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Options for Maintenance Therapy in Multiple Myeloma

Insights From: Kenneth C. Anderson, MD, Dana-Farber Cancer Institute and Harvard Medical School; Rafael Fonseca, MD, Mayo Clinic; Noopur S. Raje, MD, Massachusetts General Hospital Cancer Center
Published: Wednesday, Mar 13, 2019



Transcript: 

Kenneth C. Anderson, MD: I think that the data, a large meta-analysis of over 1200 patients, suggest that in the post-transplant setting that lenalidomide maintenance can double progression-free survival and extend overall survival relative to no maintenance. This was the database upon which the FDA approved lenalidomide maintenance as a novel strategy to prolong both progression-free and overall survival. So it is a standard of practice now. In patients who have high-risk disease, we incorporate a proteasome inhibitor in addition to the lenalidomide. This is based on studies that have looked at proteasome inhibitors’ ability to avoid or at least markedly reduce the early relapses at 1 year or 18 months—early relapses that are the hallmark of high-risk disease.

Up until now, the proteasome inhibitor that has been added is bortezomib, which is given twice a month subcutaneously along with the lenalidomide, given daily for 21 of 28 days, both of these in a continuous fashion in the high-risk patients.

Noopur S. Raje, MD: Maintenance therapy has become pretty standard for the treatment of multiple myeloma, and I think the data that are most robust are for lenalidomide right now. You know, we have 2 studies, the French study and the CALGB study, which has shown almost a doubling of the progression-free survival. And more recently, Dr Phil McCarthy has kind of done a meta-analysis, and he’s also demonstrated a survival benefit with the use of lenalidomide in the maintenance setting.

At this year’s [2018] ASH [American Society of Hematology annual meeting], you saw the TOURMALINE data, and the TOURMALINE data were comparing using a proteasome inhibitor now in the maintenance phase for multiple myeloma. Now this trial has a few issues in that it’s comparing ixazomib to placebo. Most of us have acknowledged and accepted lenalidomide as a standard of care. And so, comparing it to placebo is not necessarily the best trial. Having said that, ixazomib meets all of the criteria for a proteasome inhibitor to be used as a maintenance drug. It’s, in general, an extremely well tolerated drug. It doesn’t have this rate-limiting toxicity of neuropathy so much as bortezomib does. And if given in the dosing schedule of once a week, it’s actually extremely well tolerated. So ixazomib would be a great proteasome inhibitor.

In terms of proteasome inhibitor maintenance strategies, a lot of us extrapolate from other data. However, these data were not really a maintenance trial with bortezomib, but in that trial bortezomib was used every other week. And that trial did show a survival benefit to the bortezomib-containing arm. But it was almost comparing old drugs to new drugs, and bortezomib was used up front as well as in the back end.

There is a subset of patients who certainly need proteasome inhibitor therapy as maintenance, and I look to data that come out of Emory University. And what the investigators in Dr Sagar Lonial’s team have done at Emory is looked at dual maintenance. So they’ve looked at bortezomib as well as lenalidomide. And they’ve looked at specifically high-risk multiple myeloma patients. When I say high-risk, high-risk is defined as looking at p53-deleted myeloma, the t(4;14) translocated myeloma, and the t(14;16) translocated myeloma. And when you use dual maintenance, granted this was a single arm phase II trial, no data have replicated the kind of outcomes that the Emory group has seen. So in that patient population I certainly will use dual maintenance. I start off using bortezomib, but supplementing it or replacing it with ixazomib would be perfectly reasonable if patients had toxicity to bortezomib in the way of neuropathy.

Toxicity from long-term therapy is common with all drugs. And that’s where I think using tools such as MRD [minimal residual disease]-testing are going to be incredibly useful. Even though I say that lenalidomide is sort of a standard of care, and on average we use lenalidomide for 3 or 4 years, patients who were on it for very long periods of time have toxicities not just in the way of cytopenias, but more GI [gastrointestinal]-related toxicities, so diarrhea. Chronic diarrhea is very common. And sometimes it’s just not sustainable for patients to remain on these drugs. That’s why I think beginning to ask the question in terms of duration of maintenance treatment is incredibly important. We just don’t have that information.

As of right now, what we have started doing is managing these toxicities. So if you have a whole lot of cytopenia, you can dose reduce lenalidomide. The dose for lenalidomide maintenance is 10 mg to 15 mg. It can be given continuously. I almost never use the dose of 15 mg. Typically, my patients are on 10 mg and we typically use more of the CALGB regimen, which is 3 weeks on and 1 week off.

There are ways of minimizing that even further. You can drop the dose of lenalidomide more. I typically don’t like using a whole lot of growth factors in the maintenance setting, but I try and get to the patient’s sweet spot, whether it’s 3 weeks on of 10 mg, or 5 mg. Sometimes patients are on 2 weeks on, 2 weeks off. So you have to do what a patient is able to tolerate at the end of the day.

With ixazomib, we have been able to use ixazomib for very long periods of time as well. I’ve had patients on it for 3 or 4 years. Again, diarrhea tends to be a problem with ixazomib, and as long as you are able to manage that, patients do OK. But using the MRD tool in this setting allows us to get rid of some of these treatments if you don’t need to continue patients on treatment forever.

Rafael Fonseca, MD: In multiple myeloma, after stem cell transplant the vast majority of myeloma doctors now consider maintenance to be the standard of care. I think there’s some very thoughtful, smart people that can still make an argument that they don’t want to do that, but I would say 95%, plus, of myeloma doctors now recommend maintenance therapy. It is very clear from the data we have from phase III studies as well as from the meta-analysis that maintenance with lenalidomide should be considered for all patients. Usually this is at the lower dose. We’re following the package insert where we just do this continuously. In our practice, I tend to do this indefinitely as long as 2 things happen: As long as the patient is tolerating the treatment, and, of course, there’s lack of relapse evidence.

Now, there are important questions that need to be raised with regards to maintenance. When we think about patients who have high-risk disease, a number of trials and retrospective clinical observations have shown that while lenalidomide may help, it’s probably insufficient. So for most patients we add a proteasome inhibitor. This could be done in the form of bortezomib, such as VRd [bortezomib/lenalidomide/dexamethasone]. In my clinical practice, to try to emancipate patients from our clinics, we give them ixazomib as an alternative. So we’ve used frequently the combination of ixazomib, lenalidomide, and dexamethasone. At this last ASH meeting, we had the TOURMALINE study that looked at ixazomib as maintenance therapy for myeloma. This case was not combined with lenalidomide, but that’s what we do for our patients. And I would argue again this is particularly important for the high-risk patients to use a combination of an IMiD [immunomodulatory drug] and a proteasome inhibitor.

What’s the future of maintenance? Well, number 1, as I mentioned before, should we do consolidation before we go into this maintenance mode? How do we integrate the monoclonal antibodies? And the question is also being addressed by clinical trials. For instance, daratumumab, other CD38 antibodies—how can they be used in the maintenance setting? And I’m going to venture out to say that I think there’s a subset of patients that are better molecularly characterized, particularly the translocation t(11;14), where I think the question is going to be: Should we be doing maintenance with venetoclax, which has been proven to be a very effective drug in this subset of patients? And hopefully we’ll have the data from clinical trials to validate that hypothesis.

Transcript Edited for Clarity
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Transcript: 

Kenneth C. Anderson, MD: I think that the data, a large meta-analysis of over 1200 patients, suggest that in the post-transplant setting that lenalidomide maintenance can double progression-free survival and extend overall survival relative to no maintenance. This was the database upon which the FDA approved lenalidomide maintenance as a novel strategy to prolong both progression-free and overall survival. So it is a standard of practice now. In patients who have high-risk disease, we incorporate a proteasome inhibitor in addition to the lenalidomide. This is based on studies that have looked at proteasome inhibitors’ ability to avoid or at least markedly reduce the early relapses at 1 year or 18 months—early relapses that are the hallmark of high-risk disease.

Up until now, the proteasome inhibitor that has been added is bortezomib, which is given twice a month subcutaneously along with the lenalidomide, given daily for 21 of 28 days, both of these in a continuous fashion in the high-risk patients.

Noopur S. Raje, MD: Maintenance therapy has become pretty standard for the treatment of multiple myeloma, and I think the data that are most robust are for lenalidomide right now. You know, we have 2 studies, the French study and the CALGB study, which has shown almost a doubling of the progression-free survival. And more recently, Dr Phil McCarthy has kind of done a meta-analysis, and he’s also demonstrated a survival benefit with the use of lenalidomide in the maintenance setting.

At this year’s [2018] ASH [American Society of Hematology annual meeting], you saw the TOURMALINE data, and the TOURMALINE data were comparing using a proteasome inhibitor now in the maintenance phase for multiple myeloma. Now this trial has a few issues in that it’s comparing ixazomib to placebo. Most of us have acknowledged and accepted lenalidomide as a standard of care. And so, comparing it to placebo is not necessarily the best trial. Having said that, ixazomib meets all of the criteria for a proteasome inhibitor to be used as a maintenance drug. It’s, in general, an extremely well tolerated drug. It doesn’t have this rate-limiting toxicity of neuropathy so much as bortezomib does. And if given in the dosing schedule of once a week, it’s actually extremely well tolerated. So ixazomib would be a great proteasome inhibitor.

In terms of proteasome inhibitor maintenance strategies, a lot of us extrapolate from other data. However, these data were not really a maintenance trial with bortezomib, but in that trial bortezomib was used every other week. And that trial did show a survival benefit to the bortezomib-containing arm. But it was almost comparing old drugs to new drugs, and bortezomib was used up front as well as in the back end.

There is a subset of patients who certainly need proteasome inhibitor therapy as maintenance, and I look to data that come out of Emory University. And what the investigators in Dr Sagar Lonial’s team have done at Emory is looked at dual maintenance. So they’ve looked at bortezomib as well as lenalidomide. And they’ve looked at specifically high-risk multiple myeloma patients. When I say high-risk, high-risk is defined as looking at p53-deleted myeloma, the t(4;14) translocated myeloma, and the t(14;16) translocated myeloma. And when you use dual maintenance, granted this was a single arm phase II trial, no data have replicated the kind of outcomes that the Emory group has seen. So in that patient population I certainly will use dual maintenance. I start off using bortezomib, but supplementing it or replacing it with ixazomib would be perfectly reasonable if patients had toxicity to bortezomib in the way of neuropathy.

Toxicity from long-term therapy is common with all drugs. And that’s where I think using tools such as MRD [minimal residual disease]-testing are going to be incredibly useful. Even though I say that lenalidomide is sort of a standard of care, and on average we use lenalidomide for 3 or 4 years, patients who were on it for very long periods of time have toxicities not just in the way of cytopenias, but more GI [gastrointestinal]-related toxicities, so diarrhea. Chronic diarrhea is very common. And sometimes it’s just not sustainable for patients to remain on these drugs. That’s why I think beginning to ask the question in terms of duration of maintenance treatment is incredibly important. We just don’t have that information.

As of right now, what we have started doing is managing these toxicities. So if you have a whole lot of cytopenia, you can dose reduce lenalidomide. The dose for lenalidomide maintenance is 10 mg to 15 mg. It can be given continuously. I almost never use the dose of 15 mg. Typically, my patients are on 10 mg and we typically use more of the CALGB regimen, which is 3 weeks on and 1 week off.

There are ways of minimizing that even further. You can drop the dose of lenalidomide more. I typically don’t like using a whole lot of growth factors in the maintenance setting, but I try and get to the patient’s sweet spot, whether it’s 3 weeks on of 10 mg, or 5 mg. Sometimes patients are on 2 weeks on, 2 weeks off. So you have to do what a patient is able to tolerate at the end of the day.

With ixazomib, we have been able to use ixazomib for very long periods of time as well. I’ve had patients on it for 3 or 4 years. Again, diarrhea tends to be a problem with ixazomib, and as long as you are able to manage that, patients do OK. But using the MRD tool in this setting allows us to get rid of some of these treatments if you don’t need to continue patients on treatment forever.

Rafael Fonseca, MD: In multiple myeloma, after stem cell transplant the vast majority of myeloma doctors now consider maintenance to be the standard of care. I think there’s some very thoughtful, smart people that can still make an argument that they don’t want to do that, but I would say 95%, plus, of myeloma doctors now recommend maintenance therapy. It is very clear from the data we have from phase III studies as well as from the meta-analysis that maintenance with lenalidomide should be considered for all patients. Usually this is at the lower dose. We’re following the package insert where we just do this continuously. In our practice, I tend to do this indefinitely as long as 2 things happen: As long as the patient is tolerating the treatment, and, of course, there’s lack of relapse evidence.

Now, there are important questions that need to be raised with regards to maintenance. When we think about patients who have high-risk disease, a number of trials and retrospective clinical observations have shown that while lenalidomide may help, it’s probably insufficient. So for most patients we add a proteasome inhibitor. This could be done in the form of bortezomib, such as VRd [bortezomib/lenalidomide/dexamethasone]. In my clinical practice, to try to emancipate patients from our clinics, we give them ixazomib as an alternative. So we’ve used frequently the combination of ixazomib, lenalidomide, and dexamethasone. At this last ASH meeting, we had the TOURMALINE study that looked at ixazomib as maintenance therapy for myeloma. This case was not combined with lenalidomide, but that’s what we do for our patients. And I would argue again this is particularly important for the high-risk patients to use a combination of an IMiD [immunomodulatory drug] and a proteasome inhibitor.

What’s the future of maintenance? Well, number 1, as I mentioned before, should we do consolidation before we go into this maintenance mode? How do we integrate the monoclonal antibodies? And the question is also being addressed by clinical trials. For instance, daratumumab, other CD38 antibodies—how can they be used in the maintenance setting? And I’m going to venture out to say that I think there’s a subset of patients that are better molecularly characterized, particularly the translocation t(11;14), where I think the question is going to be: Should we be doing maintenance with venetoclax, which has been proven to be a very effective drug in this subset of patients? And hopefully we’ll have the data from clinical trials to validate that hypothesis.

Transcript Edited for Clarity
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