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Consolidation/Maintenance Therapy in Myeloma

Panelists: Keith Stewart, MB, CHB, Mayo Clinic; Sagar Lonial, MD, Winship Cancer Institute; Paul Richardson, MD, Dana-Farber Cancer Institute; Amrita Krishnan, MD, City of Hope Comprehensive Cancer Center; Saad Usmani, MD, Levine Cancer Institute
Published: Monday, Feb 06, 2017



Transcript:

Keith Stewart, MB, CHB:
Let’s talk about, just very briefly, consolidation. Are we using consolidation in everyone? Are we using it only in people who are not in complete remission? Paul?

Paul Richardson, MD: We have been deploying consolidation and building on the IFM/DFCI trial experience of 2 cycles of RVD (Revlimid/Velcade/Dexamethasone). Obviously, in a Clinical Trials Network study, which we participated in, there were 4 RVD cycles. The thing that was interesting to me in the data, Amrita, was the high-risk group. There was a 48% progression-free survival in favor of the RVD consolidation, compared to 40% for the tandem and no-RVD consolidation in the other 2 arms. Now, I think that’s interesting because there may lie a clue. Our policy is: consolidation is reasonable to consider, particularly in high-risk groups. And I would include in that category patients who don’t achieve a complete remission to intensification.

Keith Stewart, MB, CHB: What about maintenance therapy? It seems that all of these trials use maintenance routinely now. Sagar, is the question answered and finished? Should everybody be on lenalidomide maintenance? The English had an update of their trial with lenalidomide maintenance. Maybe you could comment on that as well?

Sagar Lonial, MD: I think across the board, certainly in the meta-analysis, as well as the English, the MRC trial…

Keith Stewart, MB, CHB: The audience may not be familiar with the meta-analysis, so why don’t you tell them what that was?

Sagar Lonial, MD: The meta-analysis is data that was presented at ASCO last year. The data looked at the CALGB trial, which was the United States trial of lenalidomide versus observation. It looked at the French trial, which was also lenalidomide versus observation, and it looked at the Italian study, which was lenalidomide versus observation, as well. Previously, I don’t think, other than the United States trial—the other trials were not necessarily showing improvement in overall survival. But, when you aggregate all 3 of those trials, there’s a clear improvement in overall survival with very long follow-up supporting lenalidomide maintenance.

The MRC trial continues to support that concept of lenalidomide maintenance improving duration of response. And I think what is really quite striking is the only groups that don’t necessarily benefit from lenalidomide maintenance are the high-risk genetic subsets. So, I think there is a role here for tailored maintenance therapy. It’s clear to me that patients benefit from maintenance. The HOVON study that was published years ago looking at bortezomib in the maintenance setting suggested benefit for high-risk subsets. And then, we’ve published a small series suggesting that an IMiD and a proteasome inhibitor, together, really can alter the natural history of patients with 17p deletion.

So, I think there is a tailored approach to maintenance therapy. At our center, for instance, standard risk would get lenalidomide. High-risk with 17p would get RVD as maintenance and t(4;14)s would get bortezomib as maintenance therapy. That’s just an example of one way to think about it.

Keith Stewart, MB, CHB: I think a lot of people are doing that. Saad, it seems like the question of whether to use lenalidomide maintenance is answered. The question now becomes, how long for? Are there minimal residual disease type of techniques that one can use to decide when to stop? I would like to know what your practice is, and how long you treat for?

Saad Usmani, MD: Right now, based on the CALGB- 101 and 104 trial data and this meta-analysis that was just presented at ASCO earlier this year, our practice is to continue lenalidomide maintenance until relapse, or progression, or intolerance. But, I think you ask a very important question here. Do we really need to continue patients on maintenance therapy if they are MRD-negative? This is an important question that Paul and, I believe, Peter Voorhees are trying to develop an answer for within the alliance.

Paul Richardson, MD: I would agree with everything that’s being said, Keith. I think the important point, though, is that in terms of continuous therapy, we have a slightly different approach in that we use lenalidomide as a backbone in everybody, and we do exactly as Sagar does—we deploy bortezomib in higher-risk. But, in the t(4;14)s, for example, we wouldn’t necessarily exclude lenalidomide. The continuous therapy model has been validated again and again. It’s worth mentioning that the overall survival (OS) benefit for using lenalidomide until progression in the meta-analysis was 2.5 years in OS benefit, which was really, to me, the most striking thing.

Keith Stewart, MB, CHB: The British group did a little clever analysis where they looked at people who came off lenalidomide after a year for toxicity—not for disease progression. They compared those with people who stayed on it. What did that show us?

Paul Richardson, MD: I can recall it showing continued benefit, and I think that’s important.

Keith Stewart, MB, CHB: In other words, the ones who didn’t stop did better, right?

Paul Richardson, MD: Well, those who didn’t stop did better, but there was still continued benefit from those who had to stop for toxicity. So, no, I see your point, Keith. In other words, staying on therapy was better than not. That is absolutely correct.

Saad Usmani, MD: Another anecdote was that they actually had a subset of patients within that study where they looked at the gene mutational load at baseline compared to that at the time of relapse in patients who were on lenalidomide maintenance versus not. They did not find any meaningful differences between the 2 groups. I think it’s a smaller subset, but it leads to a very important point.

Keith Stewart, MB, CHB: I guess I’ll tell you, I’m a little bit different. I don’t keep people on lenalidomide forever, because I do worry a little bit about the toxicity in the bone marrow. So, I have been using minimal residual disease testing as a guidepost for whether to continue, usually at the 2-year mark or somewhere around there. Are you using minimal residual disease testing, Amrita? And, if so, what technology do you use?

Amrita Krishnan, MD: We are using it, and mostly in the context of clinical trials. And then, probably more ad hoc. Each individual at our institution is doing it. I would venture to guess this is the same across the board?

Keith Stewart, MB, CHB: Is this flow cytometry or next-generation sequencing?

Amrita Krishnan, MD: We’ve been using next-generation sequencing.

Keith Stewart, MB, CHB: Are people happy with that?

Paul Richardson, MD: We use next-generation sequencing in the context of clinical trials. I will say that, off-protocol, we’re careful. Again, does it change management? I would be cautious there right now. We do firmly believe in the continuous therapy model based on all sorts of data.

Keith Stewart, MB, CHB: I’m an outlier here. I’ll give you a chance to finish.

Amrita Krishnan, MD: My curious question to you, Keith, would be, first of all—I think it’s not just MRD at one timepoint (which is the challenge)—it’s sustained MRD?

Paul Richardson, MD: Exactly.

Amrita Krishnan, MD: And what you would do in a patient who becomes MRD-positive, for example.

Transcript Edited for Clarity

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Transcript:

Keith Stewart, MB, CHB:
Let’s talk about, just very briefly, consolidation. Are we using consolidation in everyone? Are we using it only in people who are not in complete remission? Paul?

Paul Richardson, MD: We have been deploying consolidation and building on the IFM/DFCI trial experience of 2 cycles of RVD (Revlimid/Velcade/Dexamethasone). Obviously, in a Clinical Trials Network study, which we participated in, there were 4 RVD cycles. The thing that was interesting to me in the data, Amrita, was the high-risk group. There was a 48% progression-free survival in favor of the RVD consolidation, compared to 40% for the tandem and no-RVD consolidation in the other 2 arms. Now, I think that’s interesting because there may lie a clue. Our policy is: consolidation is reasonable to consider, particularly in high-risk groups. And I would include in that category patients who don’t achieve a complete remission to intensification.

Keith Stewart, MB, CHB: What about maintenance therapy? It seems that all of these trials use maintenance routinely now. Sagar, is the question answered and finished? Should everybody be on lenalidomide maintenance? The English had an update of their trial with lenalidomide maintenance. Maybe you could comment on that as well?

Sagar Lonial, MD: I think across the board, certainly in the meta-analysis, as well as the English, the MRC trial…

Keith Stewart, MB, CHB: The audience may not be familiar with the meta-analysis, so why don’t you tell them what that was?

Sagar Lonial, MD: The meta-analysis is data that was presented at ASCO last year. The data looked at the CALGB trial, which was the United States trial of lenalidomide versus observation. It looked at the French trial, which was also lenalidomide versus observation, and it looked at the Italian study, which was lenalidomide versus observation, as well. Previously, I don’t think, other than the United States trial—the other trials were not necessarily showing improvement in overall survival. But, when you aggregate all 3 of those trials, there’s a clear improvement in overall survival with very long follow-up supporting lenalidomide maintenance.

The MRC trial continues to support that concept of lenalidomide maintenance improving duration of response. And I think what is really quite striking is the only groups that don’t necessarily benefit from lenalidomide maintenance are the high-risk genetic subsets. So, I think there is a role here for tailored maintenance therapy. It’s clear to me that patients benefit from maintenance. The HOVON study that was published years ago looking at bortezomib in the maintenance setting suggested benefit for high-risk subsets. And then, we’ve published a small series suggesting that an IMiD and a proteasome inhibitor, together, really can alter the natural history of patients with 17p deletion.

So, I think there is a tailored approach to maintenance therapy. At our center, for instance, standard risk would get lenalidomide. High-risk with 17p would get RVD as maintenance and t(4;14)s would get bortezomib as maintenance therapy. That’s just an example of one way to think about it.

Keith Stewart, MB, CHB: I think a lot of people are doing that. Saad, it seems like the question of whether to use lenalidomide maintenance is answered. The question now becomes, how long for? Are there minimal residual disease type of techniques that one can use to decide when to stop? I would like to know what your practice is, and how long you treat for?

Saad Usmani, MD: Right now, based on the CALGB- 101 and 104 trial data and this meta-analysis that was just presented at ASCO earlier this year, our practice is to continue lenalidomide maintenance until relapse, or progression, or intolerance. But, I think you ask a very important question here. Do we really need to continue patients on maintenance therapy if they are MRD-negative? This is an important question that Paul and, I believe, Peter Voorhees are trying to develop an answer for within the alliance.

Paul Richardson, MD: I would agree with everything that’s being said, Keith. I think the important point, though, is that in terms of continuous therapy, we have a slightly different approach in that we use lenalidomide as a backbone in everybody, and we do exactly as Sagar does—we deploy bortezomib in higher-risk. But, in the t(4;14)s, for example, we wouldn’t necessarily exclude lenalidomide. The continuous therapy model has been validated again and again. It’s worth mentioning that the overall survival (OS) benefit for using lenalidomide until progression in the meta-analysis was 2.5 years in OS benefit, which was really, to me, the most striking thing.

Keith Stewart, MB, CHB: The British group did a little clever analysis where they looked at people who came off lenalidomide after a year for toxicity—not for disease progression. They compared those with people who stayed on it. What did that show us?

Paul Richardson, MD: I can recall it showing continued benefit, and I think that’s important.

Keith Stewart, MB, CHB: In other words, the ones who didn’t stop did better, right?

Paul Richardson, MD: Well, those who didn’t stop did better, but there was still continued benefit from those who had to stop for toxicity. So, no, I see your point, Keith. In other words, staying on therapy was better than not. That is absolutely correct.

Saad Usmani, MD: Another anecdote was that they actually had a subset of patients within that study where they looked at the gene mutational load at baseline compared to that at the time of relapse in patients who were on lenalidomide maintenance versus not. They did not find any meaningful differences between the 2 groups. I think it’s a smaller subset, but it leads to a very important point.

Keith Stewart, MB, CHB: I guess I’ll tell you, I’m a little bit different. I don’t keep people on lenalidomide forever, because I do worry a little bit about the toxicity in the bone marrow. So, I have been using minimal residual disease testing as a guidepost for whether to continue, usually at the 2-year mark or somewhere around there. Are you using minimal residual disease testing, Amrita? And, if so, what technology do you use?

Amrita Krishnan, MD: We are using it, and mostly in the context of clinical trials. And then, probably more ad hoc. Each individual at our institution is doing it. I would venture to guess this is the same across the board?

Keith Stewart, MB, CHB: Is this flow cytometry or next-generation sequencing?

Amrita Krishnan, MD: We’ve been using next-generation sequencing.

Keith Stewart, MB, CHB: Are people happy with that?

Paul Richardson, MD: We use next-generation sequencing in the context of clinical trials. I will say that, off-protocol, we’re careful. Again, does it change management? I would be cautious there right now. We do firmly believe in the continuous therapy model based on all sorts of data.

Keith Stewart, MB, CHB: I’m an outlier here. I’ll give you a chance to finish.

Amrita Krishnan, MD: My curious question to you, Keith, would be, first of all—I think it’s not just MRD at one timepoint (which is the challenge)—it’s sustained MRD?

Paul Richardson, MD: Exactly.

Amrita Krishnan, MD: And what you would do in a patient who becomes MRD-positive, for example.

Transcript Edited for Clarity
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