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Up-front Therapy With Carfilzomib in 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: Friday, Jan 25, 2019



Transcript:

A. Keith Stewart, MB, ChB:
Let’s move on and talk about treating newly diagnosed multiple myeloma now. Tom, how are you treating your patients today?

Thomas Martin, MD: So my practice for the newly diagnosed patient really revolves around whether or not they’re transplant eligible or not. And, I think, in the US, transplant eligible is almost everybody that’s less than 70 years of age and has a good performance status. For patients who are over age 70, they really have to have a good performance status to move on to transplant. So most of my patients are less than age 70.

If I take those patients that are less than age 70 and they’re transplant eligible, the 2 regimens that I’ve really been using, most are RVd—Revlimid, or lenalidomide, bortezomib, and dexamethasone—or, KRd —carfilzomib, lenalidomide, and dexamethasone. I’m probably the most aggressive in our practice. My personal practice is, if they’re less than age 60 and they have no cardiac issues, I pretty much give them KRd right from the start – carfilzomib, lenalidomide, and dexamethasone. Between ages 60 and 70, I’m more likely to give them lenalidomide, bortezomib, and dexamethasone, or RVd. And that’s how I start therapy for most people. Four to 6 cycles in the transplant eligible, and then go on to transplant.

A. Keith Stewart, MB, ChB: Adriana, what about you?

Adriana Rossi, MD: I think those are definitely my 2 favored triplets. I think I would have to have a very strong compelling reason to not use a triplet. And the combination of a proteasome inhibitor and immune modulator are the favored combinations. I don’t think so much about transplant eligibility, just because I think that was back when I would consider using an alkylator upfront. I think performance status is the stronger differential, and, then, to your point, the toxicity. So I would avoid cardiac toxicity. For a number of patients with diabetes or peripheral neuropathy from some other cause I would not want to use bortezomib.

A. Keith Stewart, MB, ChB: There was some market research I saw at this meeting that suggested about 70% of patients are now receiving triplet therapy. And particularly in the younger population, it may be a little bit less. In the more elderly, maybe around 50%. There seems to be consensus that that’s the right track.

Now we do have a head-to-head trial of bortezomib versus carfilzomib, but at this meeting there was a number of studies looking at carfilzomib induction. I’d like to flush out the use of carfilzomib with lenalidomide versus carfilzomib with cyclophosphamide. Faith, I don’t know if you caught that presentation, or do you want Rafael to take that one?

Faith Davies, MD, MBBCh, MRCP, FRCPath: So I was involved in one of the presentations, so I guess I’m a little biased in this conversation.

A. Keith Stewart, MB, ChB: Is this the British one?

Faith Davies, MD, MBBCh, MRCP, FRCPath: The British one, yes.

A. Keith Stewart, MB, ChB: Why don’t you tell us about that one.

Faith Davies, MD, MBBCh, MRCP, FRCPath: So the British one was carfilzomib with cyclophosphamide, Revlimid, and dexamethasone. So it’s actually taking it a step further, having 4 drugs, and comparing it to a triplet regimen. But the triplet regimen was an IMiD [immunomodulatory imide drug]-based regimen. So the cyclophosphamide followed thalidomide and DEX, or cyclophosphamide, Revlimid and DEX. And the actual question behind that was essentially if you can get deep remissions pre transplant, does that kind of move forward to post transplant and does it influence progression-free survival?

And the study showed that it did influence progression-free survival in really quite a dramatic way. I think the thing that everybody’s been saying is that the triplet regimen, and in this case the quadruplet regimen, really does induce really good responses pre transplant, with many MRD [minimal negative disease]-negative responses. And toxicity-wise for this particular regimen, the toxicity was minimal.

A. Keith Stewart, MB, ChB: Rafael, did you catch the cyclophosphamide, carfilzomib versus lenalidomide, carfilzomib study?

Rafael Fonseca, MD: Sure. I actually think that was one of the top abstracts for this particular meeting that was presented. So it was, again, KRd, the carfilzomib, LEN, DEX followed by transplant. There’s 5 cycles. A transplant is 4 cycles. And then there’s a maintenance component, which is randomized. There’s KRd times 12 cycles versus KCd, transplant, KCd, 4 cycles, and then second randomization.

At this particular meeting they presented the data for the response after the consolidation and before. They didn’t present any of the time-dependent variables yet for survival. But we saw a very impressive rate of complete responses, and specifically MRD negative—58% of those patients that have transplants plus KRd, but guess what? The KRd times 12 had an MRD of 54%.

A. Keith Stewart, MB, ChB: Yeah, I’m going to come back to MRD in a little bit. What’s your personal preference if you’re going to treat a patient?

Rafael Fonseca, MD: You know I live in a bit of a schizophrenic world where I can understand where someone writing thoughtful guidelines will say that VRd [bortezomib, lenalidomide, dexamethasone] is the perfect choice for starting therapy, but I have transitioned to use KRd as frontline therapy for my patients, primarily because of the tradeoff of someone who’s going to live now sometimes in the excess of 10 years to do so with a peripheral neuropathy is not a good tradeoff.

A. Keith Stewart, MB, ChB: We don’t have a randomized trial. There is one in progress, which we should hear about. But it sounds like all of you are using some carfilzomib upfront. Faith, the same in Arkansas?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yeah. So, obviously, in Arkansas we add a few extra drugs into the regimen. But certainly, yeah, carfilzomib is really our drug of choice as an upfront regimen, because I think there’s now a lot of data to show it induces really good responses and it’s very tolerable.

A. Keith Stewart, MB, ChB: There has been some concern about, you said you would avoid it in cardiac disease patients. Can you be a bit more specific?

Thomas Martin, MD: Sure. I think the most significant side effect from carfilzomib is hypertension, and there is a small incidence, less than 5%, of congestive heart failure. In my practice, if you control the blood pressure really well and follow it really well most people can tolerate carfilzomib. We also do check laboratories, including a BNP [brain natriuretic peptide] level, just to see what the cardiac fraction is.

A. Keith Stewart, MB, ChB: Do you do that before you treat?

Thomas Martin, MD: With each cycle. And then we follow their weight. If you follow their weight and their blood pressure you can actually safely give the carfilzomib in most patients. I will echo what Rafael said. That was my favorite abstract. And the question now becomes, it’s KRd without an autologous transplant versus KRd with an autologous transplant. The data look relatively similar in a very large study. But we’re going to now add daratumumab to that.

A. Keith Stewart, MB, ChB: Why are we abandoning VRd? Without a trial, is that a leap of fate too far?

Adriana Rossi, MD: I don’t think we have KRd versus VRd data, but we do have Kd versus Vd data. It’s an imperfect world and it’ll be a long time until we have, or probably never have the studies that we’d actually like for all the information. So most of what practice we have is extrapolation from imperfect data or phase II data.

Thomas Martin, MD: I will also say that C. Ola Landgren, MD, PhD, did a review of the CoMMpass study and looked at those patients that were treated with KRd versus…

A. Keith Stewart, MB, ChB: Tell the audience what the CoMMpass study is, because they won’t understand.

Thomas Martin, MD: OK. So, the Multiple Myeloma Research Foundation, or the MMRF, has followed over 1000 patients serially from new diagnosis throughout their course of therapy, and they’ve done molecular studies from their bone marrow biopsies, including next-generation sequencing, and also have done annotation of what therapies they’ve had, what adverse effects they’ve had, and what responses they’ve had over time.

So now we have this very rich enlarged database. Again, over 1000 patients. And we can evaluate those that were treated newly diagnosed with triplet and doublet regimens and see them over time and how well they did. So when you went to the database for CoMMpass and look at those that were treated with KRd, and I think it was around 150 patients, versus those that were treated with RVd, which was more like 400 to 450 patients, and I think that’s probably right, that 25% maybe get KRd, but 75% get RVd at the current time. But if they looked at that data, then free survival at the first year time point, it was better in KRd versus RVd. Now this is not a randomized trial.

A. Keith Stewart, MB, ChB: Yeah, I was going to say that. There was a lot of bias for what got picked for treatment.

Thomas Martin, MD: Tremendous bias. Maybe patients that were better KPS were selected to get KRd. And so we do need a randomized trial.

Transcript edited for clarity.

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Transcript:

A. Keith Stewart, MB, ChB:
Let’s move on and talk about treating newly diagnosed multiple myeloma now. Tom, how are you treating your patients today?

Thomas Martin, MD: So my practice for the newly diagnosed patient really revolves around whether or not they’re transplant eligible or not. And, I think, in the US, transplant eligible is almost everybody that’s less than 70 years of age and has a good performance status. For patients who are over age 70, they really have to have a good performance status to move on to transplant. So most of my patients are less than age 70.

If I take those patients that are less than age 70 and they’re transplant eligible, the 2 regimens that I’ve really been using, most are RVd—Revlimid, or lenalidomide, bortezomib, and dexamethasone—or, KRd —carfilzomib, lenalidomide, and dexamethasone. I’m probably the most aggressive in our practice. My personal practice is, if they’re less than age 60 and they have no cardiac issues, I pretty much give them KRd right from the start – carfilzomib, lenalidomide, and dexamethasone. Between ages 60 and 70, I’m more likely to give them lenalidomide, bortezomib, and dexamethasone, or RVd. And that’s how I start therapy for most people. Four to 6 cycles in the transplant eligible, and then go on to transplant.

A. Keith Stewart, MB, ChB: Adriana, what about you?

Adriana Rossi, MD: I think those are definitely my 2 favored triplets. I think I would have to have a very strong compelling reason to not use a triplet. And the combination of a proteasome inhibitor and immune modulator are the favored combinations. I don’t think so much about transplant eligibility, just because I think that was back when I would consider using an alkylator upfront. I think performance status is the stronger differential, and, then, to your point, the toxicity. So I would avoid cardiac toxicity. For a number of patients with diabetes or peripheral neuropathy from some other cause I would not want to use bortezomib.

A. Keith Stewart, MB, ChB: There was some market research I saw at this meeting that suggested about 70% of patients are now receiving triplet therapy. And particularly in the younger population, it may be a little bit less. In the more elderly, maybe around 50%. There seems to be consensus that that’s the right track.

Now we do have a head-to-head trial of bortezomib versus carfilzomib, but at this meeting there was a number of studies looking at carfilzomib induction. I’d like to flush out the use of carfilzomib with lenalidomide versus carfilzomib with cyclophosphamide. Faith, I don’t know if you caught that presentation, or do you want Rafael to take that one?

Faith Davies, MD, MBBCh, MRCP, FRCPath: So I was involved in one of the presentations, so I guess I’m a little biased in this conversation.

A. Keith Stewart, MB, ChB: Is this the British one?

Faith Davies, MD, MBBCh, MRCP, FRCPath: The British one, yes.

A. Keith Stewart, MB, ChB: Why don’t you tell us about that one.

Faith Davies, MD, MBBCh, MRCP, FRCPath: So the British one was carfilzomib with cyclophosphamide, Revlimid, and dexamethasone. So it’s actually taking it a step further, having 4 drugs, and comparing it to a triplet regimen. But the triplet regimen was an IMiD [immunomodulatory imide drug]-based regimen. So the cyclophosphamide followed thalidomide and DEX, or cyclophosphamide, Revlimid and DEX. And the actual question behind that was essentially if you can get deep remissions pre transplant, does that kind of move forward to post transplant and does it influence progression-free survival?

And the study showed that it did influence progression-free survival in really quite a dramatic way. I think the thing that everybody’s been saying is that the triplet regimen, and in this case the quadruplet regimen, really does induce really good responses pre transplant, with many MRD [minimal negative disease]-negative responses. And toxicity-wise for this particular regimen, the toxicity was minimal.

A. Keith Stewart, MB, ChB: Rafael, did you catch the cyclophosphamide, carfilzomib versus lenalidomide, carfilzomib study?

Rafael Fonseca, MD: Sure. I actually think that was one of the top abstracts for this particular meeting that was presented. So it was, again, KRd, the carfilzomib, LEN, DEX followed by transplant. There’s 5 cycles. A transplant is 4 cycles. And then there’s a maintenance component, which is randomized. There’s KRd times 12 cycles versus KCd, transplant, KCd, 4 cycles, and then second randomization.

At this particular meeting they presented the data for the response after the consolidation and before. They didn’t present any of the time-dependent variables yet for survival. But we saw a very impressive rate of complete responses, and specifically MRD negative—58% of those patients that have transplants plus KRd, but guess what? The KRd times 12 had an MRD of 54%.

A. Keith Stewart, MB, ChB: Yeah, I’m going to come back to MRD in a little bit. What’s your personal preference if you’re going to treat a patient?

Rafael Fonseca, MD: You know I live in a bit of a schizophrenic world where I can understand where someone writing thoughtful guidelines will say that VRd [bortezomib, lenalidomide, dexamethasone] is the perfect choice for starting therapy, but I have transitioned to use KRd as frontline therapy for my patients, primarily because of the tradeoff of someone who’s going to live now sometimes in the excess of 10 years to do so with a peripheral neuropathy is not a good tradeoff.

A. Keith Stewart, MB, ChB: We don’t have a randomized trial. There is one in progress, which we should hear about. But it sounds like all of you are using some carfilzomib upfront. Faith, the same in Arkansas?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yeah. So, obviously, in Arkansas we add a few extra drugs into the regimen. But certainly, yeah, carfilzomib is really our drug of choice as an upfront regimen, because I think there’s now a lot of data to show it induces really good responses and it’s very tolerable.

A. Keith Stewart, MB, ChB: There has been some concern about, you said you would avoid it in cardiac disease patients. Can you be a bit more specific?

Thomas Martin, MD: Sure. I think the most significant side effect from carfilzomib is hypertension, and there is a small incidence, less than 5%, of congestive heart failure. In my practice, if you control the blood pressure really well and follow it really well most people can tolerate carfilzomib. We also do check laboratories, including a BNP [brain natriuretic peptide] level, just to see what the cardiac fraction is.

A. Keith Stewart, MB, ChB: Do you do that before you treat?

Thomas Martin, MD: With each cycle. And then we follow their weight. If you follow their weight and their blood pressure you can actually safely give the carfilzomib in most patients. I will echo what Rafael said. That was my favorite abstract. And the question now becomes, it’s KRd without an autologous transplant versus KRd with an autologous transplant. The data look relatively similar in a very large study. But we’re going to now add daratumumab to that.

A. Keith Stewart, MB, ChB: Why are we abandoning VRd? Without a trial, is that a leap of fate too far?

Adriana Rossi, MD: I don’t think we have KRd versus VRd data, but we do have Kd versus Vd data. It’s an imperfect world and it’ll be a long time until we have, or probably never have the studies that we’d actually like for all the information. So most of what practice we have is extrapolation from imperfect data or phase II data.

Thomas Martin, MD: I will also say that C. Ola Landgren, MD, PhD, did a review of the CoMMpass study and looked at those patients that were treated with KRd versus…

A. Keith Stewart, MB, ChB: Tell the audience what the CoMMpass study is, because they won’t understand.

Thomas Martin, MD: OK. So, the Multiple Myeloma Research Foundation, or the MMRF, has followed over 1000 patients serially from new diagnosis throughout their course of therapy, and they’ve done molecular studies from their bone marrow biopsies, including next-generation sequencing, and also have done annotation of what therapies they’ve had, what adverse effects they’ve had, and what responses they’ve had over time.

So now we have this very rich enlarged database. Again, over 1000 patients. And we can evaluate those that were treated newly diagnosed with triplet and doublet regimens and see them over time and how well they did. So when you went to the database for CoMMpass and look at those that were treated with KRd, and I think it was around 150 patients, versus those that were treated with RVd, which was more like 400 to 450 patients, and I think that’s probably right, that 25% maybe get KRd, but 75% get RVd at the current time. But if they looked at that data, then free survival at the first year time point, it was better in KRd versus RVd. Now this is not a randomized trial.

A. Keith Stewart, MB, ChB: Yeah, I was going to say that. There was a lot of bias for what got picked for treatment.

Thomas Martin, MD: Tremendous bias. Maybe patients that were better KPS were selected to get KRd. And so we do need a randomized trial.

Transcript edited for clarity.
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