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Maintenance Therapy for Multiple Myeloma

Panelists: Keith Stewart, MB, CHB, Mayo Clinic; Gareth Morgan, MD, PhD, University of Arkansas for Medical Science; Saad Z. Usmani, MD, Levine Cancer Institute/Carolinas Healthcare System; Ivan M. Borrello, MD, Johns Hopkins Kimmel Cancer Center; Thomas G. Martin, MD, University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center; Sagar Lonial, MD, Winship Cancer Institute of Emory University
Published Online: Thursday, Jul 06, 2017



Transcript:

Keith Stewart, MB, ChB:
Let’s move on and discuss maintenance therapy. Gareth, you’ve been leading the way, here, with a large trial. Tell us about that and what it’s taught us about maintenance therapy with lenalidomide.

Gareth Morgan, MD, PhD: I think it was the final piece of evidence that really supports the use of Revlimid maintenance compared to no maintenance.

Keith Stewart, MB, ChB: This was a 2,000-patient trial, is that correct?

Gareth Morgan, MD, PhD: We have, approximately, 1,000 patients in each arm. There was an improved PFS. We should have OS benefit data by the end of the year.

Keith Stewart, MB, ChB: Improved PFS was almost a doubling if I recall, right?

Gareth Morgan, MD, PhD: Yes. The hazard ratio was 0.43—a really good hazard ratio, an amazing difference. And I think the additional data it provided was that it works across all subgroups of risk.

Keith Stewart, MB, ChB: You also looked at duration of therapy and had some interesting finds. And this has been a controversial question. Do you treat for 1 year, 2 years, 4 years, forever?

Gareth Morgan, MD, PhD: For the people that fell off treatment for reasons of toxicity or otherwise, it seemed that if you fell off in the first year, you did worse than if you fell off during the second year.

Keith Stewart, MB, ChB: So, your recommendation is lenalidomide until progression?

Gareth Morgan, MD, PhD: I think you have to. It should be the guideline recommendation, because that’s what the data are derived from.

Keith Stewart, MB, ChB: Practically speaking, Tom, that’s sometimes hard to do. What percentage of your patients, do you think, can stay on forever?

Thomas G. Martin, MD: At the University of California, San Francisco, we just had a pharmacist look at our data. During the maintenance phase, the thing that patients became toxic from was from fatigue and diarrhea. The average duration of therapy was between 2 and 2.5 years.

Keith Stewart, MB, ChB: That’s my experience, too. Sagar, what do you think?

Sagar Lonial, MD: I think we try and push to that first year based on—not knowing your data, but knowing the French data in the maintenance setting—an understanding that they seem to do better. But, I think if you use the medicines that prevent...

Gareth Morgan, MD, PhD: Cholestyramine.

Sagar Lonial, MD: Yes. That can make a big difference.

Gareth Morgan, MD, PhD: And it works.

Keith Stewart, MB, ChB: What about other drugs in the maintenance setting? It sounds like we have a consensus that lenalidomide is being used routinely. Are there other drugs that you use in maintenance therapy?

Ivan M. Borrello, MD: No, not as standard of care.

Keith Stewart, MB, ChB: Saad, do you use bortezomib in maintenance?

Saad Z. Usmani, MD: Yes, for the translocation t[4;14] patients, we add those. Yes.

Keith Stewart, MB, ChB: Is anybody else using bortezomib for high-risk patients?

Gareth Morgan, MD, PhD: We use the combination of both—Revlimid-Velcade—for 3 years, at a fixed duration. We manage to get most people through it.

Keith Stewart, MB, ChB: What do you think is coming in that space? Do the drugs excite you in the maintenance setting, Sagar?

Sagar Lonial, MD: I think the only caveat for bortezomib and lenalidomide in the maintenance setting is considering patients who have not achieved a VGPR before transplant, which tells you that they’re probably not as sensitive to RVd [bortezomib, lenalidomide, and dexamethasone] and they’re high risk.

And so, for those patients, we actually give carfilzomib and pomalidomide in the maintenance setting for 3 years, as you described. I think the antibodies, though, are going to make the biggest splash, and I think, obviously, there are emerging data from a couple of trials looking at daratumumab in the maintenance setting. And the Germans have a really interesting trial looking at elotuzumab in the maintenance setting.

Keith Stewart, MB, ChB: That’s a perfect segue into what’s coming. What’s coming for upfront therapy that people need to be aware of?

Saad Z. Usmani, MD: In the upfront setting, I think there are 2 abstracts being presented that are looking at the triplet plus antibody combinations. We have KRd [carfilzomib, lenalidomide, and dexamethasone]-daratumumab, and RVd with elotuzumab being presented, this year, at the 2017 ASCO Annual Meeting.

Keith Stewart, MB, ChB: What’s your take on those 2 abstracts?

Saad Z. Usmani, MD: I was part of both studies. With KRd-daratumumab, this was a safety and tolerability phase I study, and it appears that we don’t see any new cardiopulmonary signs or other signals from the safety perspective. The overall response was impressive. The dosing was weekly, which was better tolerated.

Keith Stewart, MB, ChB: For carfilzomib?

Saad Z. Usmani, MD: Yes, for carfilzomib. And I think that the data will be reported later, but the depth of response is very impressive.

Keith Stewart, MB, ChB: How about with elotuzumab? Did you have a chance to look at that?

Ivan M. Borrello, MD: I saw the abstract. It looks like there is evidence of responsiveness.

Keith Stewart, MB, ChB: A 100% response rate.

Ivan M. Borrello, MD: Yes, with a very favorable toxicity regimen. This is new. I think what has been a problem with elotuzumab, thus far, is really testing it in an unpractical patient population. Upfront Revlimid-naïve patients are probably much more available than relapsed Revlimid-naïve patients, as was so in the ELOQUENT trial. Showing that a lenalidomide-naïve patient can respond well and then can be consolidated with ERd [elotuzumab, lenalidomide, and dexamethasone], I think, is looking very promising.

Keith Stewart, MB, ChB: Anybody else have anything to comment? Were you part of the elotuzumab study? What was your take on that?

Sagar Lonial, MD: We’ve got a number of patients that are pretty far out. I think one of the concerning signals, just to be perfectly honest, is that there were 2 deaths in the trial. Both of them occurred early on. One was an infectious complication.

Keith Stewart, MB, ChB: 2 out of 42?

Sagar Lonial, MD: Right, something along those lines. One was very early, and another occurred after the patient had come off study. Both were infections and both were elderly transplant-ineligible patients—frail patients, potentially. But the young patients seemed to have done quite well, and there were no issues of stem cell collection.

Keith Stewart, MB, ChB: People think antibodies are going to be part of our standard of care fairly soon?

Gareth Morgan, MD, PhD: I think they are already.

Keith Stewart, MB, ChB: But, in newly diagnosed, not yet, right?

Thomas G. Martin, MD: There are 4 large frontline trials, right? 4 large frontline trials that are testing daratumumab, lenalidomide, and dexamethasone against lenalidomide and dexamethasone; elotuzumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone; carfilzomib, lenalidomide, and dexamethasone versus Velcade or bortezomib with lenalidomide and dexamethasone; and ixazomib, lenalidomide, and dexamethasone.

Keith Stewart, MB, ChB: So, there are more data to come?

Thomas G. Martin, MD: It will be really exciting, over the next 2 to 3 years, to see what we’re going to choose for frontline therapy. I do agree with what Ivan said—that the elotuzumab is very well tolerated in frontline therapy in lenalidomide-naive patients. And, in fact, I think Sagar said it earlier, too, that despite what you just said about the early deaths and the infection, it might be a really great regimen for the frail patients.

Transcript Edited for Clarity

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Transcript:

Keith Stewart, MB, ChB:
Let’s move on and discuss maintenance therapy. Gareth, you’ve been leading the way, here, with a large trial. Tell us about that and what it’s taught us about maintenance therapy with lenalidomide.

Gareth Morgan, MD, PhD: I think it was the final piece of evidence that really supports the use of Revlimid maintenance compared to no maintenance.

Keith Stewart, MB, ChB: This was a 2,000-patient trial, is that correct?

Gareth Morgan, MD, PhD: We have, approximately, 1,000 patients in each arm. There was an improved PFS. We should have OS benefit data by the end of the year.

Keith Stewart, MB, ChB: Improved PFS was almost a doubling if I recall, right?

Gareth Morgan, MD, PhD: Yes. The hazard ratio was 0.43—a really good hazard ratio, an amazing difference. And I think the additional data it provided was that it works across all subgroups of risk.

Keith Stewart, MB, ChB: You also looked at duration of therapy and had some interesting finds. And this has been a controversial question. Do you treat for 1 year, 2 years, 4 years, forever?

Gareth Morgan, MD, PhD: For the people that fell off treatment for reasons of toxicity or otherwise, it seemed that if you fell off in the first year, you did worse than if you fell off during the second year.

Keith Stewart, MB, ChB: So, your recommendation is lenalidomide until progression?

Gareth Morgan, MD, PhD: I think you have to. It should be the guideline recommendation, because that’s what the data are derived from.

Keith Stewart, MB, ChB: Practically speaking, Tom, that’s sometimes hard to do. What percentage of your patients, do you think, can stay on forever?

Thomas G. Martin, MD: At the University of California, San Francisco, we just had a pharmacist look at our data. During the maintenance phase, the thing that patients became toxic from was from fatigue and diarrhea. The average duration of therapy was between 2 and 2.5 years.

Keith Stewart, MB, ChB: That’s my experience, too. Sagar, what do you think?

Sagar Lonial, MD: I think we try and push to that first year based on—not knowing your data, but knowing the French data in the maintenance setting—an understanding that they seem to do better. But, I think if you use the medicines that prevent...

Gareth Morgan, MD, PhD: Cholestyramine.

Sagar Lonial, MD: Yes. That can make a big difference.

Gareth Morgan, MD, PhD: And it works.

Keith Stewart, MB, ChB: What about other drugs in the maintenance setting? It sounds like we have a consensus that lenalidomide is being used routinely. Are there other drugs that you use in maintenance therapy?

Ivan M. Borrello, MD: No, not as standard of care.

Keith Stewart, MB, ChB: Saad, do you use bortezomib in maintenance?

Saad Z. Usmani, MD: Yes, for the translocation t[4;14] patients, we add those. Yes.

Keith Stewart, MB, ChB: Is anybody else using bortezomib for high-risk patients?

Gareth Morgan, MD, PhD: We use the combination of both—Revlimid-Velcade—for 3 years, at a fixed duration. We manage to get most people through it.

Keith Stewart, MB, ChB: What do you think is coming in that space? Do the drugs excite you in the maintenance setting, Sagar?

Sagar Lonial, MD: I think the only caveat for bortezomib and lenalidomide in the maintenance setting is considering patients who have not achieved a VGPR before transplant, which tells you that they’re probably not as sensitive to RVd [bortezomib, lenalidomide, and dexamethasone] and they’re high risk.

And so, for those patients, we actually give carfilzomib and pomalidomide in the maintenance setting for 3 years, as you described. I think the antibodies, though, are going to make the biggest splash, and I think, obviously, there are emerging data from a couple of trials looking at daratumumab in the maintenance setting. And the Germans have a really interesting trial looking at elotuzumab in the maintenance setting.

Keith Stewart, MB, ChB: That’s a perfect segue into what’s coming. What’s coming for upfront therapy that people need to be aware of?

Saad Z. Usmani, MD: In the upfront setting, I think there are 2 abstracts being presented that are looking at the triplet plus antibody combinations. We have KRd [carfilzomib, lenalidomide, and dexamethasone]-daratumumab, and RVd with elotuzumab being presented, this year, at the 2017 ASCO Annual Meeting.

Keith Stewart, MB, ChB: What’s your take on those 2 abstracts?

Saad Z. Usmani, MD: I was part of both studies. With KRd-daratumumab, this was a safety and tolerability phase I study, and it appears that we don’t see any new cardiopulmonary signs or other signals from the safety perspective. The overall response was impressive. The dosing was weekly, which was better tolerated.

Keith Stewart, MB, ChB: For carfilzomib?

Saad Z. Usmani, MD: Yes, for carfilzomib. And I think that the data will be reported later, but the depth of response is very impressive.

Keith Stewart, MB, ChB: How about with elotuzumab? Did you have a chance to look at that?

Ivan M. Borrello, MD: I saw the abstract. It looks like there is evidence of responsiveness.

Keith Stewart, MB, ChB: A 100% response rate.

Ivan M. Borrello, MD: Yes, with a very favorable toxicity regimen. This is new. I think what has been a problem with elotuzumab, thus far, is really testing it in an unpractical patient population. Upfront Revlimid-naïve patients are probably much more available than relapsed Revlimid-naïve patients, as was so in the ELOQUENT trial. Showing that a lenalidomide-naïve patient can respond well and then can be consolidated with ERd [elotuzumab, lenalidomide, and dexamethasone], I think, is looking very promising.

Keith Stewart, MB, ChB: Anybody else have anything to comment? Were you part of the elotuzumab study? What was your take on that?

Sagar Lonial, MD: We’ve got a number of patients that are pretty far out. I think one of the concerning signals, just to be perfectly honest, is that there were 2 deaths in the trial. Both of them occurred early on. One was an infectious complication.

Keith Stewart, MB, ChB: 2 out of 42?

Sagar Lonial, MD: Right, something along those lines. One was very early, and another occurred after the patient had come off study. Both were infections and both were elderly transplant-ineligible patients—frail patients, potentially. But the young patients seemed to have done quite well, and there were no issues of stem cell collection.

Keith Stewart, MB, ChB: People think antibodies are going to be part of our standard of care fairly soon?

Gareth Morgan, MD, PhD: I think they are already.

Keith Stewart, MB, ChB: But, in newly diagnosed, not yet, right?

Thomas G. Martin, MD: There are 4 large frontline trials, right? 4 large frontline trials that are testing daratumumab, lenalidomide, and dexamethasone against lenalidomide and dexamethasone; elotuzumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone; carfilzomib, lenalidomide, and dexamethasone versus Velcade or bortezomib with lenalidomide and dexamethasone; and ixazomib, lenalidomide, and dexamethasone.

Keith Stewart, MB, ChB: So, there are more data to come?

Thomas G. Martin, MD: It will be really exciting, over the next 2 to 3 years, to see what we’re going to choose for frontline therapy. I do agree with what Ivan said—that the elotuzumab is very well tolerated in frontline therapy in lenalidomide-naive patients. And, in fact, I think Sagar said it earlier, too, that despite what you just said about the early deaths and the infection, it might be a really great regimen for the frail patients.

Transcript Edited for Clarity
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