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Risk Stratified Treatment; Maintenance or Not?

Panelists:Keith Stewart, MD, CHB, Mayo Clinic;William I. Bensinger, MD, Swedish Cancer Institute;Rafael Fonseca, MD, Mayo Clinic;C. Ola Landgren, MD, PhD, Memorial Sloan Kettering Cancer Center;Jatin P. Shah, MD, MD Anderson Cancer Center
Published: Wednesday, Jul 27, 2016


Transcript:

Keith Stewart, MD, CHB:
Since you mentioned heterogeneity, I just wanted to—because we haven’t talked about it at all yet is—you know, at Mayo Clinic, we’ve long been preaching that people should do genetic testing and risk-stratify their treatment in the newly diagnosed setting. Rafael, is that still the case with these?

Rafael Fonseca, MD: I think it matters a lot. It matters a lot for two reasons, and not in any way self-serving. First of all, when you counsel a patient, a patient who has high-risk myeloma is not a person you’re going to approach with this notion of “Well, we’re so fortunate.” It’s a very concerning disease in the shorter term than the person who doesn’t have high-risk markers. Number two—perhaps the most important one—is, what do you do with transplant, and post-transplant is quite different if you have high-risk disease or not.

There are pretty good data now that for the high-risk patients, you cannot let go, you cannot use a simple maintenance strategy of lenalidomide-based regimens. I think there’s data from several European groups, again, that show that the addition of a proteasome inhibitor is of benefit. And, arguably, there’s emerging data that perhaps the old question of the tandem transplant should be revisited for high-risk patients—which, actually, it is true—but the data are there in front of us and we can’t ignore it.

Keith Stewart, MD, CHB: Oh, yes. But is tandem important in Europe because they don’t have access to drugs we have here in the United States? Is it so important here or is it just that however you get into CR is the important thing?

Rafael Fonseca, MD: I think getting to CR, cytoreduction, intensity of treatment, and duration of treatment are proving to be important aspects of control.

Keith Stewart, MD, CHB: And all of these studies in Europe use pretty lame therapy by United States standards, right?

William I. Bensinger, MD: We will have a study that may read out at ASH—I don’t know that—but it’s the current CTN (Clinical Trial Network). Not the current trial, but the trial that’s fully accrued that looks at the question of single transplant, double transplant, or single transplant followed by four cycles of VRD consolidation. That trial was fully accrued as of a couple of years ago. And the readout from that might occur as early as this fall, in which case we’ll have a United States answer, if you will, to the question of one versus two.

Keith Stewart, MD, CHB: Yes. I suspect what matters is the complete remission, not so much how you get there.

Rafael Fonseca, MD: If I may, one of the things you mentioned with your treatments. You want to put all your treatments as packages in the lines of treatments for patients. And if you do transplant up front versus later, there’s quite a bit of a difference in the durability of the response. So, if you treat it like a financial asset of capital expense, transplant up front, you depreciate over many more years than if you do transplant down the line, right? It’s true. Because the post-transplant benefit is greater when you do it up front than when you do it down the line for the same investment in toxicity, time out of work, etc, if you do it up front.

Keith Stewart, MD, CHB: All right, Jatin, maintenance or no maintenance therapy?

Jatin P. Shah, MD: I think maintenance is absolutely the standard of care.

Keith Stewart, MD, CHB: What did you think of this meta-analysis that was presented yesterday, looking at lenalidomide across three large randomized trials? What was the conclusion of that, and what does that mean for us or did we already know the answer?

Jatin P. Shah, MD: I think we already knew the answer that, at least from the two randomized phase III studies of maintenance therapy after transplant, both the United States and the French showed progression-free survival improvement. And in the United States, progression-free survival benefit improvement. And in the United States with indefinite therapy, we see an overall survival benefit. I think where the meta-analysis really helped is there’s still that question for patients who are on therapy for 2, 3, 4, 5 years and need to come off. But now it seems meta-analysis and overall survival benefit really, I think, continue to…

Keith Stewart, MD, CHB: There’s large overall survival benefit. It’s like 2 1/2 years for people taking lenalidomide. Is that the final word on this, do you think, Bill? Are we…is lenalidomide maintenance here to stay for everybody?

William I. Bensinger, MD: I think, for the time being, we have the most robust data with lenalidomide. But we also could see emerging data with ixazomib—the oral proteasome inhibitor—which, from a convenience standpoint, is going to be the same as giving lenalidomide. The other issue to keep in mind is that there is a cost for this, not just a monetary cost. You do see a definite increase in second primary malignancies, mainly hematologic malignancies, as a result of lenalidomide maintenance.

Keith Stewart, MD, CHB: If you use it, how long do you use is it for?

William I. Bensinger, MD: I don’t think we know exactly. I use it continuously because I’m not convinced that a year versus 2 years makes a difference in terms of the risk of second primary malignancies.

Keith Stewart, MD, CHB: Does that mean you stay on for 7 years if you’re in remission, or is it more than 2 years? What is it?

William I. Bensinger, MD: I keep them on it as long as they can tolerate it and afford it.

Keith Stewart, MD, CHB: Do you worry about the MDS (myelodysplastic syndrome) or MCD (multi-centric Castleman's disease) type?

William I. Bensinger, MD: One thing I’ve done recently, based on some very early data, is to use intermittent lenalidomide. Twenty-one out of 28 days, there are some early data that maybe giving it intermittently, as opposed to continuously, may reduce that risk of secondary malignancies. But I’d like to see more data on it.

Keith Stewart, MD, CHB: I just need snapshots here. How long do you use lenalidomide maintenance for?

Jatin P. Shah, MD: I use lenalidomide maintenance indefinitely, while they’re benefiting from therapy.

Keith Stewart, MD, CHB: Is that true for both of you, as well?

Rafael Fonseca, MD: Same. As long as the patient tolerates it and the disease is under control.

Keith Stewart, MD, CHB: Who do we use a proteasome inhibitor maintenance on? And if so, why, Ola?

C. Ola Landgren, MD, PhD: I think there are occasional patients that don’t tolerate lenalidomide, and if they’re high-risk disease, I would consider doing a combination of proteasome inhibitors.

Keith Stewart, MD, CHB: Is that your standard practice?

C. Ola Landgren, MD, PhD: Yes.

Keith Stewart, MD, CHB: What do you use? Bortezomib or…?

C. Ola Landgren, MD, PhD: We have, up until now, used bortezomib with lenalidomide.

Keith Stewart, MD, CHB: Is that every 2 weeks, or how do you give it?

C. Ola Landgren, MD, PhD: We have given bortezomib every 2 weeks as maintenance. If you do that as a single drug, I would do it every 2 weeks. If you have high-risk disease, and there are different types of high-risk, it probably is every 2 weeks.

Transcript Edited for Clarity
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Transcript:

Keith Stewart, MD, CHB:
Since you mentioned heterogeneity, I just wanted to—because we haven’t talked about it at all yet is—you know, at Mayo Clinic, we’ve long been preaching that people should do genetic testing and risk-stratify their treatment in the newly diagnosed setting. Rafael, is that still the case with these?

Rafael Fonseca, MD: I think it matters a lot. It matters a lot for two reasons, and not in any way self-serving. First of all, when you counsel a patient, a patient who has high-risk myeloma is not a person you’re going to approach with this notion of “Well, we’re so fortunate.” It’s a very concerning disease in the shorter term than the person who doesn’t have high-risk markers. Number two—perhaps the most important one—is, what do you do with transplant, and post-transplant is quite different if you have high-risk disease or not.

There are pretty good data now that for the high-risk patients, you cannot let go, you cannot use a simple maintenance strategy of lenalidomide-based regimens. I think there’s data from several European groups, again, that show that the addition of a proteasome inhibitor is of benefit. And, arguably, there’s emerging data that perhaps the old question of the tandem transplant should be revisited for high-risk patients—which, actually, it is true—but the data are there in front of us and we can’t ignore it.

Keith Stewart, MD, CHB: Oh, yes. But is tandem important in Europe because they don’t have access to drugs we have here in the United States? Is it so important here or is it just that however you get into CR is the important thing?

Rafael Fonseca, MD: I think getting to CR, cytoreduction, intensity of treatment, and duration of treatment are proving to be important aspects of control.

Keith Stewart, MD, CHB: And all of these studies in Europe use pretty lame therapy by United States standards, right?

William I. Bensinger, MD: We will have a study that may read out at ASH—I don’t know that—but it’s the current CTN (Clinical Trial Network). Not the current trial, but the trial that’s fully accrued that looks at the question of single transplant, double transplant, or single transplant followed by four cycles of VRD consolidation. That trial was fully accrued as of a couple of years ago. And the readout from that might occur as early as this fall, in which case we’ll have a United States answer, if you will, to the question of one versus two.

Keith Stewart, MD, CHB: Yes. I suspect what matters is the complete remission, not so much how you get there.

Rafael Fonseca, MD: If I may, one of the things you mentioned with your treatments. You want to put all your treatments as packages in the lines of treatments for patients. And if you do transplant up front versus later, there’s quite a bit of a difference in the durability of the response. So, if you treat it like a financial asset of capital expense, transplant up front, you depreciate over many more years than if you do transplant down the line, right? It’s true. Because the post-transplant benefit is greater when you do it up front than when you do it down the line for the same investment in toxicity, time out of work, etc, if you do it up front.

Keith Stewart, MD, CHB: All right, Jatin, maintenance or no maintenance therapy?

Jatin P. Shah, MD: I think maintenance is absolutely the standard of care.

Keith Stewart, MD, CHB: What did you think of this meta-analysis that was presented yesterday, looking at lenalidomide across three large randomized trials? What was the conclusion of that, and what does that mean for us or did we already know the answer?

Jatin P. Shah, MD: I think we already knew the answer that, at least from the two randomized phase III studies of maintenance therapy after transplant, both the United States and the French showed progression-free survival improvement. And in the United States, progression-free survival benefit improvement. And in the United States with indefinite therapy, we see an overall survival benefit. I think where the meta-analysis really helped is there’s still that question for patients who are on therapy for 2, 3, 4, 5 years and need to come off. But now it seems meta-analysis and overall survival benefit really, I think, continue to…

Keith Stewart, MD, CHB: There’s large overall survival benefit. It’s like 2 1/2 years for people taking lenalidomide. Is that the final word on this, do you think, Bill? Are we…is lenalidomide maintenance here to stay for everybody?

William I. Bensinger, MD: I think, for the time being, we have the most robust data with lenalidomide. But we also could see emerging data with ixazomib—the oral proteasome inhibitor—which, from a convenience standpoint, is going to be the same as giving lenalidomide. The other issue to keep in mind is that there is a cost for this, not just a monetary cost. You do see a definite increase in second primary malignancies, mainly hematologic malignancies, as a result of lenalidomide maintenance.

Keith Stewart, MD, CHB: If you use it, how long do you use is it for?

William I. Bensinger, MD: I don’t think we know exactly. I use it continuously because I’m not convinced that a year versus 2 years makes a difference in terms of the risk of second primary malignancies.

Keith Stewart, MD, CHB: Does that mean you stay on for 7 years if you’re in remission, or is it more than 2 years? What is it?

William I. Bensinger, MD: I keep them on it as long as they can tolerate it and afford it.

Keith Stewart, MD, CHB: Do you worry about the MDS (myelodysplastic syndrome) or MCD (multi-centric Castleman's disease) type?

William I. Bensinger, MD: One thing I’ve done recently, based on some very early data, is to use intermittent lenalidomide. Twenty-one out of 28 days, there are some early data that maybe giving it intermittently, as opposed to continuously, may reduce that risk of secondary malignancies. But I’d like to see more data on it.

Keith Stewart, MD, CHB: I just need snapshots here. How long do you use lenalidomide maintenance for?

Jatin P. Shah, MD: I use lenalidomide maintenance indefinitely, while they’re benefiting from therapy.

Keith Stewart, MD, CHB: Is that true for both of you, as well?

Rafael Fonseca, MD: Same. As long as the patient tolerates it and the disease is under control.

Keith Stewart, MD, CHB: Who do we use a proteasome inhibitor maintenance on? And if so, why, Ola?

C. Ola Landgren, MD, PhD: I think there are occasional patients that don’t tolerate lenalidomide, and if they’re high-risk disease, I would consider doing a combination of proteasome inhibitors.

Keith Stewart, MD, CHB: Is that your standard practice?

C. Ola Landgren, MD, PhD: Yes.

Keith Stewart, MD, CHB: What do you use? Bortezomib or…?

C. Ola Landgren, MD, PhD: We have, up until now, used bortezomib with lenalidomide.

Keith Stewart, MD, CHB: Is that every 2 weeks, or how do you give it?

C. Ola Landgren, MD, PhD: We have given bortezomib every 2 weeks as maintenance. If you do that as a single drug, I would do it every 2 weeks. If you have high-risk disease, and there are different types of high-risk, it probably is every 2 weeks.

Transcript Edited for Clarity
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