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Impact of Maintenance Therapy in Myeloma

Panelists: A. Keith Stewart, MB, ChB, Mayo Clinic; Cristina Gasparetto, MD, Duke University Medical Center; Parameswaran Hari, MD, MRCP, MS, Medical College of Wisconsin; Robert Orlowski, MD, PhD, MD Anderson Cancer Center; Noopur Suresh Raje, MD, Massachusetts General Hospital
Published: Friday, Feb 09, 2018



Transcript: 

A. Keith Stewart, MB, ChB: Let’s go back to the elderly for a second. What about IRd/ixazomib with lenalidomide/dexamethasone in that setting? Have you had experience with that?

Noopur Suresh Raje, MD: We’ve certainly used ixazomib in patients, and I do think it’s a perfect drug for the older patient population. Rd, which is going to be the TOURMALINE trial in the up-front setting, will hopefully be read out sometime next year. Ixazomib, as all of you know, is a weekly oral drug, extremely well tolerated, and they’ve seen very high response rates with that as well.

A. Keith Stewart, MB, ChB: Christina, you’ve used ixazomib at all in the elderly group yet?

Cristina Gasparetto, MD: Yes, occasionally. It’s difficult, unfortunately, outside of a clinical trial to justify it up front. For patients, for instance, you start the RVd-lite, and if you have toxicity it makes sense to substitute the bortezomib with ixazomib, which is relatively well tolerated.

A. Keith Stewart, MB, ChB: So, your group, Bob, at this meeting is talking about using ixazomib in the maintenance setting. Do you want to give us a little update on what you’re doing there?

Robert Orlowski, MD, PhD: We are reporting a couple of trials, actually: one each with ixazomib and lenalidomide, which is a little bit more mature. And we’ve done that as a posttransplant maintenance. The safety is excellent. The tolerability is very good. The 2-year progression-free survival is a little bit north of 80%, which is positive. And then, we also have a trial of lenalidomide with elotuzumab, which isn’t finished enrolling yet, so the data are not quite that mature but actually look more like an 85% 2-year progression-free survival. And on that trial, the only people so far who have progressed are folks with high-risk disease. So, those may be applicable also to the older patients. The one other thing I’d say briefly about the older patient population, right now, we think that a proteasome inhibitor and an IMiD combo is the best, so certainly RVd-lite or ixazomib/lenalidomide/dexamethasone is great. But it will be very interesting to see the antibody data when we see lenalidomide/elotuzumab or lenalidomide/daratumumab. And before we rush to do 4 drugs in older patients—where I think it’s going to be tougher because they’re not going to tolerate them as well—I think the next question is, should we do an IMiD and a PI or an IMiD and an antibody in the older patients?

A. Keith Stewart, MB, ChB: Right. So, let’s talk about maintenance a little bit, and I’ll let anybody answer this one just to see who hits the buzzer first. What’s your strategy in maintenance today?

Parameswaran Hari, MD, MRCP, MS: Posttransplant maintenance? I think distinguishing between maintenance and continuous therapy. I think Noopur already made the point that we are in continuous therapy.

A. Keith Stewart, MB, ChB: By continuous, what does that mean? Until relapse or for 2 years? How long?

Parameswaran Hari, MD, MRCP, MS: Until progression, really, with some form of maintenance at that point. So, if you do ixazomib/Rd as the up-front treatment in a transplant-ineligible patient, as we just talked about, you would continue either R (lenalidomide) or I (ixazomib) as the maintenance program until progression, which I think we have sufficient data on from the first trial and many other data that continuing treatment in some form is beneficial.

A. Keith Stewart, MB, ChB: What about long-term toxicity? Don’t you worry about that just a little bit?

Parameswaran Hari, MD, MRCP, MS: Absolutely. The second primary malignancy signal, although it’s much higher in the posttransplant maintenance setting, that is a signal. And there is financial toxicity, plus a lot of people have to discontinue. If you look at all the studies of maintenance that have been presented at this meeting, the discontinuation rates in the lenalidomide maintenance arms are in the 10% to 14%, which is…

A. Keith Stewart, MB, ChB: I’m going to put each of you on the spot here. Whether it’s an elderly or a younger patient maintenance strategy, what do you do for low risk? What do you do for high risk? One sentence each.

Parameswaran Hari, MD, MRCP, MS: For high-risk patients, 2-drug maintenance, which is a proteasome inhibitor plus IMiD. Low-risk, 1 drug, most often an IMiD.

A. Keith Stewart, MB, ChB: And what proteasome inhibitor?

Parameswaran Hari, MD, MRCP, MS: It used to be Velcade/Revlimid, now it’s more ixazomib/Revlimid.

A. Keith Stewart, MB, ChB: Noopur?

Noopur Suresh Raje, MD: Same thing, no change.

A. Keith Stewart, MB, ChB: Christina?

Cristina Gasparetto, MD: Same thing.

Robert Orlowski, MD, PhD: Similar. I would just mention there is a large phase III study being presented by Sara Bringhen where they compared lenalidomide to lenalidomide with prednisone at ASH here. And the lenalidomide/prednisone arm looked a little bit better. I would still be a little bit concerned.

A. Keith Stewart, MB, ChB: For PFS though? Because I’ve seen that before. This is an old story with the thalidomide days.

Robert Orlowski, MD, PhD: It’s true. I would still be a little bit concerned about toxicity. And what I would argue, although they didn’t look at this, is that maybe if you achieve MRD negativity on lenalidomide alone, go for that. But if you don’t for some reason, maybe adding some kind of corticosteroid to get that last little bit out of there could be reasonable.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: Let’s go back to the elderly for a second. What about IRd/ixazomib with lenalidomide/dexamethasone in that setting? Have you had experience with that?

Noopur Suresh Raje, MD: We’ve certainly used ixazomib in patients, and I do think it’s a perfect drug for the older patient population. Rd, which is going to be the TOURMALINE trial in the up-front setting, will hopefully be read out sometime next year. Ixazomib, as all of you know, is a weekly oral drug, extremely well tolerated, and they’ve seen very high response rates with that as well.

A. Keith Stewart, MB, ChB: Christina, you’ve used ixazomib at all in the elderly group yet?

Cristina Gasparetto, MD: Yes, occasionally. It’s difficult, unfortunately, outside of a clinical trial to justify it up front. For patients, for instance, you start the RVd-lite, and if you have toxicity it makes sense to substitute the bortezomib with ixazomib, which is relatively well tolerated.

A. Keith Stewart, MB, ChB: So, your group, Bob, at this meeting is talking about using ixazomib in the maintenance setting. Do you want to give us a little update on what you’re doing there?

Robert Orlowski, MD, PhD: We are reporting a couple of trials, actually: one each with ixazomib and lenalidomide, which is a little bit more mature. And we’ve done that as a posttransplant maintenance. The safety is excellent. The tolerability is very good. The 2-year progression-free survival is a little bit north of 80%, which is positive. And then, we also have a trial of lenalidomide with elotuzumab, which isn’t finished enrolling yet, so the data are not quite that mature but actually look more like an 85% 2-year progression-free survival. And on that trial, the only people so far who have progressed are folks with high-risk disease. So, those may be applicable also to the older patients. The one other thing I’d say briefly about the older patient population, right now, we think that a proteasome inhibitor and an IMiD combo is the best, so certainly RVd-lite or ixazomib/lenalidomide/dexamethasone is great. But it will be very interesting to see the antibody data when we see lenalidomide/elotuzumab or lenalidomide/daratumumab. And before we rush to do 4 drugs in older patients—where I think it’s going to be tougher because they’re not going to tolerate them as well—I think the next question is, should we do an IMiD and a PI or an IMiD and an antibody in the older patients?

A. Keith Stewart, MB, ChB: Right. So, let’s talk about maintenance a little bit, and I’ll let anybody answer this one just to see who hits the buzzer first. What’s your strategy in maintenance today?

Parameswaran Hari, MD, MRCP, MS: Posttransplant maintenance? I think distinguishing between maintenance and continuous therapy. I think Noopur already made the point that we are in continuous therapy.

A. Keith Stewart, MB, ChB: By continuous, what does that mean? Until relapse or for 2 years? How long?

Parameswaran Hari, MD, MRCP, MS: Until progression, really, with some form of maintenance at that point. So, if you do ixazomib/Rd as the up-front treatment in a transplant-ineligible patient, as we just talked about, you would continue either R (lenalidomide) or I (ixazomib) as the maintenance program until progression, which I think we have sufficient data on from the first trial and many other data that continuing treatment in some form is beneficial.

A. Keith Stewart, MB, ChB: What about long-term toxicity? Don’t you worry about that just a little bit?

Parameswaran Hari, MD, MRCP, MS: Absolutely. The second primary malignancy signal, although it’s much higher in the posttransplant maintenance setting, that is a signal. And there is financial toxicity, plus a lot of people have to discontinue. If you look at all the studies of maintenance that have been presented at this meeting, the discontinuation rates in the lenalidomide maintenance arms are in the 10% to 14%, which is…

A. Keith Stewart, MB, ChB: I’m going to put each of you on the spot here. Whether it’s an elderly or a younger patient maintenance strategy, what do you do for low risk? What do you do for high risk? One sentence each.

Parameswaran Hari, MD, MRCP, MS: For high-risk patients, 2-drug maintenance, which is a proteasome inhibitor plus IMiD. Low-risk, 1 drug, most often an IMiD.

A. Keith Stewart, MB, ChB: And what proteasome inhibitor?

Parameswaran Hari, MD, MRCP, MS: It used to be Velcade/Revlimid, now it’s more ixazomib/Revlimid.

A. Keith Stewart, MB, ChB: Noopur?

Noopur Suresh Raje, MD: Same thing, no change.

A. Keith Stewart, MB, ChB: Christina?

Cristina Gasparetto, MD: Same thing.

Robert Orlowski, MD, PhD: Similar. I would just mention there is a large phase III study being presented by Sara Bringhen where they compared lenalidomide to lenalidomide with prednisone at ASH here. And the lenalidomide/prednisone arm looked a little bit better. I would still be a little bit concerned.

A. Keith Stewart, MB, ChB: For PFS though? Because I’ve seen that before. This is an old story with the thalidomide days.

Robert Orlowski, MD, PhD: It’s true. I would still be a little bit concerned about toxicity. And what I would argue, although they didn’t look at this, is that maybe if you achieve MRD negativity on lenalidomide alone, go for that. But if you don’t for some reason, maybe adding some kind of corticosteroid to get that last little bit out of there could be reasonable.

Transcript Edited for Clarity 
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