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Upfront Therapy for Transplant -Ineligible Patients

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, Aug 03, 2016


Transcript:

Keith Stewart, MD, CHB:
Let’s move on from this. So, for the younger patient, triplet therapy. Most people are aiming for a complete remission, but most people are still using transplant to get there; a little bit more investigational at Memorial Sloan Kettering Cancer Center. Everybody’s using maintenance. Validations by a meta-analysis. And for high-risk patients, people are adding proteasome inhibitors, as well.

Let’s just turn our attention, now, to the frailer, elderly patient, and tell me what you’re doing there, Ola. What do you do with somebody who’s 82 and comes in with myeloma? You know they’re transplant-ineligible, obviously.

C. Ola Landgren, MD, PhD: Yes, so we, as a default, probably would have lenalidomide/dexamethasone as our standard therapy. There could be instances where we could do possibly dexamethasone. If the patient tolerates three drugs, probably a lighter version of RVD would be our default. For example, if we gave lenalidomide at 15 mg or something like that, and depending on how frail a patient is, maybe we would scale back to maybe once a week or a lower dose of bortezomib twice a week.

Keith Stewart, MD, CHB: I must say that’s sort of been my approach—VRD white, as we call it. And any deviation from that of what are other people using up front?

Rafael Fonseca, MD: One important comment again about risk in the elderly: they’re highly enriched for hyperdiploid trisomies, low rate of high-risk disease. So, that’s the one thing I would diverse that from. The only patient population where I would consider a doublet, an RD (Revlimid/dexamethasone) in a frail elderly person who has hyperdiploid disease and not high-risk markers. You can always add something else. I know Antonio has rightfully stated that we can sometimes catch up. But for that population, there’s a great balance between convenience, efficacy, and tolerability.

Keith Stewart, MD, CHB: Yesterday, there were some presentations on new combinations in the frontline setting. Bill, you were the moderator of the discussion of that. One in particular, if I recall right, was a presentation on ixazomib in the frontline setting. What were your thoughts on that?

William I. Bensinger, MD: There was a presentation of a phase I/II study of ixazomib, which is the oral proteasome inhibitor. It is a baryonic-based proteasome inhibitor similar to bortezomib. But it’s given orally in combination with cyclophosphamide and dexamethasone. This was a more or less weekly therapy, 3 weeks out of 4. So, you got three drugs once a week.

They looked at a dose of 300 mg of cyclophosphamide and then 400 mg of cyclophosphamide, and what they found was that 400 mg was tolerated, but had a few more side effects—GI, some more cytopenias. They got a high overall response rate in the 70%-to-80% range, but they were giving this combination for, honestly, 12 to 13 cycles of therapy. And so one of the questions I raised at the discussion was how these data compared with bortezomib, cyclophosphamide, and dexamethasone. And there is no direct comparison trial.

But taking some of the data from the IFM study comparing VTD with VCD—looking at the VCD data with four cycles of therapy—there were higher response rates seen across 12 cycles of the oral proteasome inhibitor. A concern I raised was that we might be sacrificing efficacy for convenience by using an all-oral combination. But I have to say, there needs to be a prospective direct comparison trial to confirm that.

Keith Stewart, MD, CHB: I guess I’m biased because one of my patients went on this study. He was an 82-year-old retired radiologist, went into complete remission, and has stayed there now for about 18 months. I think for some patients, this notion that you can give something as a pill, rather than an injection, means less neuropathy than with bortezomib.

William I. Bensinger, MD: I think so for some patients.

Keith Stewart, MD, CHB: Frail patients who have trouble traveling into New York City and paying for parking. You know, I think there are people who could benefit from this.

C. Ola Landgren, MD, PhD: I also think that we shouldn’t necessarily compare it to the more potent drug, bortezomib. I think, really, in reality, the comparison should be to have two drugs versus three drugs because if you can only do oral drugs, that’s really why you’re looking at that, right? The convenience factor, with additive efficacy. That’s really what it is. So, I think that’s an important aspect of looking at that combination.

Keith Stewart, MD, CHB: Just one question we should address for the listening audience. Two versus three drugs in a very elderly patient? A lot of people might say, “Geez, lenalidomide/dexamethasone is just fine in this population,” especially, as you point out, because they’re a lot from low-risk genetics.

Rafael Fonseca, MD: I think two drugs sometimes is fine. We have several ways in which we stratify a patient. We talk about the genetics, we talk about fit versus unfit, and we also are starting to talk more and more about the aggressive relapse or the aggressive new diagnosis versus the more indolent one that you can treat. And I think for this category, you can be a little bit more cautious—particularly with the elderly—but if they can tolerate the two drugs and then you can catch up or arrange in a different way if you don’t get the results, I think that’s perfectly reasonable.

Keith Stewart, MD, CHB: Do you continue therapy for these patients or do you stop and start?

Rafael Fonseca, MD: The same is for maintenance: I continue on therapy, definitely.

Keith Stewart, MD, CHB: Everybody using long-term therapy in elderly people? Nobody is stopping and starting?

Jatin P. Shah, MD: Yes. I think it’s a little bit different than the MD Anderson older patient versus what we see in the community. Because in the community, you’re going to see those patients that are 80 and above. So, for those patients who are 80 and above, I think that using lenalidomide and dexamethasone is rather appropriate. The key there is, actually, in my mind, to start tapering down the dose. And so not to use lenalidomide/dexamethasone continuously. I stop the dexamethasone, and we can discuss when you stop the dexamethasone; is it after 12 months or 18 months? I also start tapering back down the lenalidomide, down from 15 or 25 to 10 or 15 at 12 months, after they’ve plateaued out.

So, I think that’s the key when you’re going to be using continuous therapy: it’s not continuous lenalidomide/dexamethasone forever. At some point, you need to taper off the dexamethasone completely and just continue them on single-agent lenalidomide. That’s at least what my experience has been. And I think talking about the ixazomib with lenalidomide/dexamethasone—until we have a good randomized phase III study for that in the upfront setting—it’s difficult to recommend that when we have.

Keith Stewart, MD, CHB: It’s going to be positive; you’re adding a third drug. You’re going to get longer PFS but…

Jatin P. Shah, MD: Well, we don’t know that for sure.

Keith Stewart, MD, CHB: It’s likely.

Jatin P. Shah, MD: It’s likely, but if we look at their relapsed refractory setting in a subset analysis, there are some questions that arise there.

Keith Stewart, MD, CHB: Okay. So, I think just to recap then: we’ve concluded there are more patients that need to be treated earlier a little bit, that we all recommend triplets, and we recommend going for complete remission. We like the idea of keeping people on continuous therapy, particularly lenalidomide, but adding proteasome inhibitors if they’re high-risk, right? It doesn’t always work. People relapse, right, despite our best intentions. Most myeloma patients relapse.

Transcript Edited for Clarity
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Transcript:

Keith Stewart, MD, CHB:
Let’s move on from this. So, for the younger patient, triplet therapy. Most people are aiming for a complete remission, but most people are still using transplant to get there; a little bit more investigational at Memorial Sloan Kettering Cancer Center. Everybody’s using maintenance. Validations by a meta-analysis. And for high-risk patients, people are adding proteasome inhibitors, as well.

Let’s just turn our attention, now, to the frailer, elderly patient, and tell me what you’re doing there, Ola. What do you do with somebody who’s 82 and comes in with myeloma? You know they’re transplant-ineligible, obviously.

C. Ola Landgren, MD, PhD: Yes, so we, as a default, probably would have lenalidomide/dexamethasone as our standard therapy. There could be instances where we could do possibly dexamethasone. If the patient tolerates three drugs, probably a lighter version of RVD would be our default. For example, if we gave lenalidomide at 15 mg or something like that, and depending on how frail a patient is, maybe we would scale back to maybe once a week or a lower dose of bortezomib twice a week.

Keith Stewart, MD, CHB: I must say that’s sort of been my approach—VRD white, as we call it. And any deviation from that of what are other people using up front?

Rafael Fonseca, MD: One important comment again about risk in the elderly: they’re highly enriched for hyperdiploid trisomies, low rate of high-risk disease. So, that’s the one thing I would diverse that from. The only patient population where I would consider a doublet, an RD (Revlimid/dexamethasone) in a frail elderly person who has hyperdiploid disease and not high-risk markers. You can always add something else. I know Antonio has rightfully stated that we can sometimes catch up. But for that population, there’s a great balance between convenience, efficacy, and tolerability.

Keith Stewart, MD, CHB: Yesterday, there were some presentations on new combinations in the frontline setting. Bill, you were the moderator of the discussion of that. One in particular, if I recall right, was a presentation on ixazomib in the frontline setting. What were your thoughts on that?

William I. Bensinger, MD: There was a presentation of a phase I/II study of ixazomib, which is the oral proteasome inhibitor. It is a baryonic-based proteasome inhibitor similar to bortezomib. But it’s given orally in combination with cyclophosphamide and dexamethasone. This was a more or less weekly therapy, 3 weeks out of 4. So, you got three drugs once a week.

They looked at a dose of 300 mg of cyclophosphamide and then 400 mg of cyclophosphamide, and what they found was that 400 mg was tolerated, but had a few more side effects—GI, some more cytopenias. They got a high overall response rate in the 70%-to-80% range, but they were giving this combination for, honestly, 12 to 13 cycles of therapy. And so one of the questions I raised at the discussion was how these data compared with bortezomib, cyclophosphamide, and dexamethasone. And there is no direct comparison trial.

But taking some of the data from the IFM study comparing VTD with VCD—looking at the VCD data with four cycles of therapy—there were higher response rates seen across 12 cycles of the oral proteasome inhibitor. A concern I raised was that we might be sacrificing efficacy for convenience by using an all-oral combination. But I have to say, there needs to be a prospective direct comparison trial to confirm that.

Keith Stewart, MD, CHB: I guess I’m biased because one of my patients went on this study. He was an 82-year-old retired radiologist, went into complete remission, and has stayed there now for about 18 months. I think for some patients, this notion that you can give something as a pill, rather than an injection, means less neuropathy than with bortezomib.

William I. Bensinger, MD: I think so for some patients.

Keith Stewart, MD, CHB: Frail patients who have trouble traveling into New York City and paying for parking. You know, I think there are people who could benefit from this.

C. Ola Landgren, MD, PhD: I also think that we shouldn’t necessarily compare it to the more potent drug, bortezomib. I think, really, in reality, the comparison should be to have two drugs versus three drugs because if you can only do oral drugs, that’s really why you’re looking at that, right? The convenience factor, with additive efficacy. That’s really what it is. So, I think that’s an important aspect of looking at that combination.

Keith Stewart, MD, CHB: Just one question we should address for the listening audience. Two versus three drugs in a very elderly patient? A lot of people might say, “Geez, lenalidomide/dexamethasone is just fine in this population,” especially, as you point out, because they’re a lot from low-risk genetics.

Rafael Fonseca, MD: I think two drugs sometimes is fine. We have several ways in which we stratify a patient. We talk about the genetics, we talk about fit versus unfit, and we also are starting to talk more and more about the aggressive relapse or the aggressive new diagnosis versus the more indolent one that you can treat. And I think for this category, you can be a little bit more cautious—particularly with the elderly—but if they can tolerate the two drugs and then you can catch up or arrange in a different way if you don’t get the results, I think that’s perfectly reasonable.

Keith Stewart, MD, CHB: Do you continue therapy for these patients or do you stop and start?

Rafael Fonseca, MD: The same is for maintenance: I continue on therapy, definitely.

Keith Stewart, MD, CHB: Everybody using long-term therapy in elderly people? Nobody is stopping and starting?

Jatin P. Shah, MD: Yes. I think it’s a little bit different than the MD Anderson older patient versus what we see in the community. Because in the community, you’re going to see those patients that are 80 and above. So, for those patients who are 80 and above, I think that using lenalidomide and dexamethasone is rather appropriate. The key there is, actually, in my mind, to start tapering down the dose. And so not to use lenalidomide/dexamethasone continuously. I stop the dexamethasone, and we can discuss when you stop the dexamethasone; is it after 12 months or 18 months? I also start tapering back down the lenalidomide, down from 15 or 25 to 10 or 15 at 12 months, after they’ve plateaued out.

So, I think that’s the key when you’re going to be using continuous therapy: it’s not continuous lenalidomide/dexamethasone forever. At some point, you need to taper off the dexamethasone completely and just continue them on single-agent lenalidomide. That’s at least what my experience has been. And I think talking about the ixazomib with lenalidomide/dexamethasone—until we have a good randomized phase III study for that in the upfront setting—it’s difficult to recommend that when we have.

Keith Stewart, MD, CHB: It’s going to be positive; you’re adding a third drug. You’re going to get longer PFS but…

Jatin P. Shah, MD: Well, we don’t know that for sure.

Keith Stewart, MD, CHB: It’s likely.

Jatin P. Shah, MD: It’s likely, but if we look at their relapsed refractory setting in a subset analysis, there are some questions that arise there.

Keith Stewart, MD, CHB: Okay. So, I think just to recap then: we’ve concluded there are more patients that need to be treated earlier a little bit, that we all recommend triplets, and we recommend going for complete remission. We like the idea of keeping people on continuous therapy, particularly lenalidomide, but adding proteasome inhibitors if they’re high-risk, right? It doesn’t always work. People relapse, right, despite our best intentions. Most myeloma patients relapse.

Transcript Edited for Clarity
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