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Optimizing Early Sequencing and Treatment in 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: Thursday, Aug 02, 2018



Transcript: 

A. Keith Stewart, MB, ChB: So, if we’ve all agreed that daratumumab is going to be part of our frontline therapy soon, what are we going do when patients relapse, Ed?

Edward A. Stadtmauer, MD: Develop more therapies. Even if you use these drugs early on, what we’ve really learned is that different combinations are basically different drugs. So, if we add daratumumab to pomalidomide—we introduce the bortezomib later—we can use different combinations, use alkylating agents. So, I don’t think that will eliminate our ability to treat patients who progress.

A. Keith Stewart, MB, ChB: Do you think we’ll use daratumumab again at relapse, or is it like Rituxan (rituximab) where you just use it with everything, or are we going to switch classes? Anybody can take that.

Thomas Martin, MD: Well, I think we are going to switch classes, but you can always go back to the antibody-based therapy. If I use an antibody-based therapy, the next therapy I probably won’t use an antibody-based one. But our patients get 3, 4, 5, 6, 10. Yesterday on one of the abstracts, 23 prior lines of therapy. So, I am going to go back to that antibody-based therapy at some time in the future. I usually give some 3- or 6-month break so that hopefully the CD38 can be back on the cell surface as a target.

Ajai Chari, MD: I think another important issue when we’re talking about this is the same discussion that came up with VRd. And if you use up all your drugs early, are you going to then compromise later care? And the SWOG S0777 study showed not only PFS improvement with VRd, but OS improvement. So, I think using effective drugs early doesn’t really mitigate or decrease your long-term survival. And then the other big thing I think outside of clinical trials, again, is that you’re not obligated to continue quadruplet therapy forever. And I don’t think it’s even practical from either a tolerability or a class point of view. And I think a lot of people criticized CASTOR and the ALCYONE studies because of the control arm–terminated therapy. But the reality is that outside of the United States, no one can give these drugs forever. And the health authorities mandate termination of therapy. So, I think that’s actually a strength of these studies to not continue all drugs forever.

Sagar Lonial, MD, FACP: I do think it’s important that we maintain a certain level of—and this is maybe not the right word—discipline. So, we’re saying, “Well, if you do well, maybe you don’t need a transplant.” Then we’re saying, “Well, let’s add our daratumumab upfront, then let’s give everything forever.” Then it’s going to be a mishmash of what everybody is doing out there, and we won’t know where we are in terms of outcomes. So, my view is if we’re going to incorporate an antibody upfront, it’s short-term, long enough to get a good response and collect cells. I would still consolidate with a transplant and then think about what’s the maintenance strategy that doesn’t use all 4 drugs.

A. Keith Stewart, MB, ChB: OK, so we can see a little controversy. Let’s talk about maintenance just to close out this section. I think we’re all agreed that lenalidomide maintenance is accepted worldwide now as a beneficial thing to do. You said, Tom, you were enamored with daratumumab maintenance. You just said you don’t think we should use daratumumab maintenance, if I heard you correctly. So, let’s have at it here, which is, who’s right?

Thomas Martin, MD: So, I will start by saying that we have reviewed the patients who have had an autologous transplant at UCSF and then have gone on to lenalidomide maintenance, with the intent of them taking lenalidomide forever. And in fact, at 2 years, we have less than 50% of the people still on lenalidomide. I just think after a year, after 18 months, specifically after 24 months, it becomes challenging just because of the long-term side effects. Mostly it’s fatigue, diarrhea, GI side effects. And most people at that point of time want a break.

Monthly daratumumab is very convenient, we do it with bone-strengthening drugs. We do it so many that they come in monthly. Patients will come in for a monthly infusion. I actually think it’s going to be very well tolerated. Now whether it’s lenalidomide and daratumumab for 6 months or a year, and then on to daratumumab, etc, we have to test this in clinical trials. But I think we have a lot of room to improve on our strategy for maintenance-based therapy.

A. Keith Stewart, MB, ChB: But there, we probably shouldn’t call it maintenance therapy as opposed to continuous therapy.

Ajai Chari, MD: Correct. Agreed.

A. Keith Stewart, MB, ChB: Amrita, what do you think about maintenance therapy?

Amrita Krishnan, MD, FACP: I think Tom touched upon the point, and this is a trial that we’ve been working on with Ed through SWOG and the BMTCN, which is going to try and answer that very question, how long do you really need to give maintenance? Because I also agree with Sagar. I think we’re doing patients a disservice to just blindly say, “Continue it because it’s working.” And so, the SWOG trial is going to randomize patients to lenalidomide/daratumumab after transplant or to lenalidomide alone. And then at 2 years after maintenance, check MRD status and then do a second randomization so that if you’re MRD-negative, we will stop maintenance. So, I think it would be the first trial to really use MRD and ask the question, “Can you stop maintenance?”

A. Keith Stewart, MB, ChB: That sounds so incredibly logical, it seems like a good place to stop. So, that sounds like the perfect clinical trial to address this dilemma.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: So, if we’ve all agreed that daratumumab is going to be part of our frontline therapy soon, what are we going do when patients relapse, Ed?

Edward A. Stadtmauer, MD: Develop more therapies. Even if you use these drugs early on, what we’ve really learned is that different combinations are basically different drugs. So, if we add daratumumab to pomalidomide—we introduce the bortezomib later—we can use different combinations, use alkylating agents. So, I don’t think that will eliminate our ability to treat patients who progress.

A. Keith Stewart, MB, ChB: Do you think we’ll use daratumumab again at relapse, or is it like Rituxan (rituximab) where you just use it with everything, or are we going to switch classes? Anybody can take that.

Thomas Martin, MD: Well, I think we are going to switch classes, but you can always go back to the antibody-based therapy. If I use an antibody-based therapy, the next therapy I probably won’t use an antibody-based one. But our patients get 3, 4, 5, 6, 10. Yesterday on one of the abstracts, 23 prior lines of therapy. So, I am going to go back to that antibody-based therapy at some time in the future. I usually give some 3- or 6-month break so that hopefully the CD38 can be back on the cell surface as a target.

Ajai Chari, MD: I think another important issue when we’re talking about this is the same discussion that came up with VRd. And if you use up all your drugs early, are you going to then compromise later care? And the SWOG S0777 study showed not only PFS improvement with VRd, but OS improvement. So, I think using effective drugs early doesn’t really mitigate or decrease your long-term survival. And then the other big thing I think outside of clinical trials, again, is that you’re not obligated to continue quadruplet therapy forever. And I don’t think it’s even practical from either a tolerability or a class point of view. And I think a lot of people criticized CASTOR and the ALCYONE studies because of the control arm–terminated therapy. But the reality is that outside of the United States, no one can give these drugs forever. And the health authorities mandate termination of therapy. So, I think that’s actually a strength of these studies to not continue all drugs forever.

Sagar Lonial, MD, FACP: I do think it’s important that we maintain a certain level of—and this is maybe not the right word—discipline. So, we’re saying, “Well, if you do well, maybe you don’t need a transplant.” Then we’re saying, “Well, let’s add our daratumumab upfront, then let’s give everything forever.” Then it’s going to be a mishmash of what everybody is doing out there, and we won’t know where we are in terms of outcomes. So, my view is if we’re going to incorporate an antibody upfront, it’s short-term, long enough to get a good response and collect cells. I would still consolidate with a transplant and then think about what’s the maintenance strategy that doesn’t use all 4 drugs.

A. Keith Stewart, MB, ChB: OK, so we can see a little controversy. Let’s talk about maintenance just to close out this section. I think we’re all agreed that lenalidomide maintenance is accepted worldwide now as a beneficial thing to do. You said, Tom, you were enamored with daratumumab maintenance. You just said you don’t think we should use daratumumab maintenance, if I heard you correctly. So, let’s have at it here, which is, who’s right?

Thomas Martin, MD: So, I will start by saying that we have reviewed the patients who have had an autologous transplant at UCSF and then have gone on to lenalidomide maintenance, with the intent of them taking lenalidomide forever. And in fact, at 2 years, we have less than 50% of the people still on lenalidomide. I just think after a year, after 18 months, specifically after 24 months, it becomes challenging just because of the long-term side effects. Mostly it’s fatigue, diarrhea, GI side effects. And most people at that point of time want a break.

Monthly daratumumab is very convenient, we do it with bone-strengthening drugs. We do it so many that they come in monthly. Patients will come in for a monthly infusion. I actually think it’s going to be very well tolerated. Now whether it’s lenalidomide and daratumumab for 6 months or a year, and then on to daratumumab, etc, we have to test this in clinical trials. But I think we have a lot of room to improve on our strategy for maintenance-based therapy.

A. Keith Stewart, MB, ChB: But there, we probably shouldn’t call it maintenance therapy as opposed to continuous therapy.

Ajai Chari, MD: Correct. Agreed.

A. Keith Stewart, MB, ChB: Amrita, what do you think about maintenance therapy?

Amrita Krishnan, MD, FACP: I think Tom touched upon the point, and this is a trial that we’ve been working on with Ed through SWOG and the BMTCN, which is going to try and answer that very question, how long do you really need to give maintenance? Because I also agree with Sagar. I think we’re doing patients a disservice to just blindly say, “Continue it because it’s working.” And so, the SWOG trial is going to randomize patients to lenalidomide/daratumumab after transplant or to lenalidomide alone. And then at 2 years after maintenance, check MRD status and then do a second randomization so that if you’re MRD-negative, we will stop maintenance. So, I think it would be the first trial to really use MRD and ask the question, “Can you stop maintenance?”

A. Keith Stewart, MB, ChB: That sounds so incredibly logical, it seems like a good place to stop. So, that sounds like the perfect clinical trial to address this dilemma.

Transcript Edited for Clarity 
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