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The Role of MRD Testing in Myeloma

Panelists: A. Keith Stewart, MB, ChB, Mayo Clinic; Cristina Gasparetto, MD, Duke University Medical Center; Parameswaran Hari, MD, MRCP, MS, Medical College of Wisconsin; Robert Orlowski, MD, PhD, MD Anderson Cancer Center; Noopur Suresh Raje, MD, Massachusetts General Hospital
Published: Friday, Mar 02, 2018



Transcript: 

A. Keith Stewart, MB, ChB: Well, thank you for that debate about relapsed myeloma. Let’s move on now and talk about some emerging concepts in myeloma. I think one that’s particularly fascinating is the role of minimal residual disease testing, and I’d like to just start by having one of you perhaps describe for the audience the different technologies that are available and how they might be used. So, Bob, set the stage for us.

Robert Orlowski, MD, PhD: The most common technique now is the so-called next-generation flow where right now on a bone marrow, you look at the aspirate. And for example, at MD Anderson, we look at 2 million cells by what’s called flow immunophenotyping. So, that’s like doing a fingerprint on each individual cell. The advantage from a sensitivity perspective is that number 1, you’re looking at 2 million events as opposed to maybe 100 or 200,000 for the standard flow, and number 2, you can tell the difference between a normal plasma cell versus a myeloma plasma cell. So, the sensitivity is much greater and it’s more widely available.

A. Keith Stewart, MB, ChB: It’s also faster to get. You get the result the same day, essentially.

Robert Orlowski, MD, PhD: Correct. There is next-generation sequencing, which looks at…

A. Keith Stewart, MB, ChB: Just before you go onto that, let me ask the panelists here. Are you using flow cytometry in your center?

Robert Orlowski, MD, PhD: Yes.

A. Keith Stewart, MB, ChB: And is it the 8-color flow cytometry that the Europeans use?

Robert Orlowski, MD, PhD: It is, yes.

A. Keith Stewart, MB, ChB: What about at Duke?

Cristina Gasparetto, MD: We do, but we’re not standardized with the operating system, but we do 2 million…

A. Keith Stewart, MB, ChB: So, you’re doing basically some version of, it’s called EuroFlow because they developed it, the Europeans. Hari?

Parameswaran Hari, MD, MRCP, MS: So, we do the flow, too, at our center but I would say our sensitivity is only 10-5 unlike the NGF, which is 10-6.

Noopur Suresh Raje, MD: Next generation but not routinely, not for routine everyday patients.

A. Keith Stewart, MB, ChB: Flow cytometry, right?

Noopur Suresh Raje, MD: No, next-generation sequencing.

A. Keith Stewart, MB, ChB: I’m only talking about flow cytometry just now. Are you doing that at your center?

Noopur Suresh Raje, MD: We’re not doing flow.

A. Keith Stewart, MB, ChB: At Mayo Clinic, we have been offering flow, but, like Hari, I think the sensitivity has been lower than we were hoping. We just moved to the next generation. We’ll see where that runs. Sorry to interrupt, Bob. Let’s go back to the second technology, which is next-generation sequencing.

Robert Orlowski, MD, PhD: That’s the other one that is now commonly used, at least on clinical trials, and the notion is that each myeloma patient has a different gene rearrangement that leads to the creation of the immunoglobulin gene in that plasma cell. And if you have a baseline sample that you can study, you can determine exactly what is that abnormality and then follow it through with subsequent samples. So, the major downside is that the flow, you can do at any time. You don’t need a baseline sample. Whereas with the sequencing, you certainly would be very much helped by having that.

A. Keith Stewart, MB, ChB: You need it, actually.

Robert Orlowski, MD, PhD: Exactly.

A. Keith Stewart, MB, ChB: So, we have 2 competing technologies. Which one are you using preferentially, Christina? Both of them or one of them?

Cristina Gasparetto, MD: Well, as part of a clinical trial, centralized, we use the next-generation sequencing in our institution. And it’s still unclear how you position the MRD outside of a clinical trial and what you do with the information. But we do have the flow.

Parameswaran Hari, MD, MRCP, MS: Flow routinely, sequencing only as part of clinical trial.

Noopur Suresh Raje, MD: Sequencing. I only do MRD for trials right now. I do it routinely.

A. Keith Stewart, MB, ChB: We’ve been using mostly sequencing. So, it sounds like even in this group, there’s a lot of heterogeneity in how we’re doing MRD testing. That’s problem number 1. Let’s talk about problem number 2, which is how to use it. But before we do that, Hari, talk to the audience a little bit about what evidence we have that obtaining MRD negativity is helpful.

Parameswaran Hari, MD, MRCP, MS: There is a lot of things we know about MRD and there are some things we don’t know about MRD. The first thing we know is that getting to an MRD-negative state by whatever cutoff we use is better than not getting to that state. So, if you have a 10-6 MRD, it means that we looked at the million cells-plus, and there was no myeloma detectable in that person. And that is a good endpoint. That is an endpoint that people should aspire to, but it’s not a cure. We also know that not everybody who gets there will stay cured at 4 years or 5 years.

A. Keith Stewart, MB, ChB: So, even at 10-6 negativity, people are still relapsing.

Parameswaran Hari, MD, MRCP, MS: People still relapse, but your tendency to relapse is less. The other point to make is that people who don’t get to an MRD-negative state will relapse faster and will have a shorter overall survival if followed through time. However, there is a small percentage, probably somewhere in the 15% to 20% of patients, who don’t get to MRD negativity, in fact, and who don’t even get to a complete remission who actually don’t relapse at 4 years. So, there is a small population there for whom it seems like getting to an MRD-negative state is not imperative to survival.

A. Keith Stewart, MB, ChB: What about high versus low risk? Does it make a difference? High- versus low-risk genetic patients.

Noopur Suresh Raje, MD: Right. So, there are data to show that if you’re high risk, you should try and achieve MRD negativity.

A. Keith Stewart, MB, ChB: It’s harder to get to though.

Noopur Suresh Raje, MD: It’s harder to get to and that’s where you might want to do risk-adapted therapy. We’re not quite there with the decision making, which is why I don’t use it in routine practice. But there are also data now to show that there is a subset of myeloma patients who will become MRD-negative very quickly, but they’re the ones who become MRD-positive as well, and that can be a very high-risk patient population. So, there’s a lot more to learn about MRD. I think it’s an important tool that we have that has prognostic significance, as Hari has pointed out, and the next few trials are going to help us decide how we use this in practice.

Parameswaran Hari, MD, MRCP, MS: So, one of the most fascinating trials, Keith, in this year’s ASH is that data from the Myeloma 11 trial in the UK, where they looked at MRD at beginning, lenalidomide maintenance, and then following through time.

A. Keith Stewart, MB, ChB: To be clear, this was flow cytometry with relatively low sensitivity, but go ahead.

Parameswaran Hari, MD, MRCP, MS: But they did have about 20% to 30% of patients who actually upgraded their MRD response while on maintenance, and 4% who were just observed who upgraded, and then 10% who were MRD-negative going in who lost somewhere during the course of maintenance. And it turned out that if you were MRD-negative going in and sustained your MRD response, as would be expected, those people tend to do the best. But if you lost it, just as Noopur pointed out, they tended to track with the people who were MRD-positive at baseline.

Transcript Edited for Clarity 

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Transcript: 

A. Keith Stewart, MB, ChB: Well, thank you for that debate about relapsed myeloma. Let’s move on now and talk about some emerging concepts in myeloma. I think one that’s particularly fascinating is the role of minimal residual disease testing, and I’d like to just start by having one of you perhaps describe for the audience the different technologies that are available and how they might be used. So, Bob, set the stage for us.

Robert Orlowski, MD, PhD: The most common technique now is the so-called next-generation flow where right now on a bone marrow, you look at the aspirate. And for example, at MD Anderson, we look at 2 million cells by what’s called flow immunophenotyping. So, that’s like doing a fingerprint on each individual cell. The advantage from a sensitivity perspective is that number 1, you’re looking at 2 million events as opposed to maybe 100 or 200,000 for the standard flow, and number 2, you can tell the difference between a normal plasma cell versus a myeloma plasma cell. So, the sensitivity is much greater and it’s more widely available.

A. Keith Stewart, MB, ChB: It’s also faster to get. You get the result the same day, essentially.

Robert Orlowski, MD, PhD: Correct. There is next-generation sequencing, which looks at…

A. Keith Stewart, MB, ChB: Just before you go onto that, let me ask the panelists here. Are you using flow cytometry in your center?

Robert Orlowski, MD, PhD: Yes.

A. Keith Stewart, MB, ChB: And is it the 8-color flow cytometry that the Europeans use?

Robert Orlowski, MD, PhD: It is, yes.

A. Keith Stewart, MB, ChB: What about at Duke?

Cristina Gasparetto, MD: We do, but we’re not standardized with the operating system, but we do 2 million…

A. Keith Stewart, MB, ChB: So, you’re doing basically some version of, it’s called EuroFlow because they developed it, the Europeans. Hari?

Parameswaran Hari, MD, MRCP, MS: So, we do the flow, too, at our center but I would say our sensitivity is only 10-5 unlike the NGF, which is 10-6.

Noopur Suresh Raje, MD: Next generation but not routinely, not for routine everyday patients.

A. Keith Stewart, MB, ChB: Flow cytometry, right?

Noopur Suresh Raje, MD: No, next-generation sequencing.

A. Keith Stewart, MB, ChB: I’m only talking about flow cytometry just now. Are you doing that at your center?

Noopur Suresh Raje, MD: We’re not doing flow.

A. Keith Stewart, MB, ChB: At Mayo Clinic, we have been offering flow, but, like Hari, I think the sensitivity has been lower than we were hoping. We just moved to the next generation. We’ll see where that runs. Sorry to interrupt, Bob. Let’s go back to the second technology, which is next-generation sequencing.

Robert Orlowski, MD, PhD: That’s the other one that is now commonly used, at least on clinical trials, and the notion is that each myeloma patient has a different gene rearrangement that leads to the creation of the immunoglobulin gene in that plasma cell. And if you have a baseline sample that you can study, you can determine exactly what is that abnormality and then follow it through with subsequent samples. So, the major downside is that the flow, you can do at any time. You don’t need a baseline sample. Whereas with the sequencing, you certainly would be very much helped by having that.

A. Keith Stewart, MB, ChB: You need it, actually.

Robert Orlowski, MD, PhD: Exactly.

A. Keith Stewart, MB, ChB: So, we have 2 competing technologies. Which one are you using preferentially, Christina? Both of them or one of them?

Cristina Gasparetto, MD: Well, as part of a clinical trial, centralized, we use the next-generation sequencing in our institution. And it’s still unclear how you position the MRD outside of a clinical trial and what you do with the information. But we do have the flow.

Parameswaran Hari, MD, MRCP, MS: Flow routinely, sequencing only as part of clinical trial.

Noopur Suresh Raje, MD: Sequencing. I only do MRD for trials right now. I do it routinely.

A. Keith Stewart, MB, ChB: We’ve been using mostly sequencing. So, it sounds like even in this group, there’s a lot of heterogeneity in how we’re doing MRD testing. That’s problem number 1. Let’s talk about problem number 2, which is how to use it. But before we do that, Hari, talk to the audience a little bit about what evidence we have that obtaining MRD negativity is helpful.

Parameswaran Hari, MD, MRCP, MS: There is a lot of things we know about MRD and there are some things we don’t know about MRD. The first thing we know is that getting to an MRD-negative state by whatever cutoff we use is better than not getting to that state. So, if you have a 10-6 MRD, it means that we looked at the million cells-plus, and there was no myeloma detectable in that person. And that is a good endpoint. That is an endpoint that people should aspire to, but it’s not a cure. We also know that not everybody who gets there will stay cured at 4 years or 5 years.

A. Keith Stewart, MB, ChB: So, even at 10-6 negativity, people are still relapsing.

Parameswaran Hari, MD, MRCP, MS: People still relapse, but your tendency to relapse is less. The other point to make is that people who don’t get to an MRD-negative state will relapse faster and will have a shorter overall survival if followed through time. However, there is a small percentage, probably somewhere in the 15% to 20% of patients, who don’t get to MRD negativity, in fact, and who don’t even get to a complete remission who actually don’t relapse at 4 years. So, there is a small population there for whom it seems like getting to an MRD-negative state is not imperative to survival.

A. Keith Stewart, MB, ChB: What about high versus low risk? Does it make a difference? High- versus low-risk genetic patients.

Noopur Suresh Raje, MD: Right. So, there are data to show that if you’re high risk, you should try and achieve MRD negativity.

A. Keith Stewart, MB, ChB: It’s harder to get to though.

Noopur Suresh Raje, MD: It’s harder to get to and that’s where you might want to do risk-adapted therapy. We’re not quite there with the decision making, which is why I don’t use it in routine practice. But there are also data now to show that there is a subset of myeloma patients who will become MRD-negative very quickly, but they’re the ones who become MRD-positive as well, and that can be a very high-risk patient population. So, there’s a lot more to learn about MRD. I think it’s an important tool that we have that has prognostic significance, as Hari has pointed out, and the next few trials are going to help us decide how we use this in practice.

Parameswaran Hari, MD, MRCP, MS: So, one of the most fascinating trials, Keith, in this year’s ASH is that data from the Myeloma 11 trial in the UK, where they looked at MRD at beginning, lenalidomide maintenance, and then following through time.

A. Keith Stewart, MB, ChB: To be clear, this was flow cytometry with relatively low sensitivity, but go ahead.

Parameswaran Hari, MD, MRCP, MS: But they did have about 20% to 30% of patients who actually upgraded their MRD response while on maintenance, and 4% who were just observed who upgraded, and then 10% who were MRD-negative going in who lost somewhere during the course of maintenance. And it turned out that if you were MRD-negative going in and sustained your MRD response, as would be expected, those people tend to do the best. But if you lost it, just as Noopur pointed out, they tended to track with the people who were MRD-positive at baseline.

Transcript Edited for Clarity 
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