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Defining High-Risk Multiple Myeloma

Panelists:Ajai Chari, MD, Mount Sinai Hospital; Sagar Lonial, MD, Emory University School of Medicine; Paul G. Richardson, MD, Harvard Medical School; Jatin J. Shah, MD, MD Anderson Cancer Center; Keith Stewart, MD, CHB, Mayo Clinic
Published: Monday, Jan 18, 2016


Transcript:

Keith Stewart, MB, CHB:
We know that there are patients who do very poorly and patients who do well. And do you want to speak a little bit to, maybe Paul first of all, to what defines a high-risk myeloma patient in your mind?

Paul G. Richardson, MD: Well, it's a great question. To Sagar's point, I think genetics helps us to some degree, but I think we all recognize as busy clinicians that there are patients who take us greatly by surprise in terms of how poorly their disease behaves. And I think one of the most important aspects of how a high-risk patient can be defined is on the one hand clinically, on the other hand genetically.

Obviously, the two are related, but sometimes it's not as clear-cut. And then the other thing becomes how they respond to treatment. And I think, in that regard, being very vigilant about the degree of response, rapidity of response, and aware of these aspects is key. In terms of clinical practice, I look for signs such as extramedullary disease, tumor burden, ISS stage, and, of course, genetics, particularly things like deletion 17p.

But having said all of that, I think our vast understanding…

Keith Stewart, MB, CHB: Deletion 17.

Paul G. Richardson, MD: Deletion 17, yeah, I apologize. And you're absolutely right. Deletion 13 was thought to be the sort of Damocles, and clearly isn't now. But I think that the complexity of the disease, as Sagar points out, is one of our biggest challenges in predicting who is going to do what and why.

Keith Stewart, MB, CHB: Your group has talked about some therapies that might be gnomically agnostic, which make people high-risk. Do you want to tell the audience what that's all about?

Sagar Lonial, MD: Well, I think when you use agents that require their function to be dependent on intracellular mechanisms, like proteasome inhibitors and IMIDs, and your group has done a huge amount of work to tell us the pathways for IMIDs, I think that then you're dependent on development of resistance to those same intracellular mechanisms.

And what we've talked about is the idea that immune-based therapies may be able to circumvent all that by working on the extracellular surface on an antigen that's outside recruiting immune cells. And that's been the biggest issue: the ability to recruit in immune-effector cells to ultimately kill the cell. You may be able to avoid a lot of those intracellular crossed-wiring that are so difficult for us.

Keith Stewart, MB, CHB: And this is what's going to make today's discussion so much fun, because we have some drugs now that we can actually target extracellulary as well as intracellulary.

Ajai Chari, MD: I just wanted to add, too, to Paul's comment about the genetics: that I think, particularly for community docs, it's important to look at those genetic reports that they're getting because all the myeloma studies that are done are really on plasma cell-specific tests.

So, either it's cIg FISH, where the immunoglobulin is first stained and then the FISH is done on those cells, or it’s CD138-selected FISH. And when folks get reports that are not plasma cell-specific, it's really hard to know what to do with that relative to the literature. And even if you have those specific tests, the amount of deletion 17p, for example, matters.

So, I think just knowing the presence of deletion 17p in and of itself really is not enough; you really to know a lot more. And I think it's important that we work in collaboration with community doctors to really clarify these kinds of issues.

Sagar Lonial, MD: Just to build on that a little bit: the revised international staging system takes just this into account by adding in FISH and LDH, and some other methods; it's now more than just beta-2 microglobulin and albumin levels.

Keith Stewart, MB, CHB: What are those? They're FISH, LDH, beta-2 microglobulin, and albumin all combined together?

Sagar Lonial, MD: Yeah. So, it's basically the ISS staging, the beta-2 and the microglobulin, and the albumin. And then you can up or downstage based on the presence or absence of high-risk features.

Keith Stewart, MB, CHB: How about the microenvironment in all of this, Dr. Shah? How does that impact us?

Jatin J. Shah, MD: Sure. One more thing I think it's important we talk about: some of these risk stratifications on prognostic criteria focused around the disease and the biology of the disease. I think that as practicing community oncologists, I think one thing we have to keep in mind are the patients themselves.

Since we see the kind of elderly patients, or the ones in comorbidities, some of these patients may not be able to tolerate our therapies. And so, ultimately, the definition of high-risk is somebody who passes away in the first 18 to 24 months. And that could be due to disease, but it could be due to just a patient's in a comorbidity, and I think that's important to keep in mind.

The second thing is sometimes we focus on saying this is a high-risk patient at the time of diagnosis, but then clinically and biologically you're saying that some patients surprise us—so they may not have these features—and then they get therapy and they progress within the first 18 months or 12 months, and they progress quickly after transplant. So clinically, that patient may not have deletion 17p or any of these features, but they behave that way, so we have to treat them that way.

So I think we have to be cognizant of those patients who aggressively relapse very quickly and need to be thought of as a high-risk patient. So, it's not just what you see at the baseline, it's what you see throughout.

Keith Stewart, MB, CHB: So, for our community oncologists watching, the message seems to be you should do FISH or genetic profiling and risk; you should measure the beta-2 microglobulin and albumin for risk through biochemistry assays. But you should also assess the patient as part of that complex, is that fair to say?

Paul G. Richardson, MD: Yes.

Keith Stewart, MB, CHB: What about frailty, Paul, is that an issue? Do you measure that formally or just eye-ball it?

Paul G. Richardson, MD: I think it's a complex assessment, actually, because frailty is again an area where prediction is not always so straightforward. And I think there's the younger frail patient and there's the older, more robust patient. And dissecting the two is not necessarily as black-and-white as one might imagine.

To Jatin's point, I think for the community doctors listening, it's very important to look at renal function, for example; the depth and breadth and extent of bone disease, and understand any presence of extramedullary disease that there may be. And that's where additional imaging like FCT may become relevant.

Keith Stewart, MB, CHB: Let me ask, Dr. Chari, do you do PET CT scan routinely at diagnosis

Ajai Chari, MD: I do it where it's going to make a difference in management or monitoring. So for somebody who might be smoldering and you're trying to figure out whether or not you're going to treat, absolutely. In somebody we think is being treated primarily for bone disease, it helps to monitor that patient after therapy because that's really why you're treating these patients; or somebody who is either molecular high risk or there is some concern for extramedullary disease.

So, I think in those kinds of settings, I would routinely do the PET. But if you have clear lytic lesions and there's none of those other concerns, do we really need the extra cost that's not going to change your management?

Keith Stewart, MB, CHB: I'm glad you mentioned smoldering myeloma because I want to move to that. But just to wrap up this story of complexity of disease and therapeutic choice: any last comments on that part from the panel?

Ajai Chari, MD: I think what Jatin was bringing up, “Is it really important?” When we look at and we talk about studies coming out, particularly for high-risk, it's important to not just look at the response rate, but the durability of response because even high-risk patients may have a very deep response. But who cares if that doesn't last?

Keith Stewart, MB, CHB: And actually, that's the normal thing. They’re actually quite chemotherapy-sensitive. They just have explosive relapse, which then becomes unmanageable. And those are the patients, really the patients we have to focus our energies on.

Ajai Chari, MD: Correct.

Paul G. Richardson, MD: And if I may, Keith, I think that the other takeaway I hope is that now we're in a position where we have really the highest level of evidence to support three, and even arguably four, drug approaches in the initial phase of treatment that can literally put this net around our patients in a way that some of these other confounding factors are less likely to emerge as a problem for our patients.
                                                                                                                                                                                                                                                                                                            
Transcript Edited for Clarity
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Transcript:

Keith Stewart, MB, CHB:
We know that there are patients who do very poorly and patients who do well. And do you want to speak a little bit to, maybe Paul first of all, to what defines a high-risk myeloma patient in your mind?

Paul G. Richardson, MD: Well, it's a great question. To Sagar's point, I think genetics helps us to some degree, but I think we all recognize as busy clinicians that there are patients who take us greatly by surprise in terms of how poorly their disease behaves. And I think one of the most important aspects of how a high-risk patient can be defined is on the one hand clinically, on the other hand genetically.

Obviously, the two are related, but sometimes it's not as clear-cut. And then the other thing becomes how they respond to treatment. And I think, in that regard, being very vigilant about the degree of response, rapidity of response, and aware of these aspects is key. In terms of clinical practice, I look for signs such as extramedullary disease, tumor burden, ISS stage, and, of course, genetics, particularly things like deletion 17p.

But having said all of that, I think our vast understanding…

Keith Stewart, MB, CHB: Deletion 17.

Paul G. Richardson, MD: Deletion 17, yeah, I apologize. And you're absolutely right. Deletion 13 was thought to be the sort of Damocles, and clearly isn't now. But I think that the complexity of the disease, as Sagar points out, is one of our biggest challenges in predicting who is going to do what and why.

Keith Stewart, MB, CHB: Your group has talked about some therapies that might be gnomically agnostic, which make people high-risk. Do you want to tell the audience what that's all about?

Sagar Lonial, MD: Well, I think when you use agents that require their function to be dependent on intracellular mechanisms, like proteasome inhibitors and IMIDs, and your group has done a huge amount of work to tell us the pathways for IMIDs, I think that then you're dependent on development of resistance to those same intracellular mechanisms.

And what we've talked about is the idea that immune-based therapies may be able to circumvent all that by working on the extracellular surface on an antigen that's outside recruiting immune cells. And that's been the biggest issue: the ability to recruit in immune-effector cells to ultimately kill the cell. You may be able to avoid a lot of those intracellular crossed-wiring that are so difficult for us.

Keith Stewart, MB, CHB: And this is what's going to make today's discussion so much fun, because we have some drugs now that we can actually target extracellulary as well as intracellulary.

Ajai Chari, MD: I just wanted to add, too, to Paul's comment about the genetics: that I think, particularly for community docs, it's important to look at those genetic reports that they're getting because all the myeloma studies that are done are really on plasma cell-specific tests.

So, either it's cIg FISH, where the immunoglobulin is first stained and then the FISH is done on those cells, or it’s CD138-selected FISH. And when folks get reports that are not plasma cell-specific, it's really hard to know what to do with that relative to the literature. And even if you have those specific tests, the amount of deletion 17p, for example, matters.

So, I think just knowing the presence of deletion 17p in and of itself really is not enough; you really to know a lot more. And I think it's important that we work in collaboration with community doctors to really clarify these kinds of issues.

Sagar Lonial, MD: Just to build on that a little bit: the revised international staging system takes just this into account by adding in FISH and LDH, and some other methods; it's now more than just beta-2 microglobulin and albumin levels.

Keith Stewart, MB, CHB: What are those? They're FISH, LDH, beta-2 microglobulin, and albumin all combined together?

Sagar Lonial, MD: Yeah. So, it's basically the ISS staging, the beta-2 and the microglobulin, and the albumin. And then you can up or downstage based on the presence or absence of high-risk features.

Keith Stewart, MB, CHB: How about the microenvironment in all of this, Dr. Shah? How does that impact us?

Jatin J. Shah, MD: Sure. One more thing I think it's important we talk about: some of these risk stratifications on prognostic criteria focused around the disease and the biology of the disease. I think that as practicing community oncologists, I think one thing we have to keep in mind are the patients themselves.

Since we see the kind of elderly patients, or the ones in comorbidities, some of these patients may not be able to tolerate our therapies. And so, ultimately, the definition of high-risk is somebody who passes away in the first 18 to 24 months. And that could be due to disease, but it could be due to just a patient's in a comorbidity, and I think that's important to keep in mind.

The second thing is sometimes we focus on saying this is a high-risk patient at the time of diagnosis, but then clinically and biologically you're saying that some patients surprise us—so they may not have these features—and then they get therapy and they progress within the first 18 months or 12 months, and they progress quickly after transplant. So clinically, that patient may not have deletion 17p or any of these features, but they behave that way, so we have to treat them that way.

So I think we have to be cognizant of those patients who aggressively relapse very quickly and need to be thought of as a high-risk patient. So, it's not just what you see at the baseline, it's what you see throughout.

Keith Stewart, MB, CHB: So, for our community oncologists watching, the message seems to be you should do FISH or genetic profiling and risk; you should measure the beta-2 microglobulin and albumin for risk through biochemistry assays. But you should also assess the patient as part of that complex, is that fair to say?

Paul G. Richardson, MD: Yes.

Keith Stewart, MB, CHB: What about frailty, Paul, is that an issue? Do you measure that formally or just eye-ball it?

Paul G. Richardson, MD: I think it's a complex assessment, actually, because frailty is again an area where prediction is not always so straightforward. And I think there's the younger frail patient and there's the older, more robust patient. And dissecting the two is not necessarily as black-and-white as one might imagine.

To Jatin's point, I think for the community doctors listening, it's very important to look at renal function, for example; the depth and breadth and extent of bone disease, and understand any presence of extramedullary disease that there may be. And that's where additional imaging like FCT may become relevant.

Keith Stewart, MB, CHB: Let me ask, Dr. Chari, do you do PET CT scan routinely at diagnosis

Ajai Chari, MD: I do it where it's going to make a difference in management or monitoring. So for somebody who might be smoldering and you're trying to figure out whether or not you're going to treat, absolutely. In somebody we think is being treated primarily for bone disease, it helps to monitor that patient after therapy because that's really why you're treating these patients; or somebody who is either molecular high risk or there is some concern for extramedullary disease.

So, I think in those kinds of settings, I would routinely do the PET. But if you have clear lytic lesions and there's none of those other concerns, do we really need the extra cost that's not going to change your management?

Keith Stewart, MB, CHB: I'm glad you mentioned smoldering myeloma because I want to move to that. But just to wrap up this story of complexity of disease and therapeutic choice: any last comments on that part from the panel?

Ajai Chari, MD: I think what Jatin was bringing up, “Is it really important?” When we look at and we talk about studies coming out, particularly for high-risk, it's important to not just look at the response rate, but the durability of response because even high-risk patients may have a very deep response. But who cares if that doesn't last?

Keith Stewart, MB, CHB: And actually, that's the normal thing. They’re actually quite chemotherapy-sensitive. They just have explosive relapse, which then becomes unmanageable. And those are the patients, really the patients we have to focus our energies on.

Ajai Chari, MD: Correct.

Paul G. Richardson, MD: And if I may, Keith, I think that the other takeaway I hope is that now we're in a position where we have really the highest level of evidence to support three, and even arguably four, drug approaches in the initial phase of treatment that can literally put this net around our patients in a way that some of these other confounding factors are less likely to emerge as a problem for our patients.
                                                                                                                                                                                                                                                                                                            
Transcript Edited for Clarity
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