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Role of Transplantation, Maintenance, and Early Versus Late Response

Insights From: Ajai Chari, MD, Icahn School of Medicine at Mount Sinai; Andrzej Jakubowiak, MD, PhD, University of Chicago; Sagar Lonial, MD, Winship Cancer Institute of Emory University
Published: Thursday, Jan 03, 2019



Transcript: 

Ajai Chari, MD: With respect to how to pick the front-line therapy, there is no right answer, but typically what we have learned so far is that triplets seem to do better than doublets, and we’ve been doing that for a while, but the SWOG-S0777 study supports the use of VRD [bortezomib (Velcade)/lenalidomide (Revlimid)/dexamethasone] over RD [lenalidomide (Revlimid)/dexamethasone] based on response rate, PFS [progression-free survival], and OS [overall survival]. So I think that’s been established; that was without an intent to transplant. So I think that a lot of patients and community doctors in the United States are already using. Carfilzomib/lenalidomide/dexamethasone has also been used front line. Probably we use it and think about it more for high-risk patients, particularly those who are young, without cardiac issues.

And, of course, the question out there is: How will the addition of monoclonal antibodies, particularly daratumumab, up front lead to these improvements or changes in front-line therapy? And we already have an example of dara [daratumumab]/VMP [bortezomib (Velcade), melphalan, prednisone], the ALCYONE study, showing improvement in PFS, in response rate, with the addition of dara to VMP. But I think data are eagerly awaited from the Griffin study, where VRD plus or minus dara randomization should be reading out shortly to guide that new therapy.

In terms of how the front-line therapy affects subsequent therapies, I think it’s important to distinguish, and there’s a lot of concern that using too many drugs up front might compromise with later outcomes. But we have to remember that when we start with 3 or, perhaps in the future, 4 drugs, it doesn’t mean that each one of those drugs is being used until progression. We do an initial debulking, and then we consider transplant as a consolidation for those who are eligible. And then, whether they’re transplant eligible or not, eventually you’re going to minimize the therapy and pick 1 [or] perhaps 2 drugs, depending on the patient’s risk profile, to maintain. So I think that should alleviate a lot of concern that you’re not using 3 to 4 drugs forever, and you’re not going to then breed resistance to all the drugs, just the 1 or 2 that would be used to maintain the remission.

Sagar Lonial, MD: I think the question around the role of transplantation and the management of patients in 2018 is an important one, and I think for patients who are fit, and I don’t use an age cutoff to make that distinction, collection of stem cells following 4 cycles of induction, followed by transplantation in first remission, does remain the standard. I think that there are a lot of data evaluating, potentially delaying or eliminating, the use of transplant. But it’s important to remember that in every trial that is tested, gray induction X plus transplant versus gray induction X without a transplant, the duration of remission is longer, even in the transplant group. So I think, at least with available data, transplant does remain an important goal.

If one’s going to think about a transplant, usually we typically want to collect cells after cycle 4. You don’t have to use that as an absolute limit, but the more therapy, particularly with lenalidomide, that a patient has, the more difficult it may be to collect stem cells. So typically we like to collect after 4, and then usually we go to transplant after 4 cycles. We may give an additional cycle or 2, depending on their response.
I think the maintenance question is an important one to handle in a number of different settings. It’s clear that in the posttransplant setting, lenalidomide maintenance has become the standard based on large randomized trials. I will tell you that I think that [lenalidomide] maintenance is effective except in the high-risk subset of patients. And our group has data suggesting that for the [chromosome] 414, bortezomib or proteasome inhibitor–based maintenance is probably better, and that in truly high risks, 17p, combination maintenance therapy probably is a standard recommendation. And our group, as well as groups in Minnesota, at Mayo, as well as other groups, has recommended a risk-adapted maintenance strategy. For non–transplant-eligible patients, lenalidomide does have good data, and there are emerging data on the use of proteasome inhibitors as well.

Emerging agents such as ixazomib; there are some data on bortezomib. There may also be additional data coming very soon on the use of antibodies such as daratumumab and elotuzumab that may also be useful in the non–transplant-eligible patient.

Andrzej Jakubowiak, MD, PhD: Early versus late response generally matters. Early responders are, for the most part, more likely to achieve deeper, longer response. Although it is valuable, and it may potentially be affected by other factors, including biology of the disease, still there is a sense that earlier responders seem to be having generally longer remissions. But I would like to also emphasize that I have observed, and it is established as phenomenon, that some subsets of myeloma have consistent ongoing and deepening response over time. And those who respond later will eventually also be having potentially as good an outcome as those early responders. In some of the studies that I conducted, we have done analysis to see whether there is any difference in outcome, and we have not seen a dramatic difference in those types of correlations.

Transcript Edited for Clarity 
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Transcript: 

Ajai Chari, MD: With respect to how to pick the front-line therapy, there is no right answer, but typically what we have learned so far is that triplets seem to do better than doublets, and we’ve been doing that for a while, but the SWOG-S0777 study supports the use of VRD [bortezomib (Velcade)/lenalidomide (Revlimid)/dexamethasone] over RD [lenalidomide (Revlimid)/dexamethasone] based on response rate, PFS [progression-free survival], and OS [overall survival]. So I think that’s been established; that was without an intent to transplant. So I think that a lot of patients and community doctors in the United States are already using. Carfilzomib/lenalidomide/dexamethasone has also been used front line. Probably we use it and think about it more for high-risk patients, particularly those who are young, without cardiac issues.

And, of course, the question out there is: How will the addition of monoclonal antibodies, particularly daratumumab, up front lead to these improvements or changes in front-line therapy? And we already have an example of dara [daratumumab]/VMP [bortezomib (Velcade), melphalan, prednisone], the ALCYONE study, showing improvement in PFS, in response rate, with the addition of dara to VMP. But I think data are eagerly awaited from the Griffin study, where VRD plus or minus dara randomization should be reading out shortly to guide that new therapy.

In terms of how the front-line therapy affects subsequent therapies, I think it’s important to distinguish, and there’s a lot of concern that using too many drugs up front might compromise with later outcomes. But we have to remember that when we start with 3 or, perhaps in the future, 4 drugs, it doesn’t mean that each one of those drugs is being used until progression. We do an initial debulking, and then we consider transplant as a consolidation for those who are eligible. And then, whether they’re transplant eligible or not, eventually you’re going to minimize the therapy and pick 1 [or] perhaps 2 drugs, depending on the patient’s risk profile, to maintain. So I think that should alleviate a lot of concern that you’re not using 3 to 4 drugs forever, and you’re not going to then breed resistance to all the drugs, just the 1 or 2 that would be used to maintain the remission.

Sagar Lonial, MD: I think the question around the role of transplantation and the management of patients in 2018 is an important one, and I think for patients who are fit, and I don’t use an age cutoff to make that distinction, collection of stem cells following 4 cycles of induction, followed by transplantation in first remission, does remain the standard. I think that there are a lot of data evaluating, potentially delaying or eliminating, the use of transplant. But it’s important to remember that in every trial that is tested, gray induction X plus transplant versus gray induction X without a transplant, the duration of remission is longer, even in the transplant group. So I think, at least with available data, transplant does remain an important goal.

If one’s going to think about a transplant, usually we typically want to collect cells after cycle 4. You don’t have to use that as an absolute limit, but the more therapy, particularly with lenalidomide, that a patient has, the more difficult it may be to collect stem cells. So typically we like to collect after 4, and then usually we go to transplant after 4 cycles. We may give an additional cycle or 2, depending on their response.
I think the maintenance question is an important one to handle in a number of different settings. It’s clear that in the posttransplant setting, lenalidomide maintenance has become the standard based on large randomized trials. I will tell you that I think that [lenalidomide] maintenance is effective except in the high-risk subset of patients. And our group has data suggesting that for the [chromosome] 414, bortezomib or proteasome inhibitor–based maintenance is probably better, and that in truly high risks, 17p, combination maintenance therapy probably is a standard recommendation. And our group, as well as groups in Minnesota, at Mayo, as well as other groups, has recommended a risk-adapted maintenance strategy. For non–transplant-eligible patients, lenalidomide does have good data, and there are emerging data on the use of proteasome inhibitors as well.

Emerging agents such as ixazomib; there are some data on bortezomib. There may also be additional data coming very soon on the use of antibodies such as daratumumab and elotuzumab that may also be useful in the non–transplant-eligible patient.

Andrzej Jakubowiak, MD, PhD: Early versus late response generally matters. Early responders are, for the most part, more likely to achieve deeper, longer response. Although it is valuable, and it may potentially be affected by other factors, including biology of the disease, still there is a sense that earlier responders seem to be having generally longer remissions. But I would like to also emphasize that I have observed, and it is established as phenomenon, that some subsets of myeloma have consistent ongoing and deepening response over time. And those who respond later will eventually also be having potentially as good an outcome as those early responders. In some of the studies that I conducted, we have done analysis to see whether there is any difference in outcome, and we have not seen a dramatic difference in those types of correlations.

Transcript Edited for Clarity 
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