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Transplant-Ineligible Myeloma: Daratumumab

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: Thursday, Feb 07, 2019



Transcript: 

A. Keith Stewart, MB, ChB:
Let’s talk about daratumumab in the elderly population. We’ve had 2 very large phase III trials. I’d like to spend the first couple of minutes here describing the trials and walking the audience through them. So, Adriana, do you want to take a stab at 1 of those 2 studies?

Adriana Rossi, MD: Sure. So, I think the first one, I will maybe leave the MAIA study excitement to those of you who are just champing at the bit. But I think the use of daratumumab, just with any drug that we get excited about, moving it earlier on is exciting. And the first data set that we had was comparing VMP, which is bortezomib, melphalan, and prednisone, with or without the addition of daratumumab, specifically in those patients who are not eligible for transplant. And this was exciting. It led to our approval of daratumumab in the frontline and caused a little controversy because the data did come from Europe where VMP [bortezomib, melphalan, and prednisone] is an acceptable regimen, whereas in the United States upfront melphalan is not considered our standard.

A. Keith Stewart, MB, ChB: What were the results of the study?

Adriana Rossi, MD: They were very encouraging. I think the addition of daratumumab not only responds, and now I am not remembering the numbers on the original study, but not only the deepening of response but the shape of the curve. You’re really getting a high plateau and the median survival is not reached.

A. Keith Stewart, MB, ChB: If I recall, it used to be the control arm was about 19 months, and had still not reached the median survival but it looked like it was going to come in around 3.5, 4 years maybe. Something like that.

Rafael Fonseca, MD: You know 24 months, what they have is 63% versus 36%. So it’s a huge gap there. One of the interesting things, which you see in the study but you saw in the first study, and I think we need to keep track of this in all the elderly, as soon as a regimen has therapy that stops then there’s an inflection of the curve. I mean all the survival curves with time-limited therapy go like this, and then they start going like this, which you know all these trials, they’re going to need to show that.

Thomas Martin, MD: But the other important thing about this trial is that these patients, after receiving 9 cycles of DARA [daratumumab]/VMP, were just on DARA alone as maintenance-based therapy. And there were very few patients that had to come off because of adverse effects. And again, I think the infection risk is in the first 9 cycles. But after that there wasn’t much, in terms of adverse effects or infections. And I will say, I’ll go on record, but monoclonal antibody therapy as maintenance is a great strategy in this population. They feel well. They come to the clinic. They come to socialize with the nurses once a month. They love it.

A. Keith Stewart, MB, ChB: It’s expensive.

Thomas Martin, MD: It’s expensive but the PFS [progression-free survival] curves continue to separate, and the separation becomes larger and larger over time.

A. Keith Stewart, MB, ChB: In fact, they did, if I again recall rightly, hint at the overall survival by showing PFS2. And the suggestion there was that it continues to show value for adding daratumumab, which might likely translate into overall survival eventually. Very impressive, elderly people, close to 4 years of PFS with a 4-drug cocktail. As we’ve already alluded to though, it’s not particularly applicable to the US marketplace where we hardly ever use oral melphalan any more.

Faith, did you take in the MAIA study? Or it hasn’t been presented yet, but we’ve got the abstract here.

Faith Davies, MD, MBBCh, MRCP, FRCPath: We’ve got the abstract, yes. So in the MAIA study they have compared lenalidomide and dexamethasone to lenalidomide, dexamethasone, and daratumumab. And again, the abstract looks amazing. I think that it’s 32 months for the lenalidomide/dexamethasone, and not reached for the DARA with some crazy kind of hazard ratio.

So I think it looks really very impressive. I think the question, as with all of these studies, is how do you define an elderly patient? Because I think in all of the studies we’re talking about patients who are over age 65, and maybe for some of those patients who are over age 65 you may actually think about transplanting. But it really does look exciting.

A. Keith Stewart, MB, ChB: Rafael, your thoughts? As a late-breaking abstract to this meeting that’s probably practice changing and may get approval in younger patients for daratumumab upfront….

Rafael Fonseca, MD: I still want to understand how to manage the younger patients in the transplant-eligible setting. I think we’re moving in that direction. For the elderly, I think it’s practice changing. And, again, you know when you look at the numbers and without doing a direct comparison, which we know must be done, you look at this and you compare it with the SWOG [Southwest Oncology Group] study, again, which was primarily for nontransplant candidates. The curves are much better, and without the presence of peripheral neuropathy. Now I know you say that they like to go in, but then put this in with subcutaneous daratumumab into the future—highly convenient regimen.

So I just want to see. I think that the only other thing that I think could be as tolerable, but I don’t think it will have the power, would be the ELOQUENT trial for newly diagnosed in the elderly, which has not been reported and the ELOQUENT is....

A. Keith Stewart, MB, ChB: Why?

Rafael Fonseca, MD: It’s elotuzumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone. The caveat there is that it’s incredibly well tolerated, the elotuzumab combination. So that’s kind of the one thing that’s still out there in the air. But I think this will be practice changing.

A. Keith Stewart, MB, ChB: And I should correct myself. This was a trial in the elderly, again, and I guess my point was it was more compatible with the US-based practice rather than it was the younger population.

Rafael Fonseca, MD: Correct.

A. Keith Stewart, MB, ChB: Tom?

Thomas Martin, MD: This is going to be practice changing. I think that the NCCN [National Comprehensive Cancer Network] guidelines will adopt this relatively quickly. I think this will be on-label very soon after this meeting. With the hazard ratio of 0.55, you know it’s estimated to be between 50 and 60 months PFS. That is the same in the transplant-eligible, of getting RVd [lenalidomide/bortezomib/dexamethasone]/transplant/R maintenance from this triplet. I think it’s really amazing.

Again, there are 3 things that I really want to see from the data. One, what happens in patients that have high-risk cytogenetics? Are they going to do just as well? And 2, what’s the infection rate going to be? And the last thing is counts. Are they going to have any count problems over time? And if all those are yes, yes, yes, then February 1st is going to be standard therapy for me for the....

A. Keith Stewart, MB, ChB: Are you going to be using Rd/DARA or KRd [carfilzomib/lenalidomide/dexamethasone]/DARA, or VRd/DARA, or ixazomib/Rd/DARA?

Thomas Martin, MD: I think for the transplant-ineligible patients, for the older patients, Rd/DARA is going to be such a well-tolerated regimen. No neuropathy. That’s going to be the practice.

A. Keith Stewart, MB, ChB: Any other thoughts on those studies?

Rafael Fonseca, MD: I think the one thing that we need to remember is we talked a little about the dose adjustments in the elderly. You use a cutoff of age 70. OK, if you’re age 72, you’re not a marathon runner but you’re in decent health. You have a life expectancy of at least 10 years. So I think we potentially could cut short the expected longevity from someone in that age category by now giving them the best treatment possible. And it’s very clear that the survival is better. The treatment is better. But I think it’s nice to see that we’re moving the spotlight into the elderly.

A. Keith Stewart, MB, ChB: What about carfilzomib in the elderly? Particularly, is there a way to give it at lower doses, Faith, do you think, or is it a drug you would avoid in elderly people?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Oh, no, I definitely wouldn’t avoid it in the elderly people. I was going to say, now you’ve got me worried that I’ve missed an abstract.

A. Keith Stewart, MB, ChB: I was just curious. We have VRd. I think there has been a bit of a sense that maybe that’s the drug that’s a step too far for the elderly, but you don’t think so?

Faith Davies, MD, MBBCh, MRCP, FRCPath: No, I don’t think so. I think that now we’re learning about once-weekly dosing, and I admit we may be taking that in a slightly different context. But, no, I think it’s a great drug for the elderly and should definitely be in our choices.

Adriana Rossi, MD: I think with the addition of the weekly. Because I think for some of my elderly patients it’s getting to the clinic that was the obstacle. So the schedule was the difficulty. If I have the option of dose at once-weekly, I’m more likely to use it.

A. Keith Stewart, MB, ChB: We’ll talk about that a little later in the relapsed setting, but we certainly could extrapolate to the newly diagnosed setting.


Transcript Edited for Clarity

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Transcript: 

A. Keith Stewart, MB, ChB:
Let’s talk about daratumumab in the elderly population. We’ve had 2 very large phase III trials. I’d like to spend the first couple of minutes here describing the trials and walking the audience through them. So, Adriana, do you want to take a stab at 1 of those 2 studies?

Adriana Rossi, MD: Sure. So, I think the first one, I will maybe leave the MAIA study excitement to those of you who are just champing at the bit. But I think the use of daratumumab, just with any drug that we get excited about, moving it earlier on is exciting. And the first data set that we had was comparing VMP, which is bortezomib, melphalan, and prednisone, with or without the addition of daratumumab, specifically in those patients who are not eligible for transplant. And this was exciting. It led to our approval of daratumumab in the frontline and caused a little controversy because the data did come from Europe where VMP [bortezomib, melphalan, and prednisone] is an acceptable regimen, whereas in the United States upfront melphalan is not considered our standard.

A. Keith Stewart, MB, ChB: What were the results of the study?

Adriana Rossi, MD: They were very encouraging. I think the addition of daratumumab not only responds, and now I am not remembering the numbers on the original study, but not only the deepening of response but the shape of the curve. You’re really getting a high plateau and the median survival is not reached.

A. Keith Stewart, MB, ChB: If I recall, it used to be the control arm was about 19 months, and had still not reached the median survival but it looked like it was going to come in around 3.5, 4 years maybe. Something like that.

Rafael Fonseca, MD: You know 24 months, what they have is 63% versus 36%. So it’s a huge gap there. One of the interesting things, which you see in the study but you saw in the first study, and I think we need to keep track of this in all the elderly, as soon as a regimen has therapy that stops then there’s an inflection of the curve. I mean all the survival curves with time-limited therapy go like this, and then they start going like this, which you know all these trials, they’re going to need to show that.

Thomas Martin, MD: But the other important thing about this trial is that these patients, after receiving 9 cycles of DARA [daratumumab]/VMP, were just on DARA alone as maintenance-based therapy. And there were very few patients that had to come off because of adverse effects. And again, I think the infection risk is in the first 9 cycles. But after that there wasn’t much, in terms of adverse effects or infections. And I will say, I’ll go on record, but monoclonal antibody therapy as maintenance is a great strategy in this population. They feel well. They come to the clinic. They come to socialize with the nurses once a month. They love it.

A. Keith Stewart, MB, ChB: It’s expensive.

Thomas Martin, MD: It’s expensive but the PFS [progression-free survival] curves continue to separate, and the separation becomes larger and larger over time.

A. Keith Stewart, MB, ChB: In fact, they did, if I again recall rightly, hint at the overall survival by showing PFS2. And the suggestion there was that it continues to show value for adding daratumumab, which might likely translate into overall survival eventually. Very impressive, elderly people, close to 4 years of PFS with a 4-drug cocktail. As we’ve already alluded to though, it’s not particularly applicable to the US marketplace where we hardly ever use oral melphalan any more.

Faith, did you take in the MAIA study? Or it hasn’t been presented yet, but we’ve got the abstract here.

Faith Davies, MD, MBBCh, MRCP, FRCPath: We’ve got the abstract, yes. So in the MAIA study they have compared lenalidomide and dexamethasone to lenalidomide, dexamethasone, and daratumumab. And again, the abstract looks amazing. I think that it’s 32 months for the lenalidomide/dexamethasone, and not reached for the DARA with some crazy kind of hazard ratio.

So I think it looks really very impressive. I think the question, as with all of these studies, is how do you define an elderly patient? Because I think in all of the studies we’re talking about patients who are over age 65, and maybe for some of those patients who are over age 65 you may actually think about transplanting. But it really does look exciting.

A. Keith Stewart, MB, ChB: Rafael, your thoughts? As a late-breaking abstract to this meeting that’s probably practice changing and may get approval in younger patients for daratumumab upfront….

Rafael Fonseca, MD: I still want to understand how to manage the younger patients in the transplant-eligible setting. I think we’re moving in that direction. For the elderly, I think it’s practice changing. And, again, you know when you look at the numbers and without doing a direct comparison, which we know must be done, you look at this and you compare it with the SWOG [Southwest Oncology Group] study, again, which was primarily for nontransplant candidates. The curves are much better, and without the presence of peripheral neuropathy. Now I know you say that they like to go in, but then put this in with subcutaneous daratumumab into the future—highly convenient regimen.

So I just want to see. I think that the only other thing that I think could be as tolerable, but I don’t think it will have the power, would be the ELOQUENT trial for newly diagnosed in the elderly, which has not been reported and the ELOQUENT is....

A. Keith Stewart, MB, ChB: Why?

Rafael Fonseca, MD: It’s elotuzumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone. The caveat there is that it’s incredibly well tolerated, the elotuzumab combination. So that’s kind of the one thing that’s still out there in the air. But I think this will be practice changing.

A. Keith Stewart, MB, ChB: And I should correct myself. This was a trial in the elderly, again, and I guess my point was it was more compatible with the US-based practice rather than it was the younger population.

Rafael Fonseca, MD: Correct.

A. Keith Stewart, MB, ChB: Tom?

Thomas Martin, MD: This is going to be practice changing. I think that the NCCN [National Comprehensive Cancer Network] guidelines will adopt this relatively quickly. I think this will be on-label very soon after this meeting. With the hazard ratio of 0.55, you know it’s estimated to be between 50 and 60 months PFS. That is the same in the transplant-eligible, of getting RVd [lenalidomide/bortezomib/dexamethasone]/transplant/R maintenance from this triplet. I think it’s really amazing.

Again, there are 3 things that I really want to see from the data. One, what happens in patients that have high-risk cytogenetics? Are they going to do just as well? And 2, what’s the infection rate going to be? And the last thing is counts. Are they going to have any count problems over time? And if all those are yes, yes, yes, then February 1st is going to be standard therapy for me for the....

A. Keith Stewart, MB, ChB: Are you going to be using Rd/DARA or KRd [carfilzomib/lenalidomide/dexamethasone]/DARA, or VRd/DARA, or ixazomib/Rd/DARA?

Thomas Martin, MD: I think for the transplant-ineligible patients, for the older patients, Rd/DARA is going to be such a well-tolerated regimen. No neuropathy. That’s going to be the practice.

A. Keith Stewart, MB, ChB: Any other thoughts on those studies?

Rafael Fonseca, MD: I think the one thing that we need to remember is we talked a little about the dose adjustments in the elderly. You use a cutoff of age 70. OK, if you’re age 72, you’re not a marathon runner but you’re in decent health. You have a life expectancy of at least 10 years. So I think we potentially could cut short the expected longevity from someone in that age category by now giving them the best treatment possible. And it’s very clear that the survival is better. The treatment is better. But I think it’s nice to see that we’re moving the spotlight into the elderly.

A. Keith Stewart, MB, ChB: What about carfilzomib in the elderly? Particularly, is there a way to give it at lower doses, Faith, do you think, or is it a drug you would avoid in elderly people?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Oh, no, I definitely wouldn’t avoid it in the elderly people. I was going to say, now you’ve got me worried that I’ve missed an abstract.

A. Keith Stewart, MB, ChB: I was just curious. We have VRd. I think there has been a bit of a sense that maybe that’s the drug that’s a step too far for the elderly, but you don’t think so?

Faith Davies, MD, MBBCh, MRCP, FRCPath: No, I don’t think so. I think that now we’re learning about once-weekly dosing, and I admit we may be taking that in a slightly different context. But, no, I think it’s a great drug for the elderly and should definitely be in our choices.

Adriana Rossi, MD: I think with the addition of the weekly. Because I think for some of my elderly patients it’s getting to the clinic that was the obstacle. So the schedule was the difficulty. If I have the option of dose at once-weekly, I’m more likely to use it.

A. Keith Stewart, MB, ChB: We’ll talk about that a little later in the relapsed setting, but we certainly could extrapolate to the newly diagnosed setting.


Transcript Edited for Clarity
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