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Transplant-Eligible Multiple Myeloma

Panelists: Paul Richardson, MD, Harvard Medical School; Ajai Chari, MD, Icahn School of Medicine, Mount Sinai; Amrita Krishan, MD, City of Hope Comprehensive Cancer Center; Sagar Lonial, MD, FACP, Emory University School of Medicine; Nina Shah, MD, UCSF; Kenneth Shain, MD, PhD, Moffitt Cancer Center
Published: Tuesday, Feb 11, 2020



Transcript: 

Paul G. Richardson, MD:
Let’s change gears a bit, Amrita. I’d love you to lead the discussion here in terms of transplant-eligible patients, and talk to us a little bit about what you may use as a best regimen as an induction strategy. If you wouldn’t mind, really help us understand one of the most exciting trials in the transplant space, which is Francesca Gay, MD’s FORTE trial.

Amrita Y. Krishnan, MD: I think we touched upon it a little bit earlier in terms of our frail LDH [lactate dehydrogenase] high risk that we’ve moved to carfilzomib-based. I think even more have adopted that in our young patients. Even in our young standard-risk patients more and more of us have been moving toward the carfilzomib, LEN/DEX [lenalidomide, dexamethasone] induction regimen.

And Francesca Gay’s FORTE trial was very interesting because she used KRd [carfilzomib, lenalidomide, dexamethasone], compared it to KCd [carfilzomib, cyclophosphamide, dexamethasone]. No surprise carfilzomib, lenalidomide, dexamethasone was a better regimen in terms of depth of response.

She then went on to try to answer the question most of us want, which is, carfilzomib, lenalidomide, dexamethasone for 12 cycles versus carfilzomib, lenalidomide, dexamethasone, transplanting, more carfilzomib, lenalidomide, dexamethasone. For us as transplanters, it cemented our feelings that carfilzomib, lenalidomide, dexamethasone, transplant was a better option; certainly for the high-risk patients, the risk of relapse is almost 50% lower in the group that got transplanted.

The rate of sustained MRD [minimal residual disease]-negative was higher in the transplant arm. My approach for those young patients certainly would be carfilzomib, lenalidomide, dexamethasone, transplant, and then consider carfilzomib, lenalidomide, dexamethasone, consolidation.

Paul G. Richardson, MD: In that study obviously the maintenance was randomized to lenalidomide versus carfilzomib, lenalidomide. I think there’s a maturity of information that’s going to be very important because I think in terms of high risk, I certainly would never maintain a patient, and we’re coming to this in a moment, with just lenalidomide alone. I do agree that that MRD signal that was equivalent in the early analysis, ASH [American Society of Hematology] annual meeting 2018, with the ASCO [American Society of Clinical Oncology] meeting update from Francesca, we saw that signal from the high-risk group. I think though when you actually look at the numbers they still remain relatively small, but they are significant. I do agree with you that high-risk group clearly seemed to benefit from following the stemness that presumably transplant’s embracing and capturing.

Sagar Lonial, MD, FACP: But I think the only reason that it’s shown up right now is that the high risk are going to relapse sooner. I think if you have long enough follow-up you’re going to see exactly the same thing in the standard risk where the PFS [progression-free survival] is going to suffer. I think it highlights to me one of the presumptive fallacies of the way MRD is being used right now.

That is, that a single time point at some random area is sufficient to make a treatment decision about either, yes, you don’t need a transplant, or no, you need a transplant. I just worry that that’s a message that’s getting out there. MRD is important for 2 big reasons. One, it’s a regulatory end point. If it helps us to get drugs approved quickly, because MRD is a surrogate, that’s great. But the 1 end point that really matters is PFS. I don’t know that you can say that 1 time point is sufficient to predict PFS many years down the road.

Amrita Y. Krishnan, MD: Then I would ask you what your thoughts are on Luciano Costa, MD, PhD’s abstract of using MRD very early post-transplant to direct his maintenance strategy.

Kenneth H. Shain, MD, PhD: Well, I would comment, remember he’s still using 2 MRD-negative data points. It’s 3 months, before and after transplant is the earliest. Three months of MRD, but at least it’s 2….

Amrita Y. Krishnan, MD: So it’s carfilzomib, lenalidomide, dexamethasone induction.

Kenneth H. Shain, MD, PhD: MRD-negative. The earliest you can fall off is if you’re MRD-negative after transplant, then you cannot be on observation. There forward it’s also consolidation plus. At least, you’re right, sustained is at 6 months, 12 months. I don’t think any of know what the answer really should be, 12 months is our rule, it makes a lot of sense. The point of that abstract that was enjoyable is that with the study you are looking at 2 points.

Ajai Chari, MD: I would bet money at next year’s ASH annual meeting we’ll see that those
high-risk patients will have relapsed. I think in 2019 to take high-risk patients and discontinue all therapy based on 2, 3 months separation, is very premature. I think the other important point that came up in our IMW [International Myeloma Workshop] breakfast is that we use MRD, but it’s a little misleading. We should say next-generation sequencing-negative, or next-generation flow cytometry-negative.

Because you could argue, do we say IFE [immunofixation electrophoresis]-negative is MRD-negative? Do we say free light chain normalization is MRD-negative? Just because we have 2 different techniques that are looking at the marrow we can’t, it’s specific. But MRD implies that we’ve done this global assessment of the patient and there’s no disease anywhere, and I think it’s a little misleading and we should just stick to the terms. At this time point, next-generation flow cytometry is negative, or at this time point next-generation sequencing is negative. Then people won’t feel like, “Oh, I can make all these long-term decisions.”

Paul G. Richardson, MD: I think both Sagar and you capture that beautifully, Ajai, that essentially longevity of follow-up is critical. I will just simply share with you that still in our determination trial we are hoping that we’ll have an analysis early next year. But that means the median follow-up is approaching 5 years. We still don’t have a signal, and honestly what I think is so powerful is the impact of maintenance. Because what is so true about our French partners was that if you look at the MRD loss, it all started at 12 months. If you look at that point, the curve started to separate. Even so, with delayed transplant, obviously there were a subset of patients in whom the triplet alone, plus extended maintenance, was conferring significant clinical benefit.

Sagar Lonial, MD, FACP: But you didn’t know that until 18 months after you had to make the decision about transplant.

Nina Shah, MD: You can’t do that.

Paul G. Richardson, MD: I completely agree.

Sagar Lonial, MD, FACP: To say that I can say all MRD-negative people do the same, it’s using hindsight. That’s not very fair.


Transcript Edited for Clarity

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Transcript: 

Paul G. Richardson, MD:
Let’s change gears a bit, Amrita. I’d love you to lead the discussion here in terms of transplant-eligible patients, and talk to us a little bit about what you may use as a best regimen as an induction strategy. If you wouldn’t mind, really help us understand one of the most exciting trials in the transplant space, which is Francesca Gay, MD’s FORTE trial.

Amrita Y. Krishnan, MD: I think we touched upon it a little bit earlier in terms of our frail LDH [lactate dehydrogenase] high risk that we’ve moved to carfilzomib-based. I think even more have adopted that in our young patients. Even in our young standard-risk patients more and more of us have been moving toward the carfilzomib, LEN/DEX [lenalidomide, dexamethasone] induction regimen.

And Francesca Gay’s FORTE trial was very interesting because she used KRd [carfilzomib, lenalidomide, dexamethasone], compared it to KCd [carfilzomib, cyclophosphamide, dexamethasone]. No surprise carfilzomib, lenalidomide, dexamethasone was a better regimen in terms of depth of response.

She then went on to try to answer the question most of us want, which is, carfilzomib, lenalidomide, dexamethasone for 12 cycles versus carfilzomib, lenalidomide, dexamethasone, transplanting, more carfilzomib, lenalidomide, dexamethasone. For us as transplanters, it cemented our feelings that carfilzomib, lenalidomide, dexamethasone, transplant was a better option; certainly for the high-risk patients, the risk of relapse is almost 50% lower in the group that got transplanted.

The rate of sustained MRD [minimal residual disease]-negative was higher in the transplant arm. My approach for those young patients certainly would be carfilzomib, lenalidomide, dexamethasone, transplant, and then consider carfilzomib, lenalidomide, dexamethasone, consolidation.

Paul G. Richardson, MD: In that study obviously the maintenance was randomized to lenalidomide versus carfilzomib, lenalidomide. I think there’s a maturity of information that’s going to be very important because I think in terms of high risk, I certainly would never maintain a patient, and we’re coming to this in a moment, with just lenalidomide alone. I do agree that that MRD signal that was equivalent in the early analysis, ASH [American Society of Hematology] annual meeting 2018, with the ASCO [American Society of Clinical Oncology] meeting update from Francesca, we saw that signal from the high-risk group. I think though when you actually look at the numbers they still remain relatively small, but they are significant. I do agree with you that high-risk group clearly seemed to benefit from following the stemness that presumably transplant’s embracing and capturing.

Sagar Lonial, MD, FACP: But I think the only reason that it’s shown up right now is that the high risk are going to relapse sooner. I think if you have long enough follow-up you’re going to see exactly the same thing in the standard risk where the PFS [progression-free survival] is going to suffer. I think it highlights to me one of the presumptive fallacies of the way MRD is being used right now.

That is, that a single time point at some random area is sufficient to make a treatment decision about either, yes, you don’t need a transplant, or no, you need a transplant. I just worry that that’s a message that’s getting out there. MRD is important for 2 big reasons. One, it’s a regulatory end point. If it helps us to get drugs approved quickly, because MRD is a surrogate, that’s great. But the 1 end point that really matters is PFS. I don’t know that you can say that 1 time point is sufficient to predict PFS many years down the road.

Amrita Y. Krishnan, MD: Then I would ask you what your thoughts are on Luciano Costa, MD, PhD’s abstract of using MRD very early post-transplant to direct his maintenance strategy.

Kenneth H. Shain, MD, PhD: Well, I would comment, remember he’s still using 2 MRD-negative data points. It’s 3 months, before and after transplant is the earliest. Three months of MRD, but at least it’s 2….

Amrita Y. Krishnan, MD: So it’s carfilzomib, lenalidomide, dexamethasone induction.

Kenneth H. Shain, MD, PhD: MRD-negative. The earliest you can fall off is if you’re MRD-negative after transplant, then you cannot be on observation. There forward it’s also consolidation plus. At least, you’re right, sustained is at 6 months, 12 months. I don’t think any of know what the answer really should be, 12 months is our rule, it makes a lot of sense. The point of that abstract that was enjoyable is that with the study you are looking at 2 points.

Ajai Chari, MD: I would bet money at next year’s ASH annual meeting we’ll see that those
high-risk patients will have relapsed. I think in 2019 to take high-risk patients and discontinue all therapy based on 2, 3 months separation, is very premature. I think the other important point that came up in our IMW [International Myeloma Workshop] breakfast is that we use MRD, but it’s a little misleading. We should say next-generation sequencing-negative, or next-generation flow cytometry-negative.

Because you could argue, do we say IFE [immunofixation electrophoresis]-negative is MRD-negative? Do we say free light chain normalization is MRD-negative? Just because we have 2 different techniques that are looking at the marrow we can’t, it’s specific. But MRD implies that we’ve done this global assessment of the patient and there’s no disease anywhere, and I think it’s a little misleading and we should just stick to the terms. At this time point, next-generation flow cytometry is negative, or at this time point next-generation sequencing is negative. Then people won’t feel like, “Oh, I can make all these long-term decisions.”

Paul G. Richardson, MD: I think both Sagar and you capture that beautifully, Ajai, that essentially longevity of follow-up is critical. I will just simply share with you that still in our determination trial we are hoping that we’ll have an analysis early next year. But that means the median follow-up is approaching 5 years. We still don’t have a signal, and honestly what I think is so powerful is the impact of maintenance. Because what is so true about our French partners was that if you look at the MRD loss, it all started at 12 months. If you look at that point, the curve started to separate. Even so, with delayed transplant, obviously there were a subset of patients in whom the triplet alone, plus extended maintenance, was conferring significant clinical benefit.

Sagar Lonial, MD, FACP: But you didn’t know that until 18 months after you had to make the decision about transplant.

Nina Shah, MD: You can’t do that.

Paul G. Richardson, MD: I completely agree.

Sagar Lonial, MD, FACP: To say that I can say all MRD-negative people do the same, it’s using hindsight. That’s not very fair.


Transcript Edited for Clarity
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