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Tailored Therapy for Elderly/Frail Patients With 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: Thursday, Feb 07, 2019



Transcript: 

A. Keith Stewart, MB, ChB:
OK, let’s change track a little bit. We’ve talked a lot about younger patients. We’ve come to the conclusion that 4 drugs are going to be good and MRD [minimal residual disease] negativity is a good goal to strive for. What about elderly patients where perhaps we don’t want to be quite as aggressive? Adriana, what’s your opinion on triplet versus doublet therapy in an elderly patient?

Adriana Rossi, MD: I still am biased towards triplet therapy. I would rather dose-reduce 3 drugs, either changing the schedule or the absolute dose, and maintain them on a 3-drug regimen rather than a doublet. I have very few patients that I have on doublets.

A. Keith Stewart, MB, ChB: Does anybody feel differently, that there are patients who should just get doublet therapy?

Rafael Fonseca, MD: You know I struggle with that and I concur with what Adriana is saying. But you know with the SWOG [Southwest Oncology Group] study, and I know we’re going to talk more about this, and now with MAIA, I always wonder, now should we put a little bit more and dose adjust it somehow? I mean there’s no question the convenience of the doublet is there, but it sort of bothers me….

A. Keith Stewart, MB, ChB: One abstract we wanted to hone in on was just presented this morning, actually. They took elderly patients who had lenalidomide/dexamethasone at full doses and then randomized them to either stay on the full dose or drop down to a maintenance dose of lenalidomide. And the results seemed to suggest that they actually did better with the lower dose of the drug, Faith. They stayed on drug longer and benefited because of that, because they’d had less toxicity. That’s a more nuanced approach to treating a frail patient.

Faith Davies, MD, MBBCh, MRCP, FRCPath: And I think that gives us all confidence about how we should be managing toxicities. That if we have a patient….

A. Keith Stewart, MB, ChB: But it kind of flies in the face of we should use 3 or 4 drugs and escalate toxicity for deeper responses. So maybe that’s not the solution?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Well, I think the argument back would be you can only get a deep response if you stay on your therapy. So if you start your therapy and then you’re coming off it all of the time, you’re never going to get a deep response. So you do have to tailor your treatment to the patient. And as I say, I think it gives us, particularly in the elderly/frail, it gives us confidence that if we need to take out the dexamethasone, for instance, or we need to drop the dose down, it’s OK. I think what would be a really interesting study is the next step, where you actually do dose modifications at the beginning and you compare a standard treatment to maybe a dose ramp-up in those elderly/frail patients. I think that would be kind of….

A. Keith Stewart, MB, ChB: Tom, you got out of the wrong side of bed this morning. You were grumpy and you went to this presentation. You said it should have been a poster or something like that?
 
Thomas Martin, MD: Well I think the take-home message from that… These were patients that were 75 years of age and older, in general. That was the median. It was age 75 in both arms. And they started patients off on lenalidomide at 25 mg; with DEX [dexamethasone], 20 mg. I would say that 25 mg of lenalidomide is way too high of a dose to start somebody that’s 75 years of age, or older, off with. And their creatinine clearance is probably going to be less than 50, for most of those people. The take-home message for that, from that presentation: 10% of patients stopped their therapy within the first few months of their therapy, because it was 25 mg of LEN [lenalidomide].

A. Keith Stewart, MB, ChB: You prefer to start at 15 mg and work up, or…?

Thomas Martin, MD: Correct, to start at 15 mg. But the PFS [progression-free survival] for both arms was less than 12 months. And we have the MAIA study, which is going to be the gold standard now. So there are no doublets in myeloma any more.

Rafael Fonseca, MD: But you know there’s an important point here. This reminds me of when we designed the low-dose DEX versus traditional DEX study, which was designed because of the very important input from patient advocates. And the assumption was this was going to be worse because you’re going to give less dexamethasone, but we’re doing a tradeoff for more tolerable, less effective. But the real world did show it was more effective because of the practicalities of being able to stay on the dose. I would say we see similar things with IXA [ixazomib] too.

Ixazomib doesn’t have the punch of some of the other drugs but allows for the longer-term treatment. And I think those practical considerations become important in real life.

A. Keith Stewart, MB, ChB: Yes, I just worry a little bit. You know, we talked about pneumonia and infection and it certainly is important for me to realize that when we talk about triplets in the elderly, we call it RVd [lenalidomide/bortezomib/dexamethasone]-lite, so it’s starting with lower doses of those 3 drugs. So I think most of us feel that 3-drug cocktails are probably appropriate. But you probably should start with slightly lower dosing. Is that fair too? Would everybody agree with that?


Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB:
OK, let’s change track a little bit. We’ve talked a lot about younger patients. We’ve come to the conclusion that 4 drugs are going to be good and MRD [minimal residual disease] negativity is a good goal to strive for. What about elderly patients where perhaps we don’t want to be quite as aggressive? Adriana, what’s your opinion on triplet versus doublet therapy in an elderly patient?

Adriana Rossi, MD: I still am biased towards triplet therapy. I would rather dose-reduce 3 drugs, either changing the schedule or the absolute dose, and maintain them on a 3-drug regimen rather than a doublet. I have very few patients that I have on doublets.

A. Keith Stewart, MB, ChB: Does anybody feel differently, that there are patients who should just get doublet therapy?

Rafael Fonseca, MD: You know I struggle with that and I concur with what Adriana is saying. But you know with the SWOG [Southwest Oncology Group] study, and I know we’re going to talk more about this, and now with MAIA, I always wonder, now should we put a little bit more and dose adjust it somehow? I mean there’s no question the convenience of the doublet is there, but it sort of bothers me….

A. Keith Stewart, MB, ChB: One abstract we wanted to hone in on was just presented this morning, actually. They took elderly patients who had lenalidomide/dexamethasone at full doses and then randomized them to either stay on the full dose or drop down to a maintenance dose of lenalidomide. And the results seemed to suggest that they actually did better with the lower dose of the drug, Faith. They stayed on drug longer and benefited because of that, because they’d had less toxicity. That’s a more nuanced approach to treating a frail patient.

Faith Davies, MD, MBBCh, MRCP, FRCPath: And I think that gives us all confidence about how we should be managing toxicities. That if we have a patient….

A. Keith Stewart, MB, ChB: But it kind of flies in the face of we should use 3 or 4 drugs and escalate toxicity for deeper responses. So maybe that’s not the solution?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Well, I think the argument back would be you can only get a deep response if you stay on your therapy. So if you start your therapy and then you’re coming off it all of the time, you’re never going to get a deep response. So you do have to tailor your treatment to the patient. And as I say, I think it gives us, particularly in the elderly/frail, it gives us confidence that if we need to take out the dexamethasone, for instance, or we need to drop the dose down, it’s OK. I think what would be a really interesting study is the next step, where you actually do dose modifications at the beginning and you compare a standard treatment to maybe a dose ramp-up in those elderly/frail patients. I think that would be kind of….

A. Keith Stewart, MB, ChB: Tom, you got out of the wrong side of bed this morning. You were grumpy and you went to this presentation. You said it should have been a poster or something like that?
 
Thomas Martin, MD: Well I think the take-home message from that… These were patients that were 75 years of age and older, in general. That was the median. It was age 75 in both arms. And they started patients off on lenalidomide at 25 mg; with DEX [dexamethasone], 20 mg. I would say that 25 mg of lenalidomide is way too high of a dose to start somebody that’s 75 years of age, or older, off with. And their creatinine clearance is probably going to be less than 50, for most of those people. The take-home message for that, from that presentation: 10% of patients stopped their therapy within the first few months of their therapy, because it was 25 mg of LEN [lenalidomide].

A. Keith Stewart, MB, ChB: You prefer to start at 15 mg and work up, or…?

Thomas Martin, MD: Correct, to start at 15 mg. But the PFS [progression-free survival] for both arms was less than 12 months. And we have the MAIA study, which is going to be the gold standard now. So there are no doublets in myeloma any more.

Rafael Fonseca, MD: But you know there’s an important point here. This reminds me of when we designed the low-dose DEX versus traditional DEX study, which was designed because of the very important input from patient advocates. And the assumption was this was going to be worse because you’re going to give less dexamethasone, but we’re doing a tradeoff for more tolerable, less effective. But the real world did show it was more effective because of the practicalities of being able to stay on the dose. I would say we see similar things with IXA [ixazomib] too.

Ixazomib doesn’t have the punch of some of the other drugs but allows for the longer-term treatment. And I think those practical considerations become important in real life.

A. Keith Stewart, MB, ChB: Yes, I just worry a little bit. You know, we talked about pneumonia and infection and it certainly is important for me to realize that when we talk about triplets in the elderly, we call it RVd [lenalidomide/bortezomib/dexamethasone]-lite, so it’s starting with lower doses of those 3 drugs. So I think most of us feel that 3-drug cocktails are probably appropriate. But you probably should start with slightly lower dosing. Is that fair too? Would everybody agree with that?


Transcript Edited for Clarity 
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