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MRD Negativity in Multiple 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: Friday, Jun 23, 2017



Transcript:

Keith Stewart, MB, ChB:
What percentage of your patients obtain this magical MRD [minimal residual disease] negativity, Saad?

Saad Z. Usmani, MD: If you talk about with induction therapy, the number is probably going to be in the 10% or 15% range—not more than that. In the post-transplant setting, maybe you can pose that number up to the 35% or 30% range. But, again, which metrics are we using to measure MRD negativity?

Keith Stewart, MB, ChB: Tell us what you’re doing.

Saad Z. Usmani, MD: We are utilizing MRD flow cytometry and sequencing—both methodologies. It depends on what kind of study you’re doing, but both have met their endpoints. My one concern with MRD threshold is, even at the 10-6 power, what is the chance that the patient may be MRD-positive at 10-7 or 10-8? I’m still on the fence with that definition.

Keith Stewart, MB, ChB: Minimal residual disease. What are the pros and cons, Tom?

Thomas G. Martin, MD: The first and foremost thing, really, is what is our definition? Are we calling MRD negativity 10-4 or 10-5 or 10-6? Certainly, more patients achieve 10-4. I think the IMWG [International Myeloma Working Group] criterion is 10-5, but in fact, if you take the randomized Dr. Attal study—the randomized study with RVD [lenalidomide, bortezomib, and dexamethasone] delayed transplant versus RVD up-front transplant—the patients who achieved MRD negativity in that study were at 10-4. And those patients who achieved MRD negativity had a prolonged survival with a very low hazard ratio, 0.34. That was just published in the New England Journal of Medicine. In my mind, I think it’s a threshold effect, and I think we could use any one of those numbers—10-4, 10-5, 10-6—but we have to agree on which one we’re going to use in clinical trials.

Keith Stewart, MB, ChB: What’s the clinical trial evidence that this is a useful endpoint? Sagar, you mentioned 1 trial already, but how about in the transplant setting?

Sagar Lonial, MD: It’s really important, as we talk about MRD as an endpoint of therapy, that we realize that what we know from clinical trial data right now is that in people who achieve an MRD-negative complete remission by any metric, whether it’s 10-4, 10-5, or 10-6, their outcomes are better than if they don’t—progression-free survival and overall survival. But that’s a prognostic indicator, and I think we really need the trials that are ongoing now to know how to use those data to manipulate, change, or talk about duration of therapy.

Keith Stewart, MB, ChB: There are 2 technologies to do this—flow cytometry, which the Europeans have promoted, and then there’s next-generation sequencing, which I think some of us are using here in the United States. Ivan, are you doing MRD testing yet?

Ivan M. Borrello, MD: We are. We’ve been using next-generation sequencing.

Keith Stewart, MB, ChB: Tell us about that. Are you happy with that? Ivan M. Borrello, MD: Yes. Obviously there are pros and cons to both of them. I think one of the benefits of next-generation sequencing is that it doesn’t require a fresh sample. You could go back to the original sample to actually identify the clones and its uniform. There’s a lot of variability with flow cytometry that’s operator dependent, antibody panel dependent, and many other things.

Keith Stewart, MB, ChB: One thing we found useful with flow cytometry, which I don’t think we’re very good at in my institution but we’re getting better at, is you do get the result back in 24 hours.

Ivan M. Borrello, MD: That’s true. That’s a benefit. Absolutely. As I said, there are pros and cons. I think, though, in terms of trying to form a framework within which to ultimately use for therapeutic decisions, flow cytometry offers a little bit more complexity than next-generation sequencing would.

Sagar Lonial, MD: And flow cytometry may have a role in things like immune profiling, immune surveillance, all those kinds of things, but it doesn’t need to be to the depth and complication that I think flow cytometry for MRD does. I think sequencing is just so much easier.

Keith Stewart, MB, ChB: The very first person I saw present was your colleague Dr. Wolf. You guys have been pioneers in adopting this clinically. How is your experience going with it? When do you use it?

Thomas G. Martin, MD: We’ve probably been using it for 2 years now, and we use next-generation sequencing through Adaptive. We use it as a prognostic marker more than anything else. I don’t think any clinical decisions can be made at the current time.

Keith Stewart, MB, ChB: Would you escalate or de-escalate therapy based on the result?

Thomas G. Martin, MD: What it does, I think, is when you have somebody who is getting maintenance therapy and they’re MRD-negative, and they’re having toxicity to their maintenance therapy, and the patient understands that they are MRD-negative and can’t stop maintenance therapy, it becomes a little bit of a tricky slope. You’re also in this new realm that, “Oh, they are MRD-negative. Maybe I should stop their maintenance-based therapy.” So in fact, if patients are MRD-negative, we’re probably more likely to stop their maintenance therapy. Now, I will say that if we’re going to accept this globally, not just in clinical trials, I think flow cytometry, in fact, may be an easier test for the local guys to order and get back in 24 hours, rather than them getting results back a week later or 2 weeks later, etc.

Sagar Lonial, MD: But these are patients who are in complete response. Why does it matter if you get it back in a day or in 10 days?

Thomas G. Martin, MD: I guess it really doesn’t matter. I think they’re used to seeing flow cytometry reports where they’re not used to seeing these next-generation sequencing reports. So we’ll have to see. In addition, you don’t have to go back to the original bone marrow biopsy to get the clone for flow cytometry. You can do it at any point during their therapy. I have split feelings on whether it’s going to be next-generation sequencing or whether it’s going to be flow cytometry down the road.

Gareth Morgan, MD, PhD: Does it have to be one or the other? I think it’s a false argument. We have MRD flow cytometry, which is a variable sensitivity—10-4, 10-5—when you see the patient. If somebody is negative, you can consider sending it off for sequencing.

Keith Stewart, MB, ChB: Good point. That’s good advice, I think. What do we tell community doctors about this? Is it something they should be doing? It’s premature? What’s the space? What’s the story here?

Saad Z. Usmani, MD: I think that it’s too premature for clinical application outside clinical trials right now, but there’s a wealth of data, now, showing that MRD negativity does correlate with better survival outcomes. So I think that’s the message. It’s not ready for prime time, but it’s coming.

Transcript Edited for Clarity

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Transcript:

Keith Stewart, MB, ChB:
What percentage of your patients obtain this magical MRD [minimal residual disease] negativity, Saad?

Saad Z. Usmani, MD: If you talk about with induction therapy, the number is probably going to be in the 10% or 15% range—not more than that. In the post-transplant setting, maybe you can pose that number up to the 35% or 30% range. But, again, which metrics are we using to measure MRD negativity?

Keith Stewart, MB, ChB: Tell us what you’re doing.

Saad Z. Usmani, MD: We are utilizing MRD flow cytometry and sequencing—both methodologies. It depends on what kind of study you’re doing, but both have met their endpoints. My one concern with MRD threshold is, even at the 10-6 power, what is the chance that the patient may be MRD-positive at 10-7 or 10-8? I’m still on the fence with that definition.

Keith Stewart, MB, ChB: Minimal residual disease. What are the pros and cons, Tom?

Thomas G. Martin, MD: The first and foremost thing, really, is what is our definition? Are we calling MRD negativity 10-4 or 10-5 or 10-6? Certainly, more patients achieve 10-4. I think the IMWG [International Myeloma Working Group] criterion is 10-5, but in fact, if you take the randomized Dr. Attal study—the randomized study with RVD [lenalidomide, bortezomib, and dexamethasone] delayed transplant versus RVD up-front transplant—the patients who achieved MRD negativity in that study were at 10-4. And those patients who achieved MRD negativity had a prolonged survival with a very low hazard ratio, 0.34. That was just published in the New England Journal of Medicine. In my mind, I think it’s a threshold effect, and I think we could use any one of those numbers—10-4, 10-5, 10-6—but we have to agree on which one we’re going to use in clinical trials.

Keith Stewart, MB, ChB: What’s the clinical trial evidence that this is a useful endpoint? Sagar, you mentioned 1 trial already, but how about in the transplant setting?

Sagar Lonial, MD: It’s really important, as we talk about MRD as an endpoint of therapy, that we realize that what we know from clinical trial data right now is that in people who achieve an MRD-negative complete remission by any metric, whether it’s 10-4, 10-5, or 10-6, their outcomes are better than if they don’t—progression-free survival and overall survival. But that’s a prognostic indicator, and I think we really need the trials that are ongoing now to know how to use those data to manipulate, change, or talk about duration of therapy.

Keith Stewart, MB, ChB: There are 2 technologies to do this—flow cytometry, which the Europeans have promoted, and then there’s next-generation sequencing, which I think some of us are using here in the United States. Ivan, are you doing MRD testing yet?

Ivan M. Borrello, MD: We are. We’ve been using next-generation sequencing.

Keith Stewart, MB, ChB: Tell us about that. Are you happy with that? Ivan M. Borrello, MD: Yes. Obviously there are pros and cons to both of them. I think one of the benefits of next-generation sequencing is that it doesn’t require a fresh sample. You could go back to the original sample to actually identify the clones and its uniform. There’s a lot of variability with flow cytometry that’s operator dependent, antibody panel dependent, and many other things.

Keith Stewart, MB, ChB: One thing we found useful with flow cytometry, which I don’t think we’re very good at in my institution but we’re getting better at, is you do get the result back in 24 hours.

Ivan M. Borrello, MD: That’s true. That’s a benefit. Absolutely. As I said, there are pros and cons. I think, though, in terms of trying to form a framework within which to ultimately use for therapeutic decisions, flow cytometry offers a little bit more complexity than next-generation sequencing would.

Sagar Lonial, MD: And flow cytometry may have a role in things like immune profiling, immune surveillance, all those kinds of things, but it doesn’t need to be to the depth and complication that I think flow cytometry for MRD does. I think sequencing is just so much easier.

Keith Stewart, MB, ChB: The very first person I saw present was your colleague Dr. Wolf. You guys have been pioneers in adopting this clinically. How is your experience going with it? When do you use it?

Thomas G. Martin, MD: We’ve probably been using it for 2 years now, and we use next-generation sequencing through Adaptive. We use it as a prognostic marker more than anything else. I don’t think any clinical decisions can be made at the current time.

Keith Stewart, MB, ChB: Would you escalate or de-escalate therapy based on the result?

Thomas G. Martin, MD: What it does, I think, is when you have somebody who is getting maintenance therapy and they’re MRD-negative, and they’re having toxicity to their maintenance therapy, and the patient understands that they are MRD-negative and can’t stop maintenance therapy, it becomes a little bit of a tricky slope. You’re also in this new realm that, “Oh, they are MRD-negative. Maybe I should stop their maintenance-based therapy.” So in fact, if patients are MRD-negative, we’re probably more likely to stop their maintenance therapy. Now, I will say that if we’re going to accept this globally, not just in clinical trials, I think flow cytometry, in fact, may be an easier test for the local guys to order and get back in 24 hours, rather than them getting results back a week later or 2 weeks later, etc.

Sagar Lonial, MD: But these are patients who are in complete response. Why does it matter if you get it back in a day or in 10 days?

Thomas G. Martin, MD: I guess it really doesn’t matter. I think they’re used to seeing flow cytometry reports where they’re not used to seeing these next-generation sequencing reports. So we’ll have to see. In addition, you don’t have to go back to the original bone marrow biopsy to get the clone for flow cytometry. You can do it at any point during their therapy. I have split feelings on whether it’s going to be next-generation sequencing or whether it’s going to be flow cytometry down the road.

Gareth Morgan, MD, PhD: Does it have to be one or the other? I think it’s a false argument. We have MRD flow cytometry, which is a variable sensitivity—10-4, 10-5—when you see the patient. If somebody is negative, you can consider sending it off for sequencing.

Keith Stewart, MB, ChB: Good point. That’s good advice, I think. What do we tell community doctors about this? Is it something they should be doing? It’s premature? What’s the space? What’s the story here?

Saad Z. Usmani, MD: I think that it’s too premature for clinical application outside clinical trials right now, but there’s a wealth of data, now, showing that MRD negativity does correlate with better survival outcomes. So I think that’s the message. It’s not ready for prime time, but it’s coming.

Transcript Edited for Clarity
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