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Adding Carfilzomib to R/R Myeloma Regimens

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: Wednesday, Feb 21, 2018



Transcript: 

A. Keith Stewart, MB, ChB: Let’s talk about the carfilzomib trial that Hari alluded to earlier, which shows an overall survival advantage. There was a doublet regimen with higher doses of carfilzomib in the trial called the ENDEAVOR trial. Bob, I think you might have been involved with that. That also showed an advantage to that versus bortezomib. Is anybody using carfilzomib with dexamethasone alone at relapse or is this a triplet crowd here? Anybody?

Robert Orlowski, MD, PhD: Probably a triplet crowd.

Noopur Suresh Raje, MD: Part of the reason why I think we are using triplets is we’re starting out by using triplets at the beginning. And if you think about relapse, they’re becoming more genetically complex. So, then going back to a doublet is almost going backwards, I think, except there is a toxicity issue. Of course, we will use a doublet in that situation.

A. Keith Stewart, MB, ChB: What about non-IMiD-containing regimens? There was an abstract here from the United Kingdom that looked at cyclophosphamide with carfilzomib, which I thought had really quite impressive results. I don’t know if anybody has had a chance to review that in any detail. Does anybody use that regimen at relapse? Bob, I’ll pick on you again.

Robert Orlowski, MD, PhD: Yes, I think alkylating agents are certainly reasonable to use at the time of relapse. Cyclophosphamide is a good partner. We’ve also done bendamustine with carfilzomib, and it works quite well. I think the major concern, of course, is that you can’t keep people on it for too long because you run into myelosuppression and then you may compromise what they can do next. Because if they continue to have myelosuppression, their counts are not good enough for clinical trials.

A. Keith Stewart, MB, ChB: I guess I’m a bit of a fan of carfilzomib/cyclophosphamide, particularly when you’ve been on lenalidomide and you’re progressing. Sometimes the notion of going to a second immune modulator versus switching therapy completely doesn’t sit well with me. Anybody?

Noopur Suresh Raje, MD: I tend to use carfilzomib/Cytoxan/dexamethasone quite a lot. Specifically, in those extramedullary aggressive patients, it works quite well.

A. Keith Stewart, MB, ChB: Now, we haven’t addressed toxicity of any of the drugs so far. Let’s talk about carfilzomib since we’re on that topic. What’s your latest thinking on the tolerability of carfilzomib, Hari?

Parameswaran Hari, MD, MRCP, MS: I find it actually extremely well tolerated, provided you pick the right patient and the right dose. So, we talked about the variety of KRd regimens and KCd regimens. So, the 20/27-mg dose is generally well tolerated, and once you go up to 36 mg, which is the dose that’s being tested in the ECOG trial that Noopur alluded to with IMiDs, that again is relatively well tolerated by newly diagnosed patients. But once you go up to the 56-mg and the 70-mg doses, then the tolerability becomes an issue. I find a lot of endothelial toxicities, such as hypertension and atrial fibrillation. And picking the right patient is the most important thing, in my opinion, in practice for the practicing oncologist. For an elderly patient, I would always start at the lower dose and titrate up as required and be very quick to reduce the dose if measuring their blood pressures when they show up for treatment.

A. Keith Stewart, MB, ChB: Yes, this is a very important practice point. We need to do a better job managing hypertension. Noopur, your experience?

Noopur Suresh Raje, MD: We have gone to using weekly doses of carfilzomib. We do go up to 56 mg/m2 on a weekly schedule, but I agree with you, Hari, especially in the up-front setting or if you have relapse with high disease burden, that’s where you end up seeing more endothelial toxicity. So, when you start off, start off with a lower dose. But we are generally able to build up to that dose off a higher dose weekly.

A. Keith Stewart, MB, ChB: I want to be clear for the audience. When you’re talking about endothelial toxicity, what are you referring to?

Noopur Suresh Raje, MD: You can get blood clots, PEs as were seen also in the KRd/daratumumab study, which has been presented at ASCO. They saw quite a few PEs there. So, in newly diagnosed patients where you have a high disease burden, you can actually see these kinds of toxicities.

A. Keith Stewart, MB, ChB: Thoughts on, let’s just stick with Kyprolis for a minute, carfilzomib. Bob, what’s your experience like with that?

Robert Orlowski, MD, PhD: Well, beyond the blood pressure issues and endothelial issues that were mentioned, people can have shortness of breath/dyspnea. So, that’s the other one that you can see in probably around 10%, as long as you don’t give them too much fluid, because in the early days of carfilzomib, there was a notion that maybe there was tumor lysis and you needed to pre- and post-hydrate them. But if you get away from that, it’s much less of an issue and there may be a benefit to giving the higher dose, 1 per week, based on some randomized data that so far have been announced only in a press release but that we hope to be able to see soon.

A. Keith Stewart, MB, ChB: You’re referring to the ARROW clinical trial?

Robert Orlowski, MD, PhD: Correct.

A. Keith Stewart, MB, ChB: What do you think? We have the press release that demonstrates that weekly has a slightly better progression-free survival than 11 months versus 8, or something for the weekly versus biweekly single-agent carfilzomib with dexamethasone. How do you react to that? Are you going to switch to weekly dosing? Wait for the data? What’s your plan?

Robert Orlowski, MD, PhD: Would definitely like to see the data. I think that, of course, in older patients—as was discussed earlier—the higher dose could be a little bit problematic.

A. Keith Stewart, MB, ChB: And by high, what do you mean? 70 mg?

Robert Orlowski, MD, PhD: Even 50 mg and north of that, but certainly 70ish mg, which is what was used here. But I do think the convenience factor is there, and it may make it easier to combine that with other drugs for new 3-drug regimens.

A. Keith Stewart, MB, ChB: My guess is the ARROW clinical trial we’re talking about was a phase III trial of biweekly carfilzomib at 27 mg/m2 versus once weekly at 70 mg. I think, to me, the main take-home will be that it provides a justification for moving to weekly for the convenience factor. Christina, do you use weekly or twice weekly carfilzomib?

Cristina Gasparetto, MD: Yes, but I’ve now been able to go up to the 70 mg. And we were talking about using carfilzomib with dexamethasone in the triplet. When you use that, I think going up with the dose is even more important. I think in the triplet, we see that we have to settle down with the lower dose for toxicity. But yes, I think like Noopur. I think the 56 mg is becoming my ratio for the weekly.

A. Keith Stewart, MB, ChB: That’s weekly. I want to just close this session with a couple words on daratumumab management and toxicity and maybe get, Noopur, your advice to the audience on using daratumumab.

Noopur Suresh Raje, MD: Usually most of the toxicity is infusion-related toxicities that you see with daratumumab, and it’s the first 1 and 2 infusions. We are doing a pretty good job with the pre-medications now. We use, routinely, montelukast, etc, and we are not seeing as many. But these are manageable toxicities. The first dose is a long dose, and as Bob has already pointed out at this meeting, you’re going to hear about the subcutaneous version, and the subcutaneous version soon to be had is going to be given over like 15 minutes, 5 to 10 minutes actually. So, that’s going to change this completely.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: Let’s talk about the carfilzomib trial that Hari alluded to earlier, which shows an overall survival advantage. There was a doublet regimen with higher doses of carfilzomib in the trial called the ENDEAVOR trial. Bob, I think you might have been involved with that. That also showed an advantage to that versus bortezomib. Is anybody using carfilzomib with dexamethasone alone at relapse or is this a triplet crowd here? Anybody?

Robert Orlowski, MD, PhD: Probably a triplet crowd.

Noopur Suresh Raje, MD: Part of the reason why I think we are using triplets is we’re starting out by using triplets at the beginning. And if you think about relapse, they’re becoming more genetically complex. So, then going back to a doublet is almost going backwards, I think, except there is a toxicity issue. Of course, we will use a doublet in that situation.

A. Keith Stewart, MB, ChB: What about non-IMiD-containing regimens? There was an abstract here from the United Kingdom that looked at cyclophosphamide with carfilzomib, which I thought had really quite impressive results. I don’t know if anybody has had a chance to review that in any detail. Does anybody use that regimen at relapse? Bob, I’ll pick on you again.

Robert Orlowski, MD, PhD: Yes, I think alkylating agents are certainly reasonable to use at the time of relapse. Cyclophosphamide is a good partner. We’ve also done bendamustine with carfilzomib, and it works quite well. I think the major concern, of course, is that you can’t keep people on it for too long because you run into myelosuppression and then you may compromise what they can do next. Because if they continue to have myelosuppression, their counts are not good enough for clinical trials.

A. Keith Stewart, MB, ChB: I guess I’m a bit of a fan of carfilzomib/cyclophosphamide, particularly when you’ve been on lenalidomide and you’re progressing. Sometimes the notion of going to a second immune modulator versus switching therapy completely doesn’t sit well with me. Anybody?

Noopur Suresh Raje, MD: I tend to use carfilzomib/Cytoxan/dexamethasone quite a lot. Specifically, in those extramedullary aggressive patients, it works quite well.

A. Keith Stewart, MB, ChB: Now, we haven’t addressed toxicity of any of the drugs so far. Let’s talk about carfilzomib since we’re on that topic. What’s your latest thinking on the tolerability of carfilzomib, Hari?

Parameswaran Hari, MD, MRCP, MS: I find it actually extremely well tolerated, provided you pick the right patient and the right dose. So, we talked about the variety of KRd regimens and KCd regimens. So, the 20/27-mg dose is generally well tolerated, and once you go up to 36 mg, which is the dose that’s being tested in the ECOG trial that Noopur alluded to with IMiDs, that again is relatively well tolerated by newly diagnosed patients. But once you go up to the 56-mg and the 70-mg doses, then the tolerability becomes an issue. I find a lot of endothelial toxicities, such as hypertension and atrial fibrillation. And picking the right patient is the most important thing, in my opinion, in practice for the practicing oncologist. For an elderly patient, I would always start at the lower dose and titrate up as required and be very quick to reduce the dose if measuring their blood pressures when they show up for treatment.

A. Keith Stewart, MB, ChB: Yes, this is a very important practice point. We need to do a better job managing hypertension. Noopur, your experience?

Noopur Suresh Raje, MD: We have gone to using weekly doses of carfilzomib. We do go up to 56 mg/m2 on a weekly schedule, but I agree with you, Hari, especially in the up-front setting or if you have relapse with high disease burden, that’s where you end up seeing more endothelial toxicity. So, when you start off, start off with a lower dose. But we are generally able to build up to that dose off a higher dose weekly.

A. Keith Stewart, MB, ChB: I want to be clear for the audience. When you’re talking about endothelial toxicity, what are you referring to?

Noopur Suresh Raje, MD: You can get blood clots, PEs as were seen also in the KRd/daratumumab study, which has been presented at ASCO. They saw quite a few PEs there. So, in newly diagnosed patients where you have a high disease burden, you can actually see these kinds of toxicities.

A. Keith Stewart, MB, ChB: Thoughts on, let’s just stick with Kyprolis for a minute, carfilzomib. Bob, what’s your experience like with that?

Robert Orlowski, MD, PhD: Well, beyond the blood pressure issues and endothelial issues that were mentioned, people can have shortness of breath/dyspnea. So, that’s the other one that you can see in probably around 10%, as long as you don’t give them too much fluid, because in the early days of carfilzomib, there was a notion that maybe there was tumor lysis and you needed to pre- and post-hydrate them. But if you get away from that, it’s much less of an issue and there may be a benefit to giving the higher dose, 1 per week, based on some randomized data that so far have been announced only in a press release but that we hope to be able to see soon.

A. Keith Stewart, MB, ChB: You’re referring to the ARROW clinical trial?

Robert Orlowski, MD, PhD: Correct.

A. Keith Stewart, MB, ChB: What do you think? We have the press release that demonstrates that weekly has a slightly better progression-free survival than 11 months versus 8, or something for the weekly versus biweekly single-agent carfilzomib with dexamethasone. How do you react to that? Are you going to switch to weekly dosing? Wait for the data? What’s your plan?

Robert Orlowski, MD, PhD: Would definitely like to see the data. I think that, of course, in older patients—as was discussed earlier—the higher dose could be a little bit problematic.

A. Keith Stewart, MB, ChB: And by high, what do you mean? 70 mg?

Robert Orlowski, MD, PhD: Even 50 mg and north of that, but certainly 70ish mg, which is what was used here. But I do think the convenience factor is there, and it may make it easier to combine that with other drugs for new 3-drug regimens.

A. Keith Stewart, MB, ChB: My guess is the ARROW clinical trial we’re talking about was a phase III trial of biweekly carfilzomib at 27 mg/m2 versus once weekly at 70 mg. I think, to me, the main take-home will be that it provides a justification for moving to weekly for the convenience factor. Christina, do you use weekly or twice weekly carfilzomib?

Cristina Gasparetto, MD: Yes, but I’ve now been able to go up to the 70 mg. And we were talking about using carfilzomib with dexamethasone in the triplet. When you use that, I think going up with the dose is even more important. I think in the triplet, we see that we have to settle down with the lower dose for toxicity. But yes, I think like Noopur. I think the 56 mg is becoming my ratio for the weekly.

A. Keith Stewart, MB, ChB: That’s weekly. I want to just close this session with a couple words on daratumumab management and toxicity and maybe get, Noopur, your advice to the audience on using daratumumab.

Noopur Suresh Raje, MD: Usually most of the toxicity is infusion-related toxicities that you see with daratumumab, and it’s the first 1 and 2 infusions. We are doing a pretty good job with the pre-medications now. We use, routinely, montelukast, etc, and we are not seeing as many. But these are manageable toxicities. The first dose is a long dose, and as Bob has already pointed out at this meeting, you’re going to hear about the subcutaneous version, and the subcutaneous version soon to be had is going to be given over like 15 minutes, 5 to 10 minutes actually. So, that’s going to change this completely.

Transcript Edited for Clarity 
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