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Continuing IMiD Therapy after Myeloma Relapse

Panelists: Keith Stewart, MB, CHB, Mayo Clinic; Gareth Morgan, MD, PhD, University of Arkansas for Medical Science; Saad Z. Usmani, MD, Levine Cancer Institute/Carolinas Healthcare System; Ivan M. Borrello, MD, Johns Hopkins Kimmel Cancer Center; Thomas G. Martin, MD, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center; Sagar Lonial, MD, Winship Cancer Institute of Emory University
Published Online: Thursday, Jul 13, 2017



Transcript:

Keith Stewart, MB, ChB:
In all the trials where we have used lenalidomide-dexamethasone or bortezomib-dexamethasone, most of them include lenalidomide. So, a lot of our patients are taking lenalidomide. How would you deal with that challenge, Gareth, when you’re switching therapy?

Gareth Morgan, MD, PhD: My practice is just a little bit different, because we see a lot of younger patients and we’re treating them to CRs. They’re tending to relapse many years after they’ve come off the maintenance therapy, and so, in that setting, the choice of agents is less of a problem. We try and repeat the same sort of approach upfront—which is to induce and consider consolidation with transplant or nontransplant.

Keith Stewart, MB, ChB: Tom, how about you? If you’re patient is on lenalidomide and they’re progressing, and you’re a community physician, what do you advise them to do? Do you just up the dose of lenalidomide, or do you switch to pomalidomide? Or, do you go with cyclophosphamide?

Thomas G. Martin, MD: I agree with Sagar that if somebody is relapsing on lenalidomide, I don’t think going up to a higher dose of lenalidomide is going to get you a lot of distance. We switch to carfilzomib-based therapy, or switch to pomalidomide plus antibody-based therapy.

Keith Stewart, MB, ChB: Are toxicities the same for pomalidomide and lenalidomide? Is there any difference there?

Saad Z. Usmani, MD: I think that they’re fairly comparable. If anything, pomalidomide is, maybe, a little better tolerated than lenalidomide.

Keith Stewart, MB, ChB: There has been some thought that there is more neutropenia with daratumumab than pomalidomide. Have you seen that?

Saad Z. Usmani, MD: Yes. In general, just like Sagar, we used a lot of pomalidomide once that drug was approved for combination. We saw a lot of neutropenia. Then, we started to use 2 mg/m2 as the starting dose to see how patients would do with that first cycle. If they’re responding, that’s fine. If they’re not having optimal response, we can up the dose based on tolerability.

Keith Stewart, MB, ChB: There has been a trial called ENDEAVOR, in which carfilzomib-dexamethasone is compared with bortezomib-dexamethasone. Do you want to summarize the results of that for us, Ivan? Can you remember?

Ivan M. Borrello, MD: The carfilzomib arm, clearly did better than the bortezomib arm.

Keith Stewart, MB, ChB: It’s almost a doubling of PFS.

Ivan M. Borrello, MD: A doubling, yes.

Keith Stewart, MB, ChB: Would you consider using that in somebody who is intolerant of lenalidomide or the IMiDs? Would you ever consider using a doublet therapy like that?

Ivan M. Borrello, MD: I think you have to personalize the treatment to what the patient can tolerate, in addition to what the optimal therapy is. There are data to show that there is a benefit of that combination. Certainly, carfilzomib-lenalidomide is a reasonable one with dexamethasone, or without dexamethasone, depending upon the toxicities. And we certainly have used it with good results.

Keith Stewart, MB, ChB: Are there any other comments on doublet therapy with high doses of carfilzomib? I mean, these are double the standard dose.

Gareth Morgan, MD, PhD: Every study that’s been done comparing a triplet to a doublet has favored the triplet. The real question going forward is, can you go from a triplet to a quadruplet and maximize responses?

Keith Stewart, MB, ChB: But, Gareth, you’ve already pointed out there are some economic concerns in many countries.

Gareth Morgan, MD, PhD: Some of these agents are going to be going generic in the next few years, which frees up economic space to move towards these regimens.

Keith Stewart, MB, ChB: There are also people who just can’t take them. They get rash or neuropathy. What would you do for them? Would you always use bendamustine or cyclophosphamide?

Gareth Morgan, MD, PhD: You could go for a 3-drug regimen with daratumumab.

Sagar Lonial, MD: One way to think about that—if you’re trying to think about what to do if you’re trying to use a higher dose of carfilzomib and still use it in a triplet without an IMiD—would be to combine it with panobinostat. There are nice data from Dr. Jesus Berdeja, and there are a couple other trials, where you could do it on an every-other-week schedule so that you don’t get as much of the gastrointestinal toxicity that you got with bortezomib. That has pretty reasonable efficacy as well.

Thomas G. Martin, MD: You can do the panobinostat every other week with standard carfilzomib. It’s interesting with carfilzomib. I don’t know about in your practices, but for me, there are only 2 doses of carfilzomib. It’s either 60 mg/m2 or you’re giving them 2 vials—120 mg/m2. There’s no mg/m2, in my mind. There’s no 45 mg/m2. There’s no 56 mg/m2. You give them the whole vial.

Keith Stewart, MB, ChB: You’ve been off the reservation. I don’t disagree with you, but we should probably stick to the label dosing for these things. There is a bit of confusion about the dose though—I think that’s true. Most of us are using 36 mg/m2, or some equivalent to that. I want to come back to renal failure of patients. There has been some talk that you can’t use lenalidomide, and there has been a little bit of nervousness around using carfilzomib in those patients. What’s your take on that? Is pomalidomide safe to use there? Do you use carfilzomib with renal failure? Sagar, what do you do?

Sagar Lonial, MD: The advantage of both of the proteasome inhibitors is that they are renal function independent. I don’t have an issue using carfilzomib.

Keith Stewart, MB, ChB: The creatinine can go up if you use carfilzomib.

Sagar Lonial, MD: It can, but that doesn’t mean you don’t do it. It just means you watch it and you’re careful with it. With pomalidomide, there are actually data from a PrECOG study that suggests that unless the creatinine clearance is very low, you go with full dose pomalidomide—similar to what you do with thalidomide. So, I think there are ways to do it. I think with lenalidomide, from my view, until you know where the kidney function has stabilized, if it’s going up, then I’m a little hesitant to use it because chronic myelosuppression is really the issue. That limits your ability to continue them on therapy. But, if it’s a stable creatinine, then I’m comfortable using it at the recommended dose.

Keith Stewart, MB, ChB: Tom, we haven’t talked about ixazomib much. Are you finding a home for ixazomib? What’s the advantages of using it? This is an oral proteasome inhibitor.

Thomas G. Martin, MD: I think ixazomib is a very good exchange for bortezomib, so I use it in places where I would use bortezomib and it’s very convenient. It’s convenient to just give once-weekly dosing for 3 out of 4 weeks. So, yes, we have been using it. We’ve been using it in the maintenance setting.

Keith Stewart, MB, ChB: How about toxicity? Do you find upper gastrointestinal toxicity, or are you comfortable with it?

Thomas G. Martin, MD: I do think there’s more nausea and, perhaps, a little bit more rash, but the rash that patients get is not really bothersome, and it goes away over time. I haven’t found it hard to deal with, at all, really.

Keith Stewart, MB, ChB: To our other panelists, ixazomib—your thoughts or comments?

Ivan M. Borrello, MD: I have switched some patients that were on bortezomib to ixazomib, primarily people that were traveling several hours to come to see us. It’s interesting because in people with stable but detectable disease, once switching, I saw an increase in their disease burden. When putting them back on bortezomib, I saw that the disease burden came back down. I disagree, slightly, with what Tom said. I don’t think they’re actually equally exchangeable. Obviously, they’re the same class of drugs, but as upfront therapy, I would use bortezomib. I use ixazomib in the frail patient or the patient that has a stable disease—for whatever reason I want to use a proteasome inhibitor as maintenance therapy. And I think, there, ixazomib is a very good drug.

Keith Stewart, MB, ChB: In the randomized trial of ixazomib-lenalidomide versus lenalidomide, there was quite remarkable activity in the high-risk, p53-deleted patients. Do you buy into that?

Saad Z. Usmani, MD: When you’re looking at the comparator arms, I think RVd [lenalidomide, bortezomib, and dexamethasone] would probably give you a similar response when compared that to Rd [lenalidomide plus dexamethasone]. You could make the argument that a PI, IMiD combination may give you similar PFS benefit, but I don’t think it’s an ixazomib-specific effect.

Keith Stewart, MB, ChB: We talked about MRD in the frontline setting. Are people using MRD in relapsed disease, Sagar?

Sagar Lonial, MD: We’re not using it routinely.

Keith Stewart, MB, ChB: But we said that there’s all these MRD data with DRd [daratumumab plus lenalidomide and dexamethasone].

Sagar Lonial, MD: Right. I think that the data we saw from CASTOR and POLLUX were certainly the first data we’ve ever seen looking at MRD in the relapsed and refractory setting. If you take the 10-6 cutoff for both of those trials, clearly, the incidence was higher in the group that got daratumumab than the group that didn’t. But, you’re still on the order of about 10% of patients.

Keith Stewart, MB, ChB: It’s not so many.

Sagar Lonial, MD: Right.

Keith Stewart, MB, ChB: Tom, what are your thoughts on that?

Thomas G. Martin, MD: I agree. In the relapsed/refractory setting, we’re pretty much stuck doing it in the 1 to 3 prior lines of therapy, because you don’t really achieve enough CRs in those later lines of therapy. I would say the only thing that may blow that out of the water is what Gareth said earlier about CAR-T cells. Are we going to start seeing MRD-negative in CAR-T cells?

Keith Stewart, MB, ChB: I have to tell you, I still see patients who come in that are relapsing. They have CyBorD [cyclophosphamide, bortezomib and dexamethasone], transplant, or lenalidomide maintenance. I just tell them, “I think you had an effective therapy,” and that I’m going to re-treat them. I do tell them I’m going to aim for MRD-negativity with daratumumab and Kyprolis [carfilzomib].

Gareth Morgan, MD, PhD: I think we have the tools to do that. I think it was dangerous a few years ago, because you could give people a lot of side effects. But, the tools we have now are much better. And so, I think it’s a perfectly legitimate approach in relapsed and refractory disease.

Transcript Edited for Clarity

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Transcript:

Keith Stewart, MB, ChB:
In all the trials where we have used lenalidomide-dexamethasone or bortezomib-dexamethasone, most of them include lenalidomide. So, a lot of our patients are taking lenalidomide. How would you deal with that challenge, Gareth, when you’re switching therapy?

Gareth Morgan, MD, PhD: My practice is just a little bit different, because we see a lot of younger patients and we’re treating them to CRs. They’re tending to relapse many years after they’ve come off the maintenance therapy, and so, in that setting, the choice of agents is less of a problem. We try and repeat the same sort of approach upfront—which is to induce and consider consolidation with transplant or nontransplant.

Keith Stewart, MB, ChB: Tom, how about you? If you’re patient is on lenalidomide and they’re progressing, and you’re a community physician, what do you advise them to do? Do you just up the dose of lenalidomide, or do you switch to pomalidomide? Or, do you go with cyclophosphamide?

Thomas G. Martin, MD: I agree with Sagar that if somebody is relapsing on lenalidomide, I don’t think going up to a higher dose of lenalidomide is going to get you a lot of distance. We switch to carfilzomib-based therapy, or switch to pomalidomide plus antibody-based therapy.

Keith Stewart, MB, ChB: Are toxicities the same for pomalidomide and lenalidomide? Is there any difference there?

Saad Z. Usmani, MD: I think that they’re fairly comparable. If anything, pomalidomide is, maybe, a little better tolerated than lenalidomide.

Keith Stewart, MB, ChB: There has been some thought that there is more neutropenia with daratumumab than pomalidomide. Have you seen that?

Saad Z. Usmani, MD: Yes. In general, just like Sagar, we used a lot of pomalidomide once that drug was approved for combination. We saw a lot of neutropenia. Then, we started to use 2 mg/m2 as the starting dose to see how patients would do with that first cycle. If they’re responding, that’s fine. If they’re not having optimal response, we can up the dose based on tolerability.

Keith Stewart, MB, ChB: There has been a trial called ENDEAVOR, in which carfilzomib-dexamethasone is compared with bortezomib-dexamethasone. Do you want to summarize the results of that for us, Ivan? Can you remember?

Ivan M. Borrello, MD: The carfilzomib arm, clearly did better than the bortezomib arm.

Keith Stewart, MB, ChB: It’s almost a doubling of PFS.

Ivan M. Borrello, MD: A doubling, yes.

Keith Stewart, MB, ChB: Would you consider using that in somebody who is intolerant of lenalidomide or the IMiDs? Would you ever consider using a doublet therapy like that?

Ivan M. Borrello, MD: I think you have to personalize the treatment to what the patient can tolerate, in addition to what the optimal therapy is. There are data to show that there is a benefit of that combination. Certainly, carfilzomib-lenalidomide is a reasonable one with dexamethasone, or without dexamethasone, depending upon the toxicities. And we certainly have used it with good results.

Keith Stewart, MB, ChB: Are there any other comments on doublet therapy with high doses of carfilzomib? I mean, these are double the standard dose.

Gareth Morgan, MD, PhD: Every study that’s been done comparing a triplet to a doublet has favored the triplet. The real question going forward is, can you go from a triplet to a quadruplet and maximize responses?

Keith Stewart, MB, ChB: But, Gareth, you’ve already pointed out there are some economic concerns in many countries.

Gareth Morgan, MD, PhD: Some of these agents are going to be going generic in the next few years, which frees up economic space to move towards these regimens.

Keith Stewart, MB, ChB: There are also people who just can’t take them. They get rash or neuropathy. What would you do for them? Would you always use bendamustine or cyclophosphamide?

Gareth Morgan, MD, PhD: You could go for a 3-drug regimen with daratumumab.

Sagar Lonial, MD: One way to think about that—if you’re trying to think about what to do if you’re trying to use a higher dose of carfilzomib and still use it in a triplet without an IMiD—would be to combine it with panobinostat. There are nice data from Dr. Jesus Berdeja, and there are a couple other trials, where you could do it on an every-other-week schedule so that you don’t get as much of the gastrointestinal toxicity that you got with bortezomib. That has pretty reasonable efficacy as well.

Thomas G. Martin, MD: You can do the panobinostat every other week with standard carfilzomib. It’s interesting with carfilzomib. I don’t know about in your practices, but for me, there are only 2 doses of carfilzomib. It’s either 60 mg/m2 or you’re giving them 2 vials—120 mg/m2. There’s no mg/m2, in my mind. There’s no 45 mg/m2. There’s no 56 mg/m2. You give them the whole vial.

Keith Stewart, MB, ChB: You’ve been off the reservation. I don’t disagree with you, but we should probably stick to the label dosing for these things. There is a bit of confusion about the dose though—I think that’s true. Most of us are using 36 mg/m2, or some equivalent to that. I want to come back to renal failure of patients. There has been some talk that you can’t use lenalidomide, and there has been a little bit of nervousness around using carfilzomib in those patients. What’s your take on that? Is pomalidomide safe to use there? Do you use carfilzomib with renal failure? Sagar, what do you do?

Sagar Lonial, MD: The advantage of both of the proteasome inhibitors is that they are renal function independent. I don’t have an issue using carfilzomib.

Keith Stewart, MB, ChB: The creatinine can go up if you use carfilzomib.

Sagar Lonial, MD: It can, but that doesn’t mean you don’t do it. It just means you watch it and you’re careful with it. With pomalidomide, there are actually data from a PrECOG study that suggests that unless the creatinine clearance is very low, you go with full dose pomalidomide—similar to what you do with thalidomide. So, I think there are ways to do it. I think with lenalidomide, from my view, until you know where the kidney function has stabilized, if it’s going up, then I’m a little hesitant to use it because chronic myelosuppression is really the issue. That limits your ability to continue them on therapy. But, if it’s a stable creatinine, then I’m comfortable using it at the recommended dose.

Keith Stewart, MB, ChB: Tom, we haven’t talked about ixazomib much. Are you finding a home for ixazomib? What’s the advantages of using it? This is an oral proteasome inhibitor.

Thomas G. Martin, MD: I think ixazomib is a very good exchange for bortezomib, so I use it in places where I would use bortezomib and it’s very convenient. It’s convenient to just give once-weekly dosing for 3 out of 4 weeks. So, yes, we have been using it. We’ve been using it in the maintenance setting.

Keith Stewart, MB, ChB: How about toxicity? Do you find upper gastrointestinal toxicity, or are you comfortable with it?

Thomas G. Martin, MD: I do think there’s more nausea and, perhaps, a little bit more rash, but the rash that patients get is not really bothersome, and it goes away over time. I haven’t found it hard to deal with, at all, really.

Keith Stewart, MB, ChB: To our other panelists, ixazomib—your thoughts or comments?

Ivan M. Borrello, MD: I have switched some patients that were on bortezomib to ixazomib, primarily people that were traveling several hours to come to see us. It’s interesting because in people with stable but detectable disease, once switching, I saw an increase in their disease burden. When putting them back on bortezomib, I saw that the disease burden came back down. I disagree, slightly, with what Tom said. I don’t think they’re actually equally exchangeable. Obviously, they’re the same class of drugs, but as upfront therapy, I would use bortezomib. I use ixazomib in the frail patient or the patient that has a stable disease—for whatever reason I want to use a proteasome inhibitor as maintenance therapy. And I think, there, ixazomib is a very good drug.

Keith Stewart, MB, ChB: In the randomized trial of ixazomib-lenalidomide versus lenalidomide, there was quite remarkable activity in the high-risk, p53-deleted patients. Do you buy into that?

Saad Z. Usmani, MD: When you’re looking at the comparator arms, I think RVd [lenalidomide, bortezomib, and dexamethasone] would probably give you a similar response when compared that to Rd [lenalidomide plus dexamethasone]. You could make the argument that a PI, IMiD combination may give you similar PFS benefit, but I don’t think it’s an ixazomib-specific effect.

Keith Stewart, MB, ChB: We talked about MRD in the frontline setting. Are people using MRD in relapsed disease, Sagar?

Sagar Lonial, MD: We’re not using it routinely.

Keith Stewart, MB, ChB: But we said that there’s all these MRD data with DRd [daratumumab plus lenalidomide and dexamethasone].

Sagar Lonial, MD: Right. I think that the data we saw from CASTOR and POLLUX were certainly the first data we’ve ever seen looking at MRD in the relapsed and refractory setting. If you take the 10-6 cutoff for both of those trials, clearly, the incidence was higher in the group that got daratumumab than the group that didn’t. But, you’re still on the order of about 10% of patients.

Keith Stewart, MB, ChB: It’s not so many.

Sagar Lonial, MD: Right.

Keith Stewart, MB, ChB: Tom, what are your thoughts on that?

Thomas G. Martin, MD: I agree. In the relapsed/refractory setting, we’re pretty much stuck doing it in the 1 to 3 prior lines of therapy, because you don’t really achieve enough CRs in those later lines of therapy. I would say the only thing that may blow that out of the water is what Gareth said earlier about CAR-T cells. Are we going to start seeing MRD-negative in CAR-T cells?

Keith Stewart, MB, ChB: I have to tell you, I still see patients who come in that are relapsing. They have CyBorD [cyclophosphamide, bortezomib and dexamethasone], transplant, or lenalidomide maintenance. I just tell them, “I think you had an effective therapy,” and that I’m going to re-treat them. I do tell them I’m going to aim for MRD-negativity with daratumumab and Kyprolis [carfilzomib].

Gareth Morgan, MD, PhD: I think we have the tools to do that. I think it was dangerous a few years ago, because you could give people a lot of side effects. But, the tools we have now are much better. And so, I think it’s a perfectly legitimate approach in relapsed and refractory disease.

Transcript Edited for Clarity
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