we didn’t have as good tests.

A. Keith Stewart, MB, ChB: By the way, we were all part of the old days.

Edward A. Stadtmauer, MD: We didn’t have great tests to monitor patients and so we had to wait for them to have a broken bone or bad anemia. Now with the light chain analyses, with our serum protein electrophoresis sensitivities, and our close monitoring of patients, we will detect most of the patients before some catastrophic event that their disease is progressing. My first intervention tends to be to watch them more closely rather than to initiate any therapy, if it’s just a number that’s going up.

And then we start typing to get the tempo. But a lot of it depends on how sick the patient was when they were initially presenting. Because if their disease was really nasty, I don’t want to watch someone going through renal failure. I don’t want to watch someone have worsening neuropathy. And so, it’s a very patient-specific sort of approach.

Sagar Lonial, MD, FACP: My caveat to that would be that if we know that they had a high-risk disease at the beginning, I’m less comfortable watching those patients.

Edward A. Stadtmauer, MD: Correct.

Sagar Lonial, MD, FACP: And I’m doing more PET scans at the time of biochemical relapse, because that’s where you find out stuff that you didn’t anticipate.

A. Keith Stewart, MB, ChB: I must say I’ve been disinclined to watch and wait any more. I’ve almost had the sense that if you use CyBorD and a transplant and 18 months of lenalidomide maintenance, you were undertreated and we should start again from scratch and try and get you back into MRD negativity. But maybe that’s just me, I don’t know.

So, let’s assume we’ve done what we said we would do in the last session. You’ve had RVd, you’ve had transplants and consolidation, lenalidomide maintenance, and you’re not progressing. I’d kind of like to hear from the group, understanding there’s no one-size-fits-all regimen, what kind of regimens are you using at first relapse? Maybe we’ll go this way. Tom, you can tell us.

Thomas Martin, MD: So, I think in 3 of the studies in the 1 to 3 prior lines of therapy, the daratumumab/bortezomib index—so DVd versus daratumumab/lenalidomide/dexamethasone, or DRd—and in your study, the carfilzomib/lenalidomide/dexamethasone, or KRd, both have shown, or all 3 of them have shown, significant advantage to starting one of those 3 regimens in people who have first relapse.

So, like you were just saying, I try to be pretty aggressive in the first relapse, especially in the young patients, especially in patients who can tolerate really aggressive therapy from the start. I will usually give them KRd, DRd, or DVd at the time of first progression. If they’re truly lenalidomide-refractory, then probably I’m going to do DVd as the regimen.

A. Keith Stewart, MB, ChB: You wouldn’t switch to pomalidomide instead of lenalidomide?

Thomas Martin, MD: I think it depends. For some people, if their counts are not a problem, I will do DPd. Often, I’ll actually not do it as the second regimen. I’d save pomalidomide for the next regimen.

A. Keith Stewart, MB, ChB: Ajai, what do you think? Do you class switch or do you just give the next generation of the same drugs?

Ajai Chari, MD: If you’re going to practice some evidence-based medicine, if you include the 4 lenalidomide-based backbones and the 3 bortezomib backbones, you really have 7 studies to choose from. But the reality of how many of those patients are actually applicable is who’s sitting in front of you in clinic, which is who is progressing on lenalidomide maintenance. Because then you essentially exclude those 4 studies that require lenalidomide-naïve. And then you end up with the 3 Vd backbone regimens. But I think daratumumab has shown in this first relapse consistently to really have a better reduction in the risk of progression relative to the control arm. I would favor a daratumumab-based regimen, and then the partner drug depends on the patient. So, I would favor daratumumab with pomalidomide if they have no history of thrombotic events and good blood counts. If they’re t(4;14), maybe either DKd with carfilzomib or with bortezomib. Luckily, we have so many combinations’ abilities to pick from.

A. Keith Stewart, MB, ChB: Right. I suspect we’re going to hear the same from all of you. Is that pretty much consistent with your approach?

Amrita Krishnan, MD, FACP: Yes. I think Ajai presented some interesting data with the daratumumab/Kd in terms of using carfilzomib weekly and then splitting the dose of daratumumab. So, making it a little bit more user-friendly, because that used to be a little bit of a roadblock to putting patients on that choice.

A. Keith Stewart, MB, ChB: So, carfilzomib is a bit more attractive. I think we’re going to probably talk through that study in a minute.

Sagar Lonial, MD, FACP: I think what’s really interesting is that the efficacy of pomalidomide in t(4;14) as a partner and in 17p is probably undervalued. In 17p, it actually looks as good as any other drug that’s out there. So, daratumumab/pomalidomide/dexamethasone for that reason is our go-to in the first salvage. And I’ve been really struck by the t(4;14)s and how well they’ve responded after having short responses to either K or B.

Transcript Edited for Clarity 
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