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Risk Stratification for 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: Tuesday, Jun 27, 2017



Transcript:

Keith Stewart, MB, ChB:
I’ve heard, already, that most of us are using a proteasome inhibitor and an IMiD [immunomodulatory imide drug], aiming for a deep response—MRD [minimal residual disease]. It sounds like we’re all using MRD testing in our clinical practice already, at least in academic centers. Is there any risk stratification going on? Do people still need to do FISH [fluorescence in situ hybridization] testing? If everybody is going to get RVD [lenalidomide, bortezomib, and dexamethasone] and transplant, is that a test you still recommend, Sagar?

Sagar Lonial, MD: From our perspective, we think that where you really begin to tailor it, as Gareth was talking about, is in the maintenance setting. We find that information useful because it tailors how we’re going to put people on the post-transplant consolidation and maintenance arm. One of the important points that I think Gareth brought up is that I think the days of saying, “I’m just going to put people on a regimen and see what happens,” hopefully, are over, because we really need to think about, “What is my 3-month, 6-month, and 12-month plan for a patient with newly diagnosed myeloma?” We’ve got to treat them for more than just 4 cycles.

Keith Stewart, MB, ChB: Good point. Tom?

Thomas G. Martin, MD: I couldn’t agree with that more. Many of our clinical trials do just take the approach of, “Here’s a regimen. You’re going to do it for 16 cycles or 18 cycles.” That’s not the way we practice clinically, right? So we do need these risk-adapted clinical trials that are going to give people 4 cycles, some intervention, and see what’s happening. And if it’s not good enough, you switch to some other regimen. I think we need that more in our field.

Gareth Morgan, MD, PhD: My point would be—not to argue against the point you made about stopping if you’re MRD-negative—what should you do if at a year on maintenance you’re still MRD-positive? Do you do something extra for those patients?

Keith Stewart, MB, ChB: Let’s come back to the maintenance question in a minute. I just want to focus a little bit more on this risk stratification question. Just talk me through, Ivan, a young patient who has got a p53 deletion at diagnosis. Do you treat them any differently than somebody who has got lower-risk genetics?

Ivan M. Borrello, MD: We actually do, and I would say that I think this is by FISH—I’m assuming that is what you’re talking about. We’ve been using also MyPRS [myeloma prognostic risk signature], which came out of Arkansas. There are a lot of very nice data to suggest that FISH and the molecular signature may not necessarily correspond, but assuming that they do, our approach off a specific protocol has been to talk about sending these patients to an allotransplant following induction therapy. And we’re able to do that now. I know there’s a lot of controversy, and we’ll probably talk about it, but our transplant-related mortality, now, with allotransplant is in the order of around 5%. And with the incidence of graft-versus-host disease, grade 3 or grade 4, the number is in the 10% to 15% range. So we are seeing patients who achieve a complete response have remissions up to about 5 years median progression-free survival.

Keith Stewart, MB, ChB: Is anybody else doing allotransplant in high-risk patients?

Gareth Morgan, MD, PhD: I would say that the high-risk patient setting is probably more of the setting, and we’re going to come to that at the end of the discussion when we start talking about CAR-Ts [chimeric antigen receptor T-cells] because it’s a natural place to put those agents.

Keith Stewart, MB, ChB: Very good.

Thomas G. Martin, MD: I would be curious, with you, Gareth, answering, if somebody has 17p deletion by FISH, that’s truly a variable disease process, correct?

Gareth Morgan, MD, PhD: We have a paper that has just come out in Haematologica that shows there is a cut point, and you have to, in lower risk patients, use a 60% cut point. But we’ve also got some data that it’s biallelic inactivation of p53 that’s crucial, where you lose one copy and mutate the other.

Keith Stewart, MB, ChB: We’re getting a little bit into the weeds here, so I want to keep it at a higher level for a second. We talk a lot about younger patients, but we have to realize, in the community, there are a lot of older patients. Tom, in an older patient with high-risk disease, do you treat them any differently than a low-risk patient who’s more elderly?

Thomas G. Martin, MD: We do, and pretty much we follow the RVD-light protocol. We give the same agents. We just give them in lower doses. We see how they tolerate in the lower doses, and we can increase the dose if it’s tolerated well and they’re not having such a good response. We’ll just kind of do a risk-adapted design for each individual patient. We also, in that patient population—if they’re not doing well on bortezomib and lenalidomide—would switch them to carfilzomib or to pomalidomide. We would give them something more intense if they could tolerate it.

Keith Stewart, MB, ChB: You’ve kind of pursued that approach in your Medical Research Council trials, Gareth, where you failed to have a good response and you’ve switched therapy.

Gareth Morgan, MD, PhD: I think that’s the first trial in myeloma, at least, that’s been an adaptive design from the beginning.

Keith Stewart, MB, ChB: Tell us what you did in that study.

Gareth Morgan, MD, PhD: Patients were exposed to an IMiD, initially, if they didn’t respond well.

Keith Stewart, MB, ChB: It ended up being lenalidomide or thalidomide?

Gareth Morgan, MD, PhD: Or thalidomide. If they didn’t respond well to that, they were allowed to swap, and we randomized to exposure to a proteasome inhibitor combination or nothing. And the people who had stopped responding, who responded to the proteasome inhibitor combination, had better responses—better progression-free survival and better overall survival.

Sagar Lonial, MD: But you don’t know that you can extrapolate that to somebody who’s getting an IMiD and PI [proteasome inhibitor] up front together?

Gareth Morgan, MD, PhD: I interpret it as being a biological message about resistance, but the optimum induction would be a proteasome inhibitor, an IMiD, probably an alkylating agent, and dexamethasone.

Transcript Edited for Clarity

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Transcript:

Keith Stewart, MB, ChB:
I’ve heard, already, that most of us are using a proteasome inhibitor and an IMiD [immunomodulatory imide drug], aiming for a deep response—MRD [minimal residual disease]. It sounds like we’re all using MRD testing in our clinical practice already, at least in academic centers. Is there any risk stratification going on? Do people still need to do FISH [fluorescence in situ hybridization] testing? If everybody is going to get RVD [lenalidomide, bortezomib, and dexamethasone] and transplant, is that a test you still recommend, Sagar?

Sagar Lonial, MD: From our perspective, we think that where you really begin to tailor it, as Gareth was talking about, is in the maintenance setting. We find that information useful because it tailors how we’re going to put people on the post-transplant consolidation and maintenance arm. One of the important points that I think Gareth brought up is that I think the days of saying, “I’m just going to put people on a regimen and see what happens,” hopefully, are over, because we really need to think about, “What is my 3-month, 6-month, and 12-month plan for a patient with newly diagnosed myeloma?” We’ve got to treat them for more than just 4 cycles.

Keith Stewart, MB, ChB: Good point. Tom?

Thomas G. Martin, MD: I couldn’t agree with that more. Many of our clinical trials do just take the approach of, “Here’s a regimen. You’re going to do it for 16 cycles or 18 cycles.” That’s not the way we practice clinically, right? So we do need these risk-adapted clinical trials that are going to give people 4 cycles, some intervention, and see what’s happening. And if it’s not good enough, you switch to some other regimen. I think we need that more in our field.

Gareth Morgan, MD, PhD: My point would be—not to argue against the point you made about stopping if you’re MRD-negative—what should you do if at a year on maintenance you’re still MRD-positive? Do you do something extra for those patients?

Keith Stewart, MB, ChB: Let’s come back to the maintenance question in a minute. I just want to focus a little bit more on this risk stratification question. Just talk me through, Ivan, a young patient who has got a p53 deletion at diagnosis. Do you treat them any differently than somebody who has got lower-risk genetics?

Ivan M. Borrello, MD: We actually do, and I would say that I think this is by FISH—I’m assuming that is what you’re talking about. We’ve been using also MyPRS [myeloma prognostic risk signature], which came out of Arkansas. There are a lot of very nice data to suggest that FISH and the molecular signature may not necessarily correspond, but assuming that they do, our approach off a specific protocol has been to talk about sending these patients to an allotransplant following induction therapy. And we’re able to do that now. I know there’s a lot of controversy, and we’ll probably talk about it, but our transplant-related mortality, now, with allotransplant is in the order of around 5%. And with the incidence of graft-versus-host disease, grade 3 or grade 4, the number is in the 10% to 15% range. So we are seeing patients who achieve a complete response have remissions up to about 5 years median progression-free survival.

Keith Stewart, MB, ChB: Is anybody else doing allotransplant in high-risk patients?

Gareth Morgan, MD, PhD: I would say that the high-risk patient setting is probably more of the setting, and we’re going to come to that at the end of the discussion when we start talking about CAR-Ts [chimeric antigen receptor T-cells] because it’s a natural place to put those agents.

Keith Stewart, MB, ChB: Very good.

Thomas G. Martin, MD: I would be curious, with you, Gareth, answering, if somebody has 17p deletion by FISH, that’s truly a variable disease process, correct?

Gareth Morgan, MD, PhD: We have a paper that has just come out in Haematologica that shows there is a cut point, and you have to, in lower risk patients, use a 60% cut point. But we’ve also got some data that it’s biallelic inactivation of p53 that’s crucial, where you lose one copy and mutate the other.

Keith Stewart, MB, ChB: We’re getting a little bit into the weeds here, so I want to keep it at a higher level for a second. We talk a lot about younger patients, but we have to realize, in the community, there are a lot of older patients. Tom, in an older patient with high-risk disease, do you treat them any differently than a low-risk patient who’s more elderly?

Thomas G. Martin, MD: We do, and pretty much we follow the RVD-light protocol. We give the same agents. We just give them in lower doses. We see how they tolerate in the lower doses, and we can increase the dose if it’s tolerated well and they’re not having such a good response. We’ll just kind of do a risk-adapted design for each individual patient. We also, in that patient population—if they’re not doing well on bortezomib and lenalidomide—would switch them to carfilzomib or to pomalidomide. We would give them something more intense if they could tolerate it.

Keith Stewart, MB, ChB: You’ve kind of pursued that approach in your Medical Research Council trials, Gareth, where you failed to have a good response and you’ve switched therapy.

Gareth Morgan, MD, PhD: I think that’s the first trial in myeloma, at least, that’s been an adaptive design from the beginning.

Keith Stewart, MB, ChB: Tell us what you did in that study.

Gareth Morgan, MD, PhD: Patients were exposed to an IMiD, initially, if they didn’t respond well.

Keith Stewart, MB, ChB: It ended up being lenalidomide or thalidomide?

Gareth Morgan, MD, PhD: Or thalidomide. If they didn’t respond well to that, they were allowed to swap, and we randomized to exposure to a proteasome inhibitor combination or nothing. And the people who had stopped responding, who responded to the proteasome inhibitor combination, had better responses—better progression-free survival and better overall survival.

Sagar Lonial, MD: But you don’t know that you can extrapolate that to somebody who’s getting an IMiD and PI [proteasome inhibitor] up front together?

Gareth Morgan, MD, PhD: I interpret it as being a biological message about resistance, but the optimum induction would be a proteasome inhibitor, an IMiD, probably an alkylating agent, and dexamethasone.

Transcript Edited for Clarity
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