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Choosing Triplet Therapy at Myeloma Relapse

Panelists: Keith Stewart, MB, CHB, Mayo Clinic; Sagar Lonial, MD, Winship Cancer Institute; Paul Richardson, MD, Dana-Farber Cancer Institute; Amrita Krishnan, MD, City of Hope Comprehensive Cancer Center; Saad Usmani, MD, Levine Cancer Institute
Published Online: Wednesday, Feb 15, 2017



Transcript:

Keith Stewart, MB, CHB:
We have 5 other trials that revealed that triplet therapies were superior to doublets. These include carfilzomib, elotuzumab, panobinostat, and ixazomib. They’re all approved in first relapse, essentially. How do we choose between these, Amrita? And now with daratumumab, it’s a nice thing to have choice, but how do we make these choices? Let’s talk about carfilzomib to start with. Where does that fit in there?

Amrita Krishnan, MD: I think the water has become more muddy now that daratumumab got an approval for earlier in the course of therapy. I think there are 2 situations. First, there’s real world—real life. For example, in the community, there is still a challenge to give daratumumab in terms of the infusion time. For patients, that’s a challenge. That will change with, for example, the subcutaneous formulation. We hope to see more data on that. Otherwise, I think it’s about looking at the individualized patient. Comorbidities, clearly, are a big issue. I think all of us will take patient preference strongly into account, as well as the type of relapse, obviously. In someone who has a more indolent relapse, I’d be more comfortable using ixazomib in a combination versus in someone who has a very aggressive relapse.

Keith Stewart, MB, CHB: Sagar?

Sagar Lonial, MD: I think our dominant go-to for the average patient has become a daratumumab-based approach—typically with an immunomodulatory drug (IMiD). We find that carfilzomib probably partners better with panobinostat than many of the other drugs that we have. So, we tend to use it in that situation.

Keith Stewart, MB, CHB: I was at a meeting last night with some colleagues, too, who are sticking with carfilzomib and are saving daratumumab because, I think, they’re comfortable with that regimen—carfilzomib/lenalidomide. Is everybody going to go to daratumumab first? I guess the question really is, Paul, is it one or the other, or is it both?

Paul Richardson, MD: It’s a great question. I’m going to say something that may be a left-field response. We’ve also been very pleased with elotuzumab, and I’m using that in early relapse because we need to keep things in reserve. The other thing is that I have had patients in whom daratumumab has failed, and we’ve gone on to elotuzumab-based combinations and seen response. Again, anecdotal. But, have you seen the same, Sagar?

Sagar Lonial, MD: Absolutely.

Paul Richardson, MD: The point is we have to be very clear to our audience that we’ve got these choices but it’s not a zero-sum game. We need them all. I personally am getting much more comfortable with carfilzomib and pomalidomide, combined. I use that as a go-to after lenalidomide failure.

Keith Stewart, MB, CHB: That’s also our first-line option.

Paul Richardson, MD: Absolutely. My only caution with carfilzomib/pomalidomide to daratumumab is the CD38 issue, because, of course, it’s expressed on activated endothelium. So, we just need to be a little careful.

Keith Stewart, MB, CHB: We should be clear that that has not really been studied very heavily in any studies. It’s not proven.

Paul Richardson, MD: Exactly. I think we need to just proceed with a little bit of caution, because vascular toxicity is sort of a favorite interest of mine—but it’s relevant. Having said that, I’ve certainly used 3 or 4 drug combinations with carfilzomib/pomalidomide/daratumumab off-protocol, and we’ve seen great responses. So, I think it’s very much a series of options that you can adapt to your patient.

Keith Stewart, MB, CHB: Saad, who are you using ixazomib/lenalidomide/dexamethasone in? Or ixazomib/pomalidomide/dexamethasone, for that matter?

Saad Usmani, MD: In patients who either have access issues, are coming a little ways (in distance), or patients who are elderly but you feel that they need an IMiD/proteasome inhibitor-based combination to salvage them. Many times, these patients are not florid relapse patients, so those are the situations where you can potentially use an oral agent.

Keith Stewart, MB, CHB: You think the tempo of relapse is important as well?

Saad Usmani, MD: Yes.

Sagar Lonial, MD: I think Amrita does have very nice data, as well, on ixazomib plus pomalidomide—as you brought up as a highly active regimen.

Paul Richardson, MD: I would echo that. Those really are nice data, Amrita. Congratulations on it. It also echoes Dr. Peter Voorhees’s work in the Alliance, which is very similar. One last point, Keith, if I may, is that we’ve also had great luck with the pomalidomide/bortezomib/dexamethasone/daratumumab platform. It’s very well tolerated and very active. We’ve done that off-protocol, but we have done that for very high-risk, aggressive relapses in patients in whom you’ve got to get a quick cytoreduction.

Keith Stewart, MB, CHB: It sounds like all of us are using quite a bit of pomalidomide in these patients because they’ve had lenalidomide before. Can you use pomalidomide in renal failure? What side effects do you worry about?

Sagar Lonial, MD: I think that structurally, the IMiDs are all sort of similar. But, we know that in terms of their disposition, pomalidomide acts more like thalidomide than it does lenalidomide. So, it can be used at full dose, except in the context, perhaps, of dialysis where you should reduce to 3 mg. But, in general, it’s actually a very nice drug to give in advanced disease.

Keith Stewart, MB, CHB: Any thoughts on pomalidomide, Amrita? Are you using a lot of it?

Amrita Krishnan, MD: I agree with Sagar. We use a lot of it. I do think we see more myelosuppression than with lenalidomide, but I think it’s an extremely active drug and it really has become our go-to backbone with everything else. Keith Stewart, MB, CHB: Paul, you’ve been involved quite heavily with panobinostat. Any thoughts of where that’s fitting in with today’s therapies?

Paul Richardson, MD: My colleague, Dr. Jacob Laubach, led a RVD (Revlimid/Velcade/dexamethasone)/panobinostat study, and it’s really interesting. We’ve actually seen quad-refractory and penta-refractory patients benefit from it. So I’m a firm believer—and Sagar, too—in the HDAC (histone deacetylase) platform. And so are you, Keith. We really do think there’s activity from this class of drugs, and we found that panobinostat, combined with IMiDs, is well tolerated. Panobinostat, combined with the proteasome inhibitor backbones is well tolerated, and, of course, there are next-generation HDACs that are showing great promise.

Amrita Krishnan, MD: I don’t know if you want to mention, Paul, that there’s an abstract from the 2016 ASH Annual Meeting that suggests that panobinostat can increase CD38 expression, which makes you very curious about panobinostat/daratumumab.

Paul Richardson, MD: Absolutely, I agree.

Keith Stewart, MB, CHB: Very good. Any other thoughts on treating relapsed disease? You said you’re going to go to daratumumab at first relapse before ixazomib?

Sagar Lonial, MD: Yes. What the partner is going to do may vary, but I think daratumumab is getting used, increasingly, in first relapse.

Transcript Edited for Clarity

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Transcript:

Keith Stewart, MB, CHB:
We have 5 other trials that revealed that triplet therapies were superior to doublets. These include carfilzomib, elotuzumab, panobinostat, and ixazomib. They’re all approved in first relapse, essentially. How do we choose between these, Amrita? And now with daratumumab, it’s a nice thing to have choice, but how do we make these choices? Let’s talk about carfilzomib to start with. Where does that fit in there?

Amrita Krishnan, MD: I think the water has become more muddy now that daratumumab got an approval for earlier in the course of therapy. I think there are 2 situations. First, there’s real world—real life. For example, in the community, there is still a challenge to give daratumumab in terms of the infusion time. For patients, that’s a challenge. That will change with, for example, the subcutaneous formulation. We hope to see more data on that. Otherwise, I think it’s about looking at the individualized patient. Comorbidities, clearly, are a big issue. I think all of us will take patient preference strongly into account, as well as the type of relapse, obviously. In someone who has a more indolent relapse, I’d be more comfortable using ixazomib in a combination versus in someone who has a very aggressive relapse.

Keith Stewart, MB, CHB: Sagar?

Sagar Lonial, MD: I think our dominant go-to for the average patient has become a daratumumab-based approach—typically with an immunomodulatory drug (IMiD). We find that carfilzomib probably partners better with panobinostat than many of the other drugs that we have. So, we tend to use it in that situation.

Keith Stewart, MB, CHB: I was at a meeting last night with some colleagues, too, who are sticking with carfilzomib and are saving daratumumab because, I think, they’re comfortable with that regimen—carfilzomib/lenalidomide. Is everybody going to go to daratumumab first? I guess the question really is, Paul, is it one or the other, or is it both?

Paul Richardson, MD: It’s a great question. I’m going to say something that may be a left-field response. We’ve also been very pleased with elotuzumab, and I’m using that in early relapse because we need to keep things in reserve. The other thing is that I have had patients in whom daratumumab has failed, and we’ve gone on to elotuzumab-based combinations and seen response. Again, anecdotal. But, have you seen the same, Sagar?

Sagar Lonial, MD: Absolutely.

Paul Richardson, MD: The point is we have to be very clear to our audience that we’ve got these choices but it’s not a zero-sum game. We need them all. I personally am getting much more comfortable with carfilzomib and pomalidomide, combined. I use that as a go-to after lenalidomide failure.

Keith Stewart, MB, CHB: That’s also our first-line option.

Paul Richardson, MD: Absolutely. My only caution with carfilzomib/pomalidomide to daratumumab is the CD38 issue, because, of course, it’s expressed on activated endothelium. So, we just need to be a little careful.

Keith Stewart, MB, CHB: We should be clear that that has not really been studied very heavily in any studies. It’s not proven.

Paul Richardson, MD: Exactly. I think we need to just proceed with a little bit of caution, because vascular toxicity is sort of a favorite interest of mine—but it’s relevant. Having said that, I’ve certainly used 3 or 4 drug combinations with carfilzomib/pomalidomide/daratumumab off-protocol, and we’ve seen great responses. So, I think it’s very much a series of options that you can adapt to your patient.

Keith Stewart, MB, CHB: Saad, who are you using ixazomib/lenalidomide/dexamethasone in? Or ixazomib/pomalidomide/dexamethasone, for that matter?

Saad Usmani, MD: In patients who either have access issues, are coming a little ways (in distance), or patients who are elderly but you feel that they need an IMiD/proteasome inhibitor-based combination to salvage them. Many times, these patients are not florid relapse patients, so those are the situations where you can potentially use an oral agent.

Keith Stewart, MB, CHB: You think the tempo of relapse is important as well?

Saad Usmani, MD: Yes.

Sagar Lonial, MD: I think Amrita does have very nice data, as well, on ixazomib plus pomalidomide—as you brought up as a highly active regimen.

Paul Richardson, MD: I would echo that. Those really are nice data, Amrita. Congratulations on it. It also echoes Dr. Peter Voorhees’s work in the Alliance, which is very similar. One last point, Keith, if I may, is that we’ve also had great luck with the pomalidomide/bortezomib/dexamethasone/daratumumab platform. It’s very well tolerated and very active. We’ve done that off-protocol, but we have done that for very high-risk, aggressive relapses in patients in whom you’ve got to get a quick cytoreduction.

Keith Stewart, MB, CHB: It sounds like all of us are using quite a bit of pomalidomide in these patients because they’ve had lenalidomide before. Can you use pomalidomide in renal failure? What side effects do you worry about?

Sagar Lonial, MD: I think that structurally, the IMiDs are all sort of similar. But, we know that in terms of their disposition, pomalidomide acts more like thalidomide than it does lenalidomide. So, it can be used at full dose, except in the context, perhaps, of dialysis where you should reduce to 3 mg. But, in general, it’s actually a very nice drug to give in advanced disease.

Keith Stewart, MB, CHB: Any thoughts on pomalidomide, Amrita? Are you using a lot of it?

Amrita Krishnan, MD: I agree with Sagar. We use a lot of it. I do think we see more myelosuppression than with lenalidomide, but I think it’s an extremely active drug and it really has become our go-to backbone with everything else. Keith Stewart, MB, CHB: Paul, you’ve been involved quite heavily with panobinostat. Any thoughts of where that’s fitting in with today’s therapies?

Paul Richardson, MD: My colleague, Dr. Jacob Laubach, led a RVD (Revlimid/Velcade/dexamethasone)/panobinostat study, and it’s really interesting. We’ve actually seen quad-refractory and penta-refractory patients benefit from it. So I’m a firm believer—and Sagar, too—in the HDAC (histone deacetylase) platform. And so are you, Keith. We really do think there’s activity from this class of drugs, and we found that panobinostat, combined with IMiDs, is well tolerated. Panobinostat, combined with the proteasome inhibitor backbones is well tolerated, and, of course, there are next-generation HDACs that are showing great promise.

Amrita Krishnan, MD: I don’t know if you want to mention, Paul, that there’s an abstract from the 2016 ASH Annual Meeting that suggests that panobinostat can increase CD38 expression, which makes you very curious about panobinostat/daratumumab.

Paul Richardson, MD: Absolutely, I agree.

Keith Stewart, MB, CHB: Very good. Any other thoughts on treating relapsed disease? You said you’re going to go to daratumumab at first relapse before ixazomib?

Sagar Lonial, MD: Yes. What the partner is going to do may vary, but I think daratumumab is getting used, increasingly, in first relapse.

Transcript Edited for Clarity
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