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Treatment Regimens for Transplant Ineligible Myeloma

Panelists:Ajai Chari, MD, Mount Sinai Hospital; Sagar Lonial, MD, Emory University School of Medicine; Paul G. Richardson, MD, Harvard Medical School; Jatin J. Shah, MD, MD Anderson Cancer Center; Keith Stewart, MD, CHB, Mayo Clinic
Published: Monday, Feb 01, 2016


Transcript:

Keith Stewart, MB, CHB: So let's move on now to the patient who does, probably, need treatment. We'll start with the transplant ineligible patients. And I did ask a little earlier about frailty, but I want to come back to that because it's becoming a more talked about issue. I've heard people say we should do a formal frailty assessment on each of our patients. It certainly hasn't been my practice, to date.

Sagar Lonial, MD: Yes, we haven't routinely incorporated it into our practice, but I think the principles are things that we certainly do use. And you're right, I guess it's in the eye of the beholder. And if you're unsure, I think as Paul said earlier, and I think you presume that they're going to get better and that the frailty's a consequence of disease, and if they don't, you can always change your treatment approach.

Keith Stewart, MB, CHB: So let's say we have a patient and they're not terribly frail and we're going to treat them, but they're not of the transplant age. Jatin, what are your goals of therapy when you start treatment for that patient?

Jatin J. Shah, MD: I think when you talk about making treatment decisions for patients, at any point, it's really going to be a balance between what the patient's objectives are and trying to meet those. And so I think that when you talk about older patients it's going to be important to have a combination that's safe and well tolerated. That's going to be the critical aspect there.

Keith Stewart, MB, CHB: Safe and well tolerated means you're not going to treat for deep remission, you're going to be more worried about the quality of life or what?

Jatin J. Shah, MD: No, I think you still want to be aggressive with options where I think we have more new options now that are well tolerated, and I think that's the key. So I don't think we need to be less intensive in our approach, but I think we just need to be thoughtful and nuanced, in terms of dose reductions and dose modifications, and more supportive care. Many of our therapies, now, I think are very well tolerated, in fact.

Keith Stewart, MB, CHB: Let me very specifically ask each of you very quickly, I'm going to give you a case and ask you to respond how you would treat it, okay? Let's say an 80-year-old, pretty healthy, I'll take my mother, just think of her. Out walking every day with the dog, pretty active, 80-years-old. Some mild comorbidities, nothing significant. What's your front-line therapy for that patient?

Ajai Chari, MD: Dose-attenuated RVD.

Keith Stewart, MB, CHB: Our standard risk, dose-attenuated and RVD. Sagar Lonial, MD: Yes, either that or RD, depending upon the eyeball test. Keith Stewart, MB, CHB: The frailty index by the Lonial eyeballs it.

Sagar Lonial, MD: Yes, that's right.

Keith Stewart, MB, CHB: Yes. This is relatively healthy. You would RVD?

Sagar Lonial, MD: Modified RVD.

Keith Stewart, MB, CHB: What do you mean by modified, for those watching?

Sagar Lonial, MD: So either weekly dosing of the bortezomib and a lower dose of lenalidomide, lower dose of corticosteroids.

Paul G. Richardson, MD: Yes, exactly. Subcutaneous bortezomib, as well, is critical because that, and then the RVD light regimen, as we affectionately call it, that's critical to reducing neurotoxicity.

Keith Stewart, MB, CHB: What are the actual doses for people watching?

Paul G. Richardson, MD: We use 15 mg, three weeks on, one week off of lenalidomide. The dexamethasone is partnered with the bortezomib on the day of it and the day after, and typically using a lower dose, particularly in patients over the age of 75. And we use subcutaneous bortezomib. Actually on the weekly schedule 1.3 is relatively well tolerated, but a low threshold for going to a milligram.

Ajai Chari, MD: I just wanted to add that, for particularly elderly patients, it's really important to calculate creatinine clearance.

Keith Stewart, MB, CHB: Why?

Ajai Chari, MD: Because, as I'm sure our community oncologists know, even a normal serum creatinine in a small elderly female may be correlated with significant problems.

Keith Stewart, MB, CHB: What difference does that make to a treatment?

Ajai Chari, MD: Because of the lenalidomide being cleared renally.

Keith Stewart, MB, CHB: Do you think that's true? Do you really have to dose reduce lenalidomide?

Ajai Chari, MD: I do.

Paul G. Richardson, MD: I do, I agree.

Ajai Chari, MD: I think, and the label says that. So the point is the label is based on renal clearance, creatinine clearance, and if you don't take the trouble of calculating it, particularly in an older patient, I think you might run into more cytopenia.

Keith Stewart, MB, CHB: Jatin, you didn't have a chance to respond.

Jatin J. Shah, MD: So I think that's a great question. I think that it's a little bit different in terms of what we practice in academic centers where I think that those patients may be a little more biased than the one that you described that's going to come in and drive into Houston, or any of these academic centers, versus what we see in the community, where there may be more older patients in that setting who may not be able to travel, and quite frankly, there are other issues that come into our older patients. They may not be able to come back and forth weekly for Velcade. They may not have the supportive care and social support and caregivers to allow them to do that. So I think that we've got to keep those things in mind. Data supports RVD now, especially with a SWOG Study.

Keith Stewart, MB, CHB: Well since you mentioned it, let's just talk about the SWOG Study for a minute. And that's not RVD light, to be clear.

Paul G. Richardson, MD: No.

Jatin J. Shah, MD: Yes.

Keith Stewart, MB, CHB: Paul, describe the SWOG Study to the audience.

Paul G. Richardson, MD: Yes, the SWOG Study is a very important trial. It's almost 556-patients strong, and it was a randomized comparison of classical RVD with the intravenous route used for bortezomib compared to RD. And basically, it showed an impressive progression-free and overall survival benefit to the three-drug platform compared to the two. And the toxicities are very, actually, well balanced with the exception of neuropathy, which is more of a challenge for the RVD, as one might expect.

And I think the critical message there, as well, is the use of intravenous bortezomib was the choice at the time for this randomized trial, and I think that's very, very important. Subcutaneously, you halve the rate of significant toxicity. So I think that's tremendously valuable to community oncologists going forward. But if I may, Keith, I think beyond RVD and beyond that, we now have other choices.

Keith Stewart, MB, CHB: Let me come back to that.

Paul G. Richardson, MD: Come back to that? Good, good.

Keith Stewart, MB, CHB: What I'm sitting here thinking is about the FIRST trial of lenalidomide and low-dose dexamethasone, maybe even a year ago everybody said that's how you should treat an elderly patient based on this trial, which showed this was superior to MPT, and particularly when you use the lenalidomide for a long period of time, continuous therapy. Are there any patients left? Should everybody get RVD light?

Ajai Chari, MD: I think it's important to distinguish between your initial question is, what would you treat your 80-year-old mother with, versus, what would you do until progression?

Keith Stewart, MB, CHB: I hope she's not watching, by the way.

Ajai Chari, MD: But, I think we might treat with RVD dose-attenuated, but it doesn't mean you have to continue that triple regimen forever. In our practice, we would dose-attenuate that further by eliminating typically the parenteral drug, because it can be difficult to come weekly, and then even drop the dexamethasone, and eventually maintain on a very low dose of lenalidomide.

Keith Stewart, MB, CHB: When you said about that the patients, and a lot of them are out there in the community who can't drive into New York City, or wherever. Do you think lenalidomide/dexamethasone is the right treatment for them, or do you think they should still be offered subcutaneous bortezomib locally?

Jatin J. Shah, MD: Interestingly with the SWOG Study, it's only 8 cycles of RVD they get. So I want to be clear that when they compare RVD to RD, it's actually 8 cycles of RVD, then they go on to Revlimid/dexamethasone, and so, I think that that's actually very helpful, because you don't necessarily need to continue RVD indefinitely. So, this trial very nicely shows that, even with 8 cycles, you get a tremendous improvement in progression-free survival.

Keith Stewart, MB, CHB: And I might be jumping the gun on this a bit, but lenalidomide, how long do you keep it going for you? Is it indefinite or do you stop?

Jatin J. Shah, MD: If they're tolerating and clinically benefiting, and they have a good quality of life, then I think it's reasonable to continue on.

Keith Stewart, MB, CHB: Till progression or; do you do the same thing Paul?

Paul G. Richardson, MD: Yes, we do. I would say, in our view, the overwhelming evidence supports this and we would refer from, in the nontransplant population to the FIRST trial obviously, and then in the transplant eligible population, obviously we've got the Alliance CLGB 100, 104 data that continues to look very promising.

Keith Stewart, MB, CHB: That being, because most people wouldn't know what that is.

Paul G. Richardson, MD: Yes. It's a trial published by Dr. Phil McCarthy and colleagues in the New England Journal of Medicine a few years ago where we showed that lenalidomide, until progression post-transplant, resulted in, not only a significant progression-free survival, but also an overall survival benefit.

Keith Stewart, MB, CHB: And you both; so everybody says treat until progression, but in reality, if you're five years out will you just keep going? Or is progression?

Sagar Lonial, MD: It continues.

Keith Stewart, MB, CHB: Does indefinitely mean 3-1/2 years or when do you stop?

Sagar Lonial, MD: We stop at progression or toxicity.

Keith Stewart, MB, CHB: You'd keep somebody on for 10 years if you had to?

Sagar Lonial, MD: We would, we would.

Ajai Chari, MD: I think that's what the data showed. Every lenalidomide-based study has been treated to progression, not a fixed duration. And I think the number of people who are getting out past three to four years, is probably very small, unfortunately. And at that point, if somebody is lucky enough to have that durable remission, then you go back to the patient. It's a risk benefit question again.

Sagar Lonial, MD: But the median duration of response is over 40 months. So half the patients are getting out that far, it's not a small number.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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Transcript:

Keith Stewart, MB, CHB: So let's move on now to the patient who does, probably, need treatment. We'll start with the transplant ineligible patients. And I did ask a little earlier about frailty, but I want to come back to that because it's becoming a more talked about issue. I've heard people say we should do a formal frailty assessment on each of our patients. It certainly hasn't been my practice, to date.

Sagar Lonial, MD: Yes, we haven't routinely incorporated it into our practice, but I think the principles are things that we certainly do use. And you're right, I guess it's in the eye of the beholder. And if you're unsure, I think as Paul said earlier, and I think you presume that they're going to get better and that the frailty's a consequence of disease, and if they don't, you can always change your treatment approach.

Keith Stewart, MB, CHB: So let's say we have a patient and they're not terribly frail and we're going to treat them, but they're not of the transplant age. Jatin, what are your goals of therapy when you start treatment for that patient?

Jatin J. Shah, MD: I think when you talk about making treatment decisions for patients, at any point, it's really going to be a balance between what the patient's objectives are and trying to meet those. And so I think that when you talk about older patients it's going to be important to have a combination that's safe and well tolerated. That's going to be the critical aspect there.

Keith Stewart, MB, CHB: Safe and well tolerated means you're not going to treat for deep remission, you're going to be more worried about the quality of life or what?

Jatin J. Shah, MD: No, I think you still want to be aggressive with options where I think we have more new options now that are well tolerated, and I think that's the key. So I don't think we need to be less intensive in our approach, but I think we just need to be thoughtful and nuanced, in terms of dose reductions and dose modifications, and more supportive care. Many of our therapies, now, I think are very well tolerated, in fact.

Keith Stewart, MB, CHB: Let me very specifically ask each of you very quickly, I'm going to give you a case and ask you to respond how you would treat it, okay? Let's say an 80-year-old, pretty healthy, I'll take my mother, just think of her. Out walking every day with the dog, pretty active, 80-years-old. Some mild comorbidities, nothing significant. What's your front-line therapy for that patient?

Ajai Chari, MD: Dose-attenuated RVD.

Keith Stewart, MB, CHB: Our standard risk, dose-attenuated and RVD. Sagar Lonial, MD: Yes, either that or RD, depending upon the eyeball test. Keith Stewart, MB, CHB: The frailty index by the Lonial eyeballs it.

Sagar Lonial, MD: Yes, that's right.

Keith Stewart, MB, CHB: Yes. This is relatively healthy. You would RVD?

Sagar Lonial, MD: Modified RVD.

Keith Stewart, MB, CHB: What do you mean by modified, for those watching?

Sagar Lonial, MD: So either weekly dosing of the bortezomib and a lower dose of lenalidomide, lower dose of corticosteroids.

Paul G. Richardson, MD: Yes, exactly. Subcutaneous bortezomib, as well, is critical because that, and then the RVD light regimen, as we affectionately call it, that's critical to reducing neurotoxicity.

Keith Stewart, MB, CHB: What are the actual doses for people watching?

Paul G. Richardson, MD: We use 15 mg, three weeks on, one week off of lenalidomide. The dexamethasone is partnered with the bortezomib on the day of it and the day after, and typically using a lower dose, particularly in patients over the age of 75. And we use subcutaneous bortezomib. Actually on the weekly schedule 1.3 is relatively well tolerated, but a low threshold for going to a milligram.

Ajai Chari, MD: I just wanted to add that, for particularly elderly patients, it's really important to calculate creatinine clearance.

Keith Stewart, MB, CHB: Why?

Ajai Chari, MD: Because, as I'm sure our community oncologists know, even a normal serum creatinine in a small elderly female may be correlated with significant problems.

Keith Stewart, MB, CHB: What difference does that make to a treatment?

Ajai Chari, MD: Because of the lenalidomide being cleared renally.

Keith Stewart, MB, CHB: Do you think that's true? Do you really have to dose reduce lenalidomide?

Ajai Chari, MD: I do.

Paul G. Richardson, MD: I do, I agree.

Ajai Chari, MD: I think, and the label says that. So the point is the label is based on renal clearance, creatinine clearance, and if you don't take the trouble of calculating it, particularly in an older patient, I think you might run into more cytopenia.

Keith Stewart, MB, CHB: Jatin, you didn't have a chance to respond.

Jatin J. Shah, MD: So I think that's a great question. I think that it's a little bit different in terms of what we practice in academic centers where I think that those patients may be a little more biased than the one that you described that's going to come in and drive into Houston, or any of these academic centers, versus what we see in the community, where there may be more older patients in that setting who may not be able to travel, and quite frankly, there are other issues that come into our older patients. They may not be able to come back and forth weekly for Velcade. They may not have the supportive care and social support and caregivers to allow them to do that. So I think that we've got to keep those things in mind. Data supports RVD now, especially with a SWOG Study.

Keith Stewart, MB, CHB: Well since you mentioned it, let's just talk about the SWOG Study for a minute. And that's not RVD light, to be clear.

Paul G. Richardson, MD: No.

Jatin J. Shah, MD: Yes.

Keith Stewart, MB, CHB: Paul, describe the SWOG Study to the audience.

Paul G. Richardson, MD: Yes, the SWOG Study is a very important trial. It's almost 556-patients strong, and it was a randomized comparison of classical RVD with the intravenous route used for bortezomib compared to RD. And basically, it showed an impressive progression-free and overall survival benefit to the three-drug platform compared to the two. And the toxicities are very, actually, well balanced with the exception of neuropathy, which is more of a challenge for the RVD, as one might expect.

And I think the critical message there, as well, is the use of intravenous bortezomib was the choice at the time for this randomized trial, and I think that's very, very important. Subcutaneously, you halve the rate of significant toxicity. So I think that's tremendously valuable to community oncologists going forward. But if I may, Keith, I think beyond RVD and beyond that, we now have other choices.

Keith Stewart, MB, CHB: Let me come back to that.

Paul G. Richardson, MD: Come back to that? Good, good.

Keith Stewart, MB, CHB: What I'm sitting here thinking is about the FIRST trial of lenalidomide and low-dose dexamethasone, maybe even a year ago everybody said that's how you should treat an elderly patient based on this trial, which showed this was superior to MPT, and particularly when you use the lenalidomide for a long period of time, continuous therapy. Are there any patients left? Should everybody get RVD light?

Ajai Chari, MD: I think it's important to distinguish between your initial question is, what would you treat your 80-year-old mother with, versus, what would you do until progression?

Keith Stewart, MB, CHB: I hope she's not watching, by the way.

Ajai Chari, MD: But, I think we might treat with RVD dose-attenuated, but it doesn't mean you have to continue that triple regimen forever. In our practice, we would dose-attenuate that further by eliminating typically the parenteral drug, because it can be difficult to come weekly, and then even drop the dexamethasone, and eventually maintain on a very low dose of lenalidomide.

Keith Stewart, MB, CHB: When you said about that the patients, and a lot of them are out there in the community who can't drive into New York City, or wherever. Do you think lenalidomide/dexamethasone is the right treatment for them, or do you think they should still be offered subcutaneous bortezomib locally?

Jatin J. Shah, MD: Interestingly with the SWOG Study, it's only 8 cycles of RVD they get. So I want to be clear that when they compare RVD to RD, it's actually 8 cycles of RVD, then they go on to Revlimid/dexamethasone, and so, I think that that's actually very helpful, because you don't necessarily need to continue RVD indefinitely. So, this trial very nicely shows that, even with 8 cycles, you get a tremendous improvement in progression-free survival.

Keith Stewart, MB, CHB: And I might be jumping the gun on this a bit, but lenalidomide, how long do you keep it going for you? Is it indefinite or do you stop?

Jatin J. Shah, MD: If they're tolerating and clinically benefiting, and they have a good quality of life, then I think it's reasonable to continue on.

Keith Stewart, MB, CHB: Till progression or; do you do the same thing Paul?

Paul G. Richardson, MD: Yes, we do. I would say, in our view, the overwhelming evidence supports this and we would refer from, in the nontransplant population to the FIRST trial obviously, and then in the transplant eligible population, obviously we've got the Alliance CLGB 100, 104 data that continues to look very promising.

Keith Stewart, MB, CHB: That being, because most people wouldn't know what that is.

Paul G. Richardson, MD: Yes. It's a trial published by Dr. Phil McCarthy and colleagues in the New England Journal of Medicine a few years ago where we showed that lenalidomide, until progression post-transplant, resulted in, not only a significant progression-free survival, but also an overall survival benefit.

Keith Stewart, MB, CHB: And you both; so everybody says treat until progression, but in reality, if you're five years out will you just keep going? Or is progression?

Sagar Lonial, MD: It continues.

Keith Stewart, MB, CHB: Does indefinitely mean 3-1/2 years or when do you stop?

Sagar Lonial, MD: We stop at progression or toxicity.

Keith Stewart, MB, CHB: You'd keep somebody on for 10 years if you had to?

Sagar Lonial, MD: We would, we would.

Ajai Chari, MD: I think that's what the data showed. Every lenalidomide-based study has been treated to progression, not a fixed duration. And I think the number of people who are getting out past three to four years, is probably very small, unfortunately. And at that point, if somebody is lucky enough to have that durable remission, then you go back to the patient. It's a risk benefit question again.

Sagar Lonial, MD: But the median duration of response is over 40 months. So half the patients are getting out that far, it's not a small number.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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