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Newly Diagnosed Myeloma: Transplant Ineligibility and Treatment

Panelists: Sagar Lonial, MD, FACP, Winship Cancer Institute of Emory University; Amrita Y. Krishnan, MD, City of Hope Comprehensive Cancer Center; Thomas G. Martin, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Krina K. Patel, MD, MSc, University of Texas MD Anderson Cancer Center; Saad Z. Usmani, MD, FACP, Levine Cancer Institute
Published: Tuesday, Jul 16, 2019



Transcript: 

Sagar Lonial, MD, FACP: Let’s switch gears a little bit and talk about the transplant-ineligible patients. I have to say it’s a distinction that drives me crazy because I don’t like the 65 years old arbitrary distinction that the Europeans have given us. For me, it’s about frail, the truly frail people where you’re even going to have trouble getting them through their initial therapy. We had melphalan-based approaches for decades. We replaced that with LEN-DEX [lenalidomide/dexamethasone]. SWOG gave us VRd [bortezomib/lenalidomide/dexamethasone] being better than Rd [lenalidomide/dexamethasone] for those patients, and now we have Saad’s trial with DRd [daratumumab/lenalidomide/dexamethasone]. Where do you guys sit on how to use that, and how do you approach your folks?

Thomas G. Martin, MD: I would say that the 2 big trials obviously are ALCYONE and MAIA, and those are both daratumumab-containing trials, and they’re both large phase III trials in the transplant-ineligible patients. The daratumumab-containing arm in both trials had overall response rates of greater than 90%, improved PFS [progression-free survival], and improved MRD [minimal residual disease]-negativity rates. In fact, the 30-month PFS in the DARA/VMP [daratumumab/bortezomib/melphalan/prednisone] arm was 60%, and in 30-month PFS, the DARA/Rd [daratumumab/lenalidomide/dexamethasone] arm was 71%. So that’s pretty impressive actually for a triplet and a quadruplet. Now, we don’t really use this quadruplet much in the United States and that, even though it’s an approved regimen in the United States, has not really caught on and I don’t think many of us have used it. In fact, I don’t think I’ve ever prescribed it. But daratumumab/lenalidomide/dexamethasone, especially for the transplant-ineligible patients, is a great regimen. In terms of quality of life and the ability to continue the regimen for a long time, it’s a very easy regimen to give, especially after you get into every-4-week daratumumab.

Sagar Lonial, MD, FACP: Saad, you presented some data on age and the effect of age. Do you want to talk a little bit about that?

Saad Z. Usmani, MD, FACP: Sure. One of the unique features about the MAIA trial was the proportion of patients enrolled who were 75 or older, and that’s the patient population that we truly believe is transplant-ineligible. This analysis actually looked at response rates and median PFS for that specific group. There were no differences between the younger than 75 versus 75 or older in terms of the PFS benefit that patients get. The only thing that we saw—again, with small numbers of patients, as only 14% of the patients were high risk—was that benefit was not seen for the high-risk patients in MAIA. And that’s where I would still be on the fence, I would still be thinking about maybe adding a PI [proteasome inhibitor] to the IMiD [immunomodulatory drug] instead of daratumumab for those patients. But I think from the tolerability standpoint, I agree, daratumumab/lenalidomide/dexamethasone would probably be the easiest regimen to give to patients. In fact, all of my patients who were on the 3-drug arm on MAIA were taken off of lenalidomide/dexamethasone because of cytopenia issues and had been cruising on just once-a-month daratumumab. So I think that’s the other thing, that you’d be able to take patients off the partner drugs and just keep them on daratumumab.

Sagar Lonial, MD, FACP: Krina, you were mentioning QOL [quality of life]. How do you think that fits in with what we know about whether it’s daratumumab/lenalidomide/dexamethasone or bortezomib/lenalidomide/dexamethasone, and we know that there is a trial in progress using bortezomib/lenalidomide/dexamethasone plus daratumumab for a frail patient.

Krina K. Patel, MD, MSc: Coming back to the definition of frail and who really is transplant-ineligible, for me 80% of my patients still go to a transplant. So you have to have an organ reason as to why you don’t get a transplant, pulmonary or cardiac. And I think quality of life is so important in these patients because I don’t want to harm them. My goal is to help them and actually improve their quality of life. And what was surprising at the trial that was presented, that the quality of life in the MAIA, the daratumumab/lenalidomide/dexamethasone versus lenalidomide/dexamethasone, patients actually had better quality of life with daratumumab/lenalidomide/dexamethasone, so adding that third drug for a frail patient doesn’t actually make them more toxic. The idea was that there were fewer patients who came off the daratumumab/lenalidomide/dexamethasone as well compared to lenalidomide/dexamethasone. So hopefully it was because of better disease control, potentially. I think those are really important factors, especially in our frail patients, to look at.

Sagar Lonial, MD, FACP: I think you raised a really important question, and I think we have 5 transplanters sitting at the table here. Whenever I bring up the artificial age barrier of 65 and I’m in Europe, they all look at me like I’m crazy. And I think practically speaking, how do you all approach transplant in a 70- to 74-year-old? At least at our center it’s not a no unless they’re, as you mentioned, pretty frail or they have uncontrolled diabetes or something else. I’m curious how, on the West Coast and the East Coast, how it’s managed.

Amrita Y. Krishnan, MD: In California a 75-year-old is an Atlanta 50-year-old.

Sagar Lonial, MD, FACP: I’m 50.

Amrita Y. Krishnan, MD: We don’t have large phase III trials, but we have comparative studies…transplant-related mortality is similar, engraftment is similar, and PFS benefit is similar. So I have no issue in terms of transplanting that 70- to 75-year-old.

Thomas G. Martin, MD: It is really about fitness more than age, and I think we all believe in that. And most of us can tell the first 5 seconds that we’re in the room whether that patient is really going to be a transplant person or not. And I think we all go to transplant as to provide a deeper response.

Sagar Lonial, MD, FACP: Saad?
 
Saad Z. Usmani, MD, FACP: I agree with that. And then there are patients who may not look like transplant-eligible at the time when they’re diagnosed because of sequalae of disease, but that too gets better as you cytoreduce and their performance status improves. So I think, again, it’s not a 1 time point evaluation. I think we look at those patients during the course of induction. Many times they may actually look transplant-eligible, but they declare themselves as ineligible, based on how they handle induction.

Amrita Y. Krishnan, MD: But the one point I would make is the alternative is maybe shifting, because the alternative is that you’re going to keep someone on RVd [lenalidomide/bortezomib/dexamethasone] for 8, 12 cycles with neuropathy in a patient over 70. And now with MAIA, the alternative may be better, so that may be a shift a little bit in our thinking as well.

Sagar Lonial, MD, FACP: You would say put them on something less intense and not even collect cells and think about transplant. I guess that’s the question because sometimes you can reduce the risk of long-term complications by consolidating early and moving on, right?

Amrita Y. Krishnan, MD: But we never really just move on, right? We’re always going to keep them on lenalidomide or keep them on something. I guess the question becomes do you do just daratumumab/lenalidomide/dexamethasone, collect cells, but not transplant in someone in that 70- to 75-year-old range? And I don’t think that’s an unreasonable discussion to have, at least with standard-risk patients.

Sagar Lonial, MD, FACP: Krina?

Krina K. Patel, MD, MSc: And we’re quick on decreasing the melphalan to 140 mg, and so to me 75 is an artificial age. I have 84-, 85-year-olds who go to transplant. We worry about MDS [myelodysplastic syndrome] and that’s something we’re looking at, of course, but with the melphalan 140 they do really well. They don’t have adverse effects, and then I get off the Revlimid after a little while, and they have great response, golfing and doing everything they want to do again. So I don’t think age should be a cutoff.

Amrita Y. Krishnan, MD: But I do think you raise a good point because as we learn more about clonal hematopoiesis increasing as you age, I think that may also make us a little bit smarter about deciding if we’re going to transplant someone.

Saad Z. Usmani, MD, FACP: I think those are some data being generated by several groups now. When we’re doing those marrows at the time of diagnosis, we’re looking at CHIP [clonal hematopoiesis of indeterminate potential] in those patients from the get-go and maybe we’ll have more information about which patients to avoid lenalidomide maintenance in.

Sagar Lonial, MD, FACP: I was going to say do you want to give that patient daratumumab/lenalidomide/dexamethasone then, if you’re worried about CHIP? Let’s go back to your paradigm-changing.

Saad Z. Usmani, MD, FACP: Maybe take them off of lenalidomide/dexamethasone quickly and just keep them on daratumumab.

Sagar Lonial, MD, FACP: Interesting. All right, good.


Transcript Edited for Clarity

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Transcript: 

Sagar Lonial, MD, FACP: Let’s switch gears a little bit and talk about the transplant-ineligible patients. I have to say it’s a distinction that drives me crazy because I don’t like the 65 years old arbitrary distinction that the Europeans have given us. For me, it’s about frail, the truly frail people where you’re even going to have trouble getting them through their initial therapy. We had melphalan-based approaches for decades. We replaced that with LEN-DEX [lenalidomide/dexamethasone]. SWOG gave us VRd [bortezomib/lenalidomide/dexamethasone] being better than Rd [lenalidomide/dexamethasone] for those patients, and now we have Saad’s trial with DRd [daratumumab/lenalidomide/dexamethasone]. Where do you guys sit on how to use that, and how do you approach your folks?

Thomas G. Martin, MD: I would say that the 2 big trials obviously are ALCYONE and MAIA, and those are both daratumumab-containing trials, and they’re both large phase III trials in the transplant-ineligible patients. The daratumumab-containing arm in both trials had overall response rates of greater than 90%, improved PFS [progression-free survival], and improved MRD [minimal residual disease]-negativity rates. In fact, the 30-month PFS in the DARA/VMP [daratumumab/bortezomib/melphalan/prednisone] arm was 60%, and in 30-month PFS, the DARA/Rd [daratumumab/lenalidomide/dexamethasone] arm was 71%. So that’s pretty impressive actually for a triplet and a quadruplet. Now, we don’t really use this quadruplet much in the United States and that, even though it’s an approved regimen in the United States, has not really caught on and I don’t think many of us have used it. In fact, I don’t think I’ve ever prescribed it. But daratumumab/lenalidomide/dexamethasone, especially for the transplant-ineligible patients, is a great regimen. In terms of quality of life and the ability to continue the regimen for a long time, it’s a very easy regimen to give, especially after you get into every-4-week daratumumab.

Sagar Lonial, MD, FACP: Saad, you presented some data on age and the effect of age. Do you want to talk a little bit about that?

Saad Z. Usmani, MD, FACP: Sure. One of the unique features about the MAIA trial was the proportion of patients enrolled who were 75 or older, and that’s the patient population that we truly believe is transplant-ineligible. This analysis actually looked at response rates and median PFS for that specific group. There were no differences between the younger than 75 versus 75 or older in terms of the PFS benefit that patients get. The only thing that we saw—again, with small numbers of patients, as only 14% of the patients were high risk—was that benefit was not seen for the high-risk patients in MAIA. And that’s where I would still be on the fence, I would still be thinking about maybe adding a PI [proteasome inhibitor] to the IMiD [immunomodulatory drug] instead of daratumumab for those patients. But I think from the tolerability standpoint, I agree, daratumumab/lenalidomide/dexamethasone would probably be the easiest regimen to give to patients. In fact, all of my patients who were on the 3-drug arm on MAIA were taken off of lenalidomide/dexamethasone because of cytopenia issues and had been cruising on just once-a-month daratumumab. So I think that’s the other thing, that you’d be able to take patients off the partner drugs and just keep them on daratumumab.

Sagar Lonial, MD, FACP: Krina, you were mentioning QOL [quality of life]. How do you think that fits in with what we know about whether it’s daratumumab/lenalidomide/dexamethasone or bortezomib/lenalidomide/dexamethasone, and we know that there is a trial in progress using bortezomib/lenalidomide/dexamethasone plus daratumumab for a frail patient.

Krina K. Patel, MD, MSc: Coming back to the definition of frail and who really is transplant-ineligible, for me 80% of my patients still go to a transplant. So you have to have an organ reason as to why you don’t get a transplant, pulmonary or cardiac. And I think quality of life is so important in these patients because I don’t want to harm them. My goal is to help them and actually improve their quality of life. And what was surprising at the trial that was presented, that the quality of life in the MAIA, the daratumumab/lenalidomide/dexamethasone versus lenalidomide/dexamethasone, patients actually had better quality of life with daratumumab/lenalidomide/dexamethasone, so adding that third drug for a frail patient doesn’t actually make them more toxic. The idea was that there were fewer patients who came off the daratumumab/lenalidomide/dexamethasone as well compared to lenalidomide/dexamethasone. So hopefully it was because of better disease control, potentially. I think those are really important factors, especially in our frail patients, to look at.

Sagar Lonial, MD, FACP: I think you raised a really important question, and I think we have 5 transplanters sitting at the table here. Whenever I bring up the artificial age barrier of 65 and I’m in Europe, they all look at me like I’m crazy. And I think practically speaking, how do you all approach transplant in a 70- to 74-year-old? At least at our center it’s not a no unless they’re, as you mentioned, pretty frail or they have uncontrolled diabetes or something else. I’m curious how, on the West Coast and the East Coast, how it’s managed.

Amrita Y. Krishnan, MD: In California a 75-year-old is an Atlanta 50-year-old.

Sagar Lonial, MD, FACP: I’m 50.

Amrita Y. Krishnan, MD: We don’t have large phase III trials, but we have comparative studies…transplant-related mortality is similar, engraftment is similar, and PFS benefit is similar. So I have no issue in terms of transplanting that 70- to 75-year-old.

Thomas G. Martin, MD: It is really about fitness more than age, and I think we all believe in that. And most of us can tell the first 5 seconds that we’re in the room whether that patient is really going to be a transplant person or not. And I think we all go to transplant as to provide a deeper response.

Sagar Lonial, MD, FACP: Saad?
 
Saad Z. Usmani, MD, FACP: I agree with that. And then there are patients who may not look like transplant-eligible at the time when they’re diagnosed because of sequalae of disease, but that too gets better as you cytoreduce and their performance status improves. So I think, again, it’s not a 1 time point evaluation. I think we look at those patients during the course of induction. Many times they may actually look transplant-eligible, but they declare themselves as ineligible, based on how they handle induction.

Amrita Y. Krishnan, MD: But the one point I would make is the alternative is maybe shifting, because the alternative is that you’re going to keep someone on RVd [lenalidomide/bortezomib/dexamethasone] for 8, 12 cycles with neuropathy in a patient over 70. And now with MAIA, the alternative may be better, so that may be a shift a little bit in our thinking as well.

Sagar Lonial, MD, FACP: You would say put them on something less intense and not even collect cells and think about transplant. I guess that’s the question because sometimes you can reduce the risk of long-term complications by consolidating early and moving on, right?

Amrita Y. Krishnan, MD: But we never really just move on, right? We’re always going to keep them on lenalidomide or keep them on something. I guess the question becomes do you do just daratumumab/lenalidomide/dexamethasone, collect cells, but not transplant in someone in that 70- to 75-year-old range? And I don’t think that’s an unreasonable discussion to have, at least with standard-risk patients.

Sagar Lonial, MD, FACP: Krina?

Krina K. Patel, MD, MSc: And we’re quick on decreasing the melphalan to 140 mg, and so to me 75 is an artificial age. I have 84-, 85-year-olds who go to transplant. We worry about MDS [myelodysplastic syndrome] and that’s something we’re looking at, of course, but with the melphalan 140 they do really well. They don’t have adverse effects, and then I get off the Revlimid after a little while, and they have great response, golfing and doing everything they want to do again. So I don’t think age should be a cutoff.

Amrita Y. Krishnan, MD: But I do think you raise a good point because as we learn more about clonal hematopoiesis increasing as you age, I think that may also make us a little bit smarter about deciding if we’re going to transplant someone.

Saad Z. Usmani, MD, FACP: I think those are some data being generated by several groups now. When we’re doing those marrows at the time of diagnosis, we’re looking at CHIP [clonal hematopoiesis of indeterminate potential] in those patients from the get-go and maybe we’ll have more information about which patients to avoid lenalidomide maintenance in.

Sagar Lonial, MD, FACP: I was going to say do you want to give that patient daratumumab/lenalidomide/dexamethasone then, if you’re worried about CHIP? Let’s go back to your paradigm-changing.

Saad Z. Usmani, MD, FACP: Maybe take them off of lenalidomide/dexamethasone quickly and just keep them on daratumumab.

Sagar Lonial, MD, FACP: Interesting. All right, good.


Transcript Edited for Clarity
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