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Clinical Trials' Impact on Smoldering Myeloma Management

Panelists: Sagar Lonial, MD, FACP, Winship Cancer Institute of Emory University; Amrita Y. Krishnan, MD, City of Hope Comprehensive Cancer Center; Thomas G. Martin, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Krina K. Patel, MD, MSc, University of Texas MD Anderson Cancer Center; Saad Z. Usmani, MD, FACP, Levine Cancer Institute
Published: Wednesday, Jul 03, 2019



Transcript: 

Sagar Lonial, MD, FACP: Amrita, you get to talk a little bit about the therapeutic trials in this area. And I think 1 of the struggles is that they all defined high risk in different ways. But what can we glean from the data that were presented at ASCO [the American Society of Clinical Oncology Annual Meeting]?

Amrita Y. Krishnan, MD: I can tell you that I left for ASCO seeing a patient with high-risk myeloma by whichever criteria you can pick, and I said “Let me wait until I go to ASCO, where Dr Lonial is presenting this trial that we’ve all been waiting for, the ECOG-E3A06 trial, and maybe I’ll have some answers when I come back.” Be careful what you wish for, right, because we all asked for a phase III trial. I think you clearly demonstrated in that trial a progression-free survival [PFS] benefit for giving lenalidomide, and you did a nice job because you also showed it by any risk stratification criteria.

You anticipated some of the questions people would ask. I think the challenges I have is the 50% of patients coming off therapy. Again, do you really need to continue? Maybe you can give a shorter duration of therapy is 1 question that’s in my mind. The second thing is Krina’s point: for an 80-year-old, I am worried about progression with renal, but I’m also worried about giving 25 mg of lenalidomide to an older patient. And then the third thing, which is probably not as relevant in terms of my patient population but is an interesting question, is why on the forest plot were African Americans so not improved by the use lenalidomide? I have to say, it was a very well-designed trial and very well presented in a complex field, but I’m still left with more questions than answers from it.

Thomas G. Martin, MD: I’ll comment on that. I do think the presentation was wonderful, Dr Lonial. However, I’m not sure about the design. You mixed intermediate and high-risk smoldering myeloma patients, and I think in the intermediate category, there are going to be more patients who really did not need therapy, or it would have taken a long time before they showed symptoms of disease and needed therapy. It just makes that population a little bit more heterogeneous, which is tough.

I do think that trials in the smoldering myeloma population are very difficult, but I think you have to look at PFS1 [PFS for first line] together with PFS2 [PFS for second line] because there is some lead time versus when you start therapy compared with when you would have started therapy. And that lead time does bring on, I think, some bias. So you have to look at their first-remission duration but also at that point in time, the second-remission duration when you start therapy for their active multiple myeloma. Is it a benefit to start early? I still think we’re challenged to know the answer to that question.

Sagar Lonial, MD, FACP: Let me at least try to address a couple of them, and then I’ll let you continue on. I think in terms of the point you last raised, if you look at it by the Mayo Clinic 2018 criteria, which is consistent with what you described from the IMWG [International Myeloma Working Group], people who really gained the greatest benefit were the high risk, and that’s all we’re really suggesting should get early intervention. The second is—and we had a lot of discussion as we were preparing the abstract—I personally don’t think of this as treatment. I think of this as prevention. It’s low-intensity therapy with the goal of prevention. Similar to a patient who has a polyp on colonoscopy, you don’t give them FOLFOX [leucovorin calcium, fluorouracil, oxaliplatin] after you identify a polyp. You give them something to try and prevent the progression of that cancer. Same with DCIS [ductal carcinoma in situ] in breast cancer.

I would argue you can give 2 years of therapy, and I think that addresses your question about duration, because that’s what the Spanish did. They gave 2 years of therapy and then stopped and walked away, and you have a 78% risk reduction of progression; that’s a pretty good trade-off, I think. In terms of the dosing, that’s the last question I’ll answer. In terms of the dosing, it was all based on renal function. If you have an 80-year-old with a creatinine clearance of 40 mL/min/1.73 m2, they weren’t going to get 25, they were automatically dose reduced based on renal function. But…I’m closer to the data, so I’m a little biased.

Saad Z. Usmani, MD, FACP: That’s understandable. And you did a fantastic job in presenting the data, and I think you were struggling with how to bring that data in light of how we’re approaching myeloma right now and how we’re thinking about myeloma right now. I think from that perspective, you did a fantastic job. I do not have any issues treating an older, high-risk myeloma patient in this fashion. My only concern is the younger patients who are considered high-risk smolderers. Are we really doing the right thing by treating them in this fashion rather than treating them like an active, real myeloma patient who’s about to get end-organ damage? Here, again, how do you define the early myeloma that is about to go into end-organ damage? And where do we move? Where we do draw that line? I think that’s the issue that I was struggling with. With 2 years of lenalidomide and how successful we’ll be in collecting them, what kind of damage potentially have we done to the bone marrow, microenvironment, and the precursor hematopoietic stem cells? We don’t know those answers, so I think that those were some of the things I was struggling with.

Amrita Y. Krishnan, MD: I think what you do for me is change the paradigm for the older patients, 75 years and older, no question. I think that’s reasonable. It’s not even just the really young. Actually, Tom and I have a mutual patient, he’s in his late 30s, early 40s, who has a very high M spike [myeloma gamma globulin], about 4 or 5 g/dL. And we ended up treating as active myeloma. It’s the patients in between, the 60-, 65-year-old where you’re thinking still you’re going to transplant him, etc. I don’t know what to do with those, and I’m not sure that I would be comfortable.

Saad Z. Usmani, MD, FACP: Well, 60 is the new 40.

Thomas G. Martin, MD: But the preventive premise is really a great premise. And the question then becomes, are we treating the myeloma cell, or are we treating the microenvironment? I do think that we’re going to understand much more in the next 2 to 5 years about the microenvironment. And there might be better drugs than lenalidomide in terms of changing the microenvironment around to provide that preventive, the snare per say to cut off that polyp. And when that happens, I think we’ll all be treating patients, even with intermediate-risk smoldering myeloma.

Saad Z. Usmani, MD, FACP: Agreed.

Krina K. Patel, MD, MSc: The 1 thing I was surprised by was the quality of life, though, considering that most of my patients, when they’re on Revlimid, always complain of fatigue. But the quality of life was actually the same if they got therapy or not. As I said at the beginning, my patients are always worried about starting therapy. They’d rather not so they don’t have symptoms. I was actually happily surprised that the quality of life was pretty similar in observation.

Saad Z. Usmani, MD, FACP: Wait until you see the quality-of-life curves with selinexor. It will be the same.

Amrita Y. Krishnan, MD: I think the best thing you did is not use dexamethasone, because when I look at 1 of the other abstracts, you take ixa-len [ixazomib-lenalidamide] and dex [dexamethasone], and elo-len-dex [elotuzumab-lenalidamide-dexamethasone], you see hypoglycemia, there was a DKA [diabetic ketoacidosis]. And we all know the morbidity of dexamethasone. So I think that was definitely a huge step.

Sagar Lonial, MD, FACP: And if you believe it, it’s the immune component that keeps the clone in check, using single-agent IMiD [immunomodulatory drug] without steroids may actually be the better way to go. That was some of the hypothesis behind it. It’s all post hoc now, but that’s all right. There were several other abstracts in the smoldering area. Anything anybody else wants to touch on? We had some data on ird [ixazomib-lenalidomide-dexamethasone], we had some data you mentioned on elo [elotuzumab]. There are some data on just ixa-dex [ixazomib-dexamethasone]. Anything else catch anybody’s fancy?

Thomas G. Martin, MD: These are all early studies with small numbers of patients, and I think the biggest splash was the 1 that you presented because you had so many patients and it was randomized phase III. At the end of the line, it’s not going to change the way I treat smoldering myeloma at this current time. I do again look at the movie, of course, and then treat people who I think have evolving disease, just as Saad was saying. Evolving diseases need to be treated, and I treat them like myeloma.

Sagar Lonial, MD, FACP: Any other parting thoughts on smoldering myeloma?

Saad Z. Usmani, MD, FACP: I think your study does set up the precedence for larger Eastern Cooperative Oncology Group trials to answer that question in that patient population. And I think what you’ve proven is these trials can be done, patients can enroll on these studies, and we have a baseline to go off.

Transcript Edited for Clarity

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Transcript: 

Sagar Lonial, MD, FACP: Amrita, you get to talk a little bit about the therapeutic trials in this area. And I think 1 of the struggles is that they all defined high risk in different ways. But what can we glean from the data that were presented at ASCO [the American Society of Clinical Oncology Annual Meeting]?

Amrita Y. Krishnan, MD: I can tell you that I left for ASCO seeing a patient with high-risk myeloma by whichever criteria you can pick, and I said “Let me wait until I go to ASCO, where Dr Lonial is presenting this trial that we’ve all been waiting for, the ECOG-E3A06 trial, and maybe I’ll have some answers when I come back.” Be careful what you wish for, right, because we all asked for a phase III trial. I think you clearly demonstrated in that trial a progression-free survival [PFS] benefit for giving lenalidomide, and you did a nice job because you also showed it by any risk stratification criteria.

You anticipated some of the questions people would ask. I think the challenges I have is the 50% of patients coming off therapy. Again, do you really need to continue? Maybe you can give a shorter duration of therapy is 1 question that’s in my mind. The second thing is Krina’s point: for an 80-year-old, I am worried about progression with renal, but I’m also worried about giving 25 mg of lenalidomide to an older patient. And then the third thing, which is probably not as relevant in terms of my patient population but is an interesting question, is why on the forest plot were African Americans so not improved by the use lenalidomide? I have to say, it was a very well-designed trial and very well presented in a complex field, but I’m still left with more questions than answers from it.

Thomas G. Martin, MD: I’ll comment on that. I do think the presentation was wonderful, Dr Lonial. However, I’m not sure about the design. You mixed intermediate and high-risk smoldering myeloma patients, and I think in the intermediate category, there are going to be more patients who really did not need therapy, or it would have taken a long time before they showed symptoms of disease and needed therapy. It just makes that population a little bit more heterogeneous, which is tough.

I do think that trials in the smoldering myeloma population are very difficult, but I think you have to look at PFS1 [PFS for first line] together with PFS2 [PFS for second line] because there is some lead time versus when you start therapy compared with when you would have started therapy. And that lead time does bring on, I think, some bias. So you have to look at their first-remission duration but also at that point in time, the second-remission duration when you start therapy for their active multiple myeloma. Is it a benefit to start early? I still think we’re challenged to know the answer to that question.

Sagar Lonial, MD, FACP: Let me at least try to address a couple of them, and then I’ll let you continue on. I think in terms of the point you last raised, if you look at it by the Mayo Clinic 2018 criteria, which is consistent with what you described from the IMWG [International Myeloma Working Group], people who really gained the greatest benefit were the high risk, and that’s all we’re really suggesting should get early intervention. The second is—and we had a lot of discussion as we were preparing the abstract—I personally don’t think of this as treatment. I think of this as prevention. It’s low-intensity therapy with the goal of prevention. Similar to a patient who has a polyp on colonoscopy, you don’t give them FOLFOX [leucovorin calcium, fluorouracil, oxaliplatin] after you identify a polyp. You give them something to try and prevent the progression of that cancer. Same with DCIS [ductal carcinoma in situ] in breast cancer.

I would argue you can give 2 years of therapy, and I think that addresses your question about duration, because that’s what the Spanish did. They gave 2 years of therapy and then stopped and walked away, and you have a 78% risk reduction of progression; that’s a pretty good trade-off, I think. In terms of the dosing, that’s the last question I’ll answer. In terms of the dosing, it was all based on renal function. If you have an 80-year-old with a creatinine clearance of 40 mL/min/1.73 m2, they weren’t going to get 25, they were automatically dose reduced based on renal function. But…I’m closer to the data, so I’m a little biased.

Saad Z. Usmani, MD, FACP: That’s understandable. And you did a fantastic job in presenting the data, and I think you were struggling with how to bring that data in light of how we’re approaching myeloma right now and how we’re thinking about myeloma right now. I think from that perspective, you did a fantastic job. I do not have any issues treating an older, high-risk myeloma patient in this fashion. My only concern is the younger patients who are considered high-risk smolderers. Are we really doing the right thing by treating them in this fashion rather than treating them like an active, real myeloma patient who’s about to get end-organ damage? Here, again, how do you define the early myeloma that is about to go into end-organ damage? And where do we move? Where we do draw that line? I think that’s the issue that I was struggling with. With 2 years of lenalidomide and how successful we’ll be in collecting them, what kind of damage potentially have we done to the bone marrow, microenvironment, and the precursor hematopoietic stem cells? We don’t know those answers, so I think that those were some of the things I was struggling with.

Amrita Y. Krishnan, MD: I think what you do for me is change the paradigm for the older patients, 75 years and older, no question. I think that’s reasonable. It’s not even just the really young. Actually, Tom and I have a mutual patient, he’s in his late 30s, early 40s, who has a very high M spike [myeloma gamma globulin], about 4 or 5 g/dL. And we ended up treating as active myeloma. It’s the patients in between, the 60-, 65-year-old where you’re thinking still you’re going to transplant him, etc. I don’t know what to do with those, and I’m not sure that I would be comfortable.

Saad Z. Usmani, MD, FACP: Well, 60 is the new 40.

Thomas G. Martin, MD: But the preventive premise is really a great premise. And the question then becomes, are we treating the myeloma cell, or are we treating the microenvironment? I do think that we’re going to understand much more in the next 2 to 5 years about the microenvironment. And there might be better drugs than lenalidomide in terms of changing the microenvironment around to provide that preventive, the snare per say to cut off that polyp. And when that happens, I think we’ll all be treating patients, even with intermediate-risk smoldering myeloma.

Saad Z. Usmani, MD, FACP: Agreed.

Krina K. Patel, MD, MSc: The 1 thing I was surprised by was the quality of life, though, considering that most of my patients, when they’re on Revlimid, always complain of fatigue. But the quality of life was actually the same if they got therapy or not. As I said at the beginning, my patients are always worried about starting therapy. They’d rather not so they don’t have symptoms. I was actually happily surprised that the quality of life was pretty similar in observation.

Saad Z. Usmani, MD, FACP: Wait until you see the quality-of-life curves with selinexor. It will be the same.

Amrita Y. Krishnan, MD: I think the best thing you did is not use dexamethasone, because when I look at 1 of the other abstracts, you take ixa-len [ixazomib-lenalidamide] and dex [dexamethasone], and elo-len-dex [elotuzumab-lenalidamide-dexamethasone], you see hypoglycemia, there was a DKA [diabetic ketoacidosis]. And we all know the morbidity of dexamethasone. So I think that was definitely a huge step.

Sagar Lonial, MD, FACP: And if you believe it, it’s the immune component that keeps the clone in check, using single-agent IMiD [immunomodulatory drug] without steroids may actually be the better way to go. That was some of the hypothesis behind it. It’s all post hoc now, but that’s all right. There were several other abstracts in the smoldering area. Anything anybody else wants to touch on? We had some data on ird [ixazomib-lenalidomide-dexamethasone], we had some data you mentioned on elo [elotuzumab]. There are some data on just ixa-dex [ixazomib-dexamethasone]. Anything else catch anybody’s fancy?

Thomas G. Martin, MD: These are all early studies with small numbers of patients, and I think the biggest splash was the 1 that you presented because you had so many patients and it was randomized phase III. At the end of the line, it’s not going to change the way I treat smoldering myeloma at this current time. I do again look at the movie, of course, and then treat people who I think have evolving disease, just as Saad was saying. Evolving diseases need to be treated, and I treat them like myeloma.

Sagar Lonial, MD, FACP: Any other parting thoughts on smoldering myeloma?

Saad Z. Usmani, MD, FACP: I think your study does set up the precedence for larger Eastern Cooperative Oncology Group trials to answer that question in that patient population. And I think what you’ve proven is these trials can be done, patients can enroll on these studies, and we have a baseline to go off.

Transcript Edited for Clarity
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