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Daratumumab-Based Regimens in R/R Myeloma

Panelists: A. Keith Stewart, MB, ChB, Mayo Clinic; Cristina Gasparetto, MD, Duke University Medical Center; Parameswaran Hari, MD, MRCP, MS, Medical College of Wisconsin; Robert Orlowski, MD, PhD, MD Anderson Cancer Center; Noopur Suresh Raje, MD, Massachusetts General Hospital
Published: Tuesday, Feb 13, 2018



Transcript: 

A. Keith Stewart, MB, ChB: Let’s move on to relapsed myeloma. Unfortunately, this remains a chronic relapsing disease, and we have to face reality that many of our patients will relapse despite triple therapy, transplant, and prolonged maintenance. How is the availability of daratumumab changing your approach? Christina, how are you using that drug?

Cristina Gasparetto, MD: Yes. I think it’s my first drug—combination, of course—in first relapse. We do have the data from the CASTOR and the POLLUX trials. They look great, with a huge number of patients achieving very deep responses in the first relapse, which is amazing. We have never seen it before.

A. Keith Stewart, MB, ChB: So, just for the audience, CASTOR was bortezomib/daratumumab/dexamethasone.

Cristina Gasparetto, MD: Bortezomib/daratumumab/dexamethasone.

A. Keith Stewart, MB, ChB: Against?

Cristina Gasparetto, MD: Bortezomib and dexamethasone.

A. Keith Stewart, MB, ChB: And what was the POLLUX trial?

Cristina Gasparetto, MD: Daratumumab with lenalidomide/dexamethasone compared to lenalidomide/dexamethasone. And so, we do have strong data, also updated here at this ASH meeting, showing 26% of patients achieving MRD in first relapse, and it looks like that will translate with the longer duration of response. And daratumumab is definitely improving the depth of response…

A. Keith Stewart, MB, ChB: So, maybe I’ll turn this one to Bob. A lot of us have been using carfilzomib at first relapse. Are you using daratumumab or carfilzomib, or how do you decide which?

Robert Orlowski, MD, PhD: Because many of these folks who relapse after frontline therapy are on some kind of lenalidomide-containing maintenance. What we’ve been very frequently doing is pomalidomide with daratumumab, especially if people have really rapidly progressive disease. I think if you have a small biochemical progression, you could even argue maybe not to do daratumumab and just add a little bit of steroid or up the dose of the lenalidomide a little bit. But if you have clinical progression or rapid biochemical progression, I like to use 2 new drugs. And so, I do use daratumumab with pomalidomide, and you can use daratumumab with carfilzomib as well, although it’s not FDA approved. So, that’s a good combination. And then finally, carfilzomib with pomalidomide and dexamethasone is another good regimen.

A. Keith Stewart, MB, ChB: So, forced to make a decision. Is it patient specific or do you have your favorite?

Robert Orlowski, MD, PhD: I would say my favorite is probably daratumumab with pomalidomide and dexamethasone, in part because since it has FDA approval, it’s a little bit easier to get approved from an insurance perspective. But I’m equally comfortable with carfilzomib, pomalidomide, and dexamethasone.

A. Keith Stewart, MB, ChB: OK, let’s hear from the others. Noopur?

Noopur Suresh Raje, MD: I use either or, and I do think it’s really patient dependent also. And when you’re talking about relapses, so many factors come into play. I think it’s important to try and appreciate how long a patient has been on lenalidomide maintenance. Somebody who has been on lenalidomide maintenance for 4 years, I’m not going to jump to a daratumumab-based regimen right away. Somebody who’s relapsing within 2 years of a transplant has a much more aggressive relapse. And those are the kind of factors that help you decide one over the other.

A. Keith Stewart, MB, ChB: Is everybody using pomalidomide in a patient who has been on lenalidomide maintenance or is anybody increasing the lenalidomide dose?

Parameswaran Hari, MD, MRCP, MS: There’s a lot of nuance to treating relapse, as you very well know. So, for me, the only study that now has shown a triplet showing survival advantage is your study, Keith, of the ASPIRE data that are now being presented at the meeting with overall survival advantage now for…

A. Keith Stewart, MB, ChB: And for the audience, the ASPIRE trial is?

Parameswaran Hari, MD, MRCP, MS: The ASPIRE trial was this large randomized study headed by our host, Dr. Stewart, comparing lenalidomide/dexamethasone versus carfilzomib/lenalidomide/dexamethasone for early relapse of myeloma. And now this study has an overall survival advantage for the triplet with carfilzomib/lenalidomide/dexamethasone. So, for me, a carfilzomib-based regimen versus a daratumumab regimen is the backbone, as we just discussed. For patients who have been on a very low dose of lenalidomide and are just progressing, I usually go up on the lenalidomide and add carfilzomib in. But for patients who have a rapid progression and prior proteasome inhibitor exposure, I’m with Bob and try to go with daratumumab there.

A. Keith Stewart, MB, ChB: In patients who are a bit older, carfilzomib could be a little bit more challenging. What is your regimen of choice, Bob, in an elderly patient who’s relapsing? Would it still be daratumumab-based?

Robert Orlowski, MD, PhD: I think daratumumab/pomalidomide/dexamethasone is a good agent or combination for those folks, and with, hopefully soon, the ability to give daratumumab subcutaneously, which seems to be even better tolerated, that would be a good regimen. And then ixazomib with pomalidomide and dexamethasone, although another one of those not yet FDA-approved combinations, but that can be very effective as well.

A. Keith Stewart, MB, ChB: We’ll come back to elotuzumab and ixazomib in a minute. But since we’re on pomalidomide, there was one abstract that caught my attention in which the incidence of deep venous thrombosis—in a very large study from the United Kingdom—was quite high, about 10%. And compliance of the treating physician with recommended guidelines wasn’t very good. So, Christina, what do you tell your patients about blood clots and using immune-modulating drugs?

Cristina Gasparetto, MD: Yes. In that abstract you’re referring to, the incidence was quite high, particularly during induction therapy, and they noticed the incidence was higher on patients that they are deemed to be at high risk of that. But despite that, they were only on aspirin, so I think we have to be cautious about these and maybe be more aggressive, particularly in the induction of patients with high risk.

A. Keith Stewart, MB, ChB: So, aspirin for most but the high risk.

Cristina Gasparetto, MD: Yes, right, we may need to select these patients. I think that was the message, that we have to go back to a more aggressive, more sustainable anticoagulation load.

A. Keith Stewart, MB, ChB: So, fully anticoagulate them.

Noopur Suresh Raje, MD: I think the point of that study, though, also is it was chemotherapy with an IMiD, Cytoxan-based treatment, and that’s maybe why the risk was a little bit higher there. So, we don’t necessarily see the same risk in a PI/IMiD-based combination.

A. Keith Stewart, MB, ChB: I’m glad you mentioned Cytoxan. We often forget to talk about that in these sessions, but it’s still a very useful drug in combination in many of these patients.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: Let’s move on to relapsed myeloma. Unfortunately, this remains a chronic relapsing disease, and we have to face reality that many of our patients will relapse despite triple therapy, transplant, and prolonged maintenance. How is the availability of daratumumab changing your approach? Christina, how are you using that drug?

Cristina Gasparetto, MD: Yes. I think it’s my first drug—combination, of course—in first relapse. We do have the data from the CASTOR and the POLLUX trials. They look great, with a huge number of patients achieving very deep responses in the first relapse, which is amazing. We have never seen it before.

A. Keith Stewart, MB, ChB: So, just for the audience, CASTOR was bortezomib/daratumumab/dexamethasone.

Cristina Gasparetto, MD: Bortezomib/daratumumab/dexamethasone.

A. Keith Stewart, MB, ChB: Against?

Cristina Gasparetto, MD: Bortezomib and dexamethasone.

A. Keith Stewart, MB, ChB: And what was the POLLUX trial?

Cristina Gasparetto, MD: Daratumumab with lenalidomide/dexamethasone compared to lenalidomide/dexamethasone. And so, we do have strong data, also updated here at this ASH meeting, showing 26% of patients achieving MRD in first relapse, and it looks like that will translate with the longer duration of response. And daratumumab is definitely improving the depth of response…

A. Keith Stewart, MB, ChB: So, maybe I’ll turn this one to Bob. A lot of us have been using carfilzomib at first relapse. Are you using daratumumab or carfilzomib, or how do you decide which?

Robert Orlowski, MD, PhD: Because many of these folks who relapse after frontline therapy are on some kind of lenalidomide-containing maintenance. What we’ve been very frequently doing is pomalidomide with daratumumab, especially if people have really rapidly progressive disease. I think if you have a small biochemical progression, you could even argue maybe not to do daratumumab and just add a little bit of steroid or up the dose of the lenalidomide a little bit. But if you have clinical progression or rapid biochemical progression, I like to use 2 new drugs. And so, I do use daratumumab with pomalidomide, and you can use daratumumab with carfilzomib as well, although it’s not FDA approved. So, that’s a good combination. And then finally, carfilzomib with pomalidomide and dexamethasone is another good regimen.

A. Keith Stewart, MB, ChB: So, forced to make a decision. Is it patient specific or do you have your favorite?

Robert Orlowski, MD, PhD: I would say my favorite is probably daratumumab with pomalidomide and dexamethasone, in part because since it has FDA approval, it’s a little bit easier to get approved from an insurance perspective. But I’m equally comfortable with carfilzomib, pomalidomide, and dexamethasone.

A. Keith Stewart, MB, ChB: OK, let’s hear from the others. Noopur?

Noopur Suresh Raje, MD: I use either or, and I do think it’s really patient dependent also. And when you’re talking about relapses, so many factors come into play. I think it’s important to try and appreciate how long a patient has been on lenalidomide maintenance. Somebody who has been on lenalidomide maintenance for 4 years, I’m not going to jump to a daratumumab-based regimen right away. Somebody who’s relapsing within 2 years of a transplant has a much more aggressive relapse. And those are the kind of factors that help you decide one over the other.

A. Keith Stewart, MB, ChB: Is everybody using pomalidomide in a patient who has been on lenalidomide maintenance or is anybody increasing the lenalidomide dose?

Parameswaran Hari, MD, MRCP, MS: There’s a lot of nuance to treating relapse, as you very well know. So, for me, the only study that now has shown a triplet showing survival advantage is your study, Keith, of the ASPIRE data that are now being presented at the meeting with overall survival advantage now for…

A. Keith Stewart, MB, ChB: And for the audience, the ASPIRE trial is?

Parameswaran Hari, MD, MRCP, MS: The ASPIRE trial was this large randomized study headed by our host, Dr. Stewart, comparing lenalidomide/dexamethasone versus carfilzomib/lenalidomide/dexamethasone for early relapse of myeloma. And now this study has an overall survival advantage for the triplet with carfilzomib/lenalidomide/dexamethasone. So, for me, a carfilzomib-based regimen versus a daratumumab regimen is the backbone, as we just discussed. For patients who have been on a very low dose of lenalidomide and are just progressing, I usually go up on the lenalidomide and add carfilzomib in. But for patients who have a rapid progression and prior proteasome inhibitor exposure, I’m with Bob and try to go with daratumumab there.

A. Keith Stewart, MB, ChB: In patients who are a bit older, carfilzomib could be a little bit more challenging. What is your regimen of choice, Bob, in an elderly patient who’s relapsing? Would it still be daratumumab-based?

Robert Orlowski, MD, PhD: I think daratumumab/pomalidomide/dexamethasone is a good agent or combination for those folks, and with, hopefully soon, the ability to give daratumumab subcutaneously, which seems to be even better tolerated, that would be a good regimen. And then ixazomib with pomalidomide and dexamethasone, although another one of those not yet FDA-approved combinations, but that can be very effective as well.

A. Keith Stewart, MB, ChB: We’ll come back to elotuzumab and ixazomib in a minute. But since we’re on pomalidomide, there was one abstract that caught my attention in which the incidence of deep venous thrombosis—in a very large study from the United Kingdom—was quite high, about 10%. And compliance of the treating physician with recommended guidelines wasn’t very good. So, Christina, what do you tell your patients about blood clots and using immune-modulating drugs?

Cristina Gasparetto, MD: Yes. In that abstract you’re referring to, the incidence was quite high, particularly during induction therapy, and they noticed the incidence was higher on patients that they are deemed to be at high risk of that. But despite that, they were only on aspirin, so I think we have to be cautious about these and maybe be more aggressive, particularly in the induction of patients with high risk.

A. Keith Stewart, MB, ChB: So, aspirin for most but the high risk.

Cristina Gasparetto, MD: Yes, right, we may need to select these patients. I think that was the message, that we have to go back to a more aggressive, more sustainable anticoagulation load.

A. Keith Stewart, MB, ChB: So, fully anticoagulate them.

Noopur Suresh Raje, MD: I think the point of that study, though, also is it was chemotherapy with an IMiD, Cytoxan-based treatment, and that’s maybe why the risk was a little bit higher there. So, we don’t necessarily see the same risk in a PI/IMiD-based combination.

A. Keith Stewart, MB, ChB: I’m glad you mentioned Cytoxan. We often forget to talk about that in these sessions, but it’s still a very useful drug in combination in many of these patients.

Transcript Edited for Clarity 
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