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Defining Progression and an Approach to Management

Insights From: Ajai Chari, MD, Icahn School of Medicine at Mount Sinai; Andrzej Jakubowiak, MD, PhD, University of Chicago; Sagar Lonial, MD, Winship Cancer Institute of Emory University
Published: Monday, Jan 07, 2019



Transcript: 

Ajai Chari, MD: In terms of the type of relapse that patients can have, they’re basically broken down into biochemical relapses and symptomatic relapses. Biochemical would be defined as somebody whose paraproteins are increasing versus the clinical relapse, where they’re actually getting hypercalcemia, renal failure, anemia, bone disease, hyperviscosity, something that’s causing problems to the patient. And the question is: What type of relapse gets treated with which drugs?

In contrast to a biochemical relapse, the symptomatic relapse really demands urgent therapy. We know that in the relapsed setting, combination therapy, study after study has shown triplets are better than doublets, and we want to use active drugs and change the backbone as well. So, for example, if somebody is again progressing on lenalidomide and they’re having a clinical relapse, we may want to consider changing that up, maybe adding a monoclonal antibody, adding a proteasome inhibitor, possibly switching the lenalidomide to pomalidomide. So those are some strategies to consider rather than just keeping the same drug going that you might use for a biochemical relapse.

When we think about the approach to a relapsed patient, the urgency in a biochemical relapse typically would be perceived as less. Therefore, we may want to use drugs perhaps that are not necessarily as toxic or aggressive but perhaps have been shown to be very well tolerated. So an example of this might be elotuzumab, where it has no single-agent activity, its approval is only with lenalidomide, and perhaps coming forward soon with pomalidomide, but in our program, we have found that the elotuzumab/Revlimid/dexamethasone regimen is very well tolerated. So in somebody who has progression on low-dose lenalidomide 10 mg—again, this is not supported by clinical trial data, and I think that’s a data gap where somebody who progresses on [lenalidomide] maintenance technically is not eligible for a lot of phase III studies that are currently there.

But [elotuzumab] might be an example of a drug that you would not use in a very aggressive relapse because, again, it has no single-agent activity, but it might be something you could do in a biochemical relapse. Certainly you could also add, up-titrate the drug like lenalidomide to full dose and add steroids, although, again, we don’t know how long those remissions last. And the last point I would make is that we really need to distinguish when to pull the trigger. So when somebody goes from immunofixation negative to positive, that’s not an immediate crisis. And in fact, in the future what we’re going to have to worry about is when somebody becomes MRD [minimal residual disease] negative previously becomes MRD positive, does that require an immediate change in therapy?

So as we get more and more sensitive with our detection limits, we may be picking up these relapses earlier and earlier. And deciding when to initiate therapy is difficult. But as a general rule, I would say that you want to make sure that you at least have some measurable disease, with an M spike of 0.5, a light chain of 100 mg per liter, or a Bence Jones protein of more than 200. And that way you’ll feel confident that if you do make a treatment change, it’s not just the disease ebbing and flowing, but the treatment is actually having an impact.

Sagar Lonial, MD: Progression is defined by the International Myeloma Working Group as not only an increase in the M protein or the free light chain but as also associated with symptoms. So recurrence of those CRAB [hypercalcemia, renal failure, anemia, bone lesions] criteria that we used in the diagnosis to say somebody is symptomatic versus smoldering. Now, practically speaking, many clinicians, many patients, and many clinical trials have not held to those same CRAB criteria for the development of progression.

I will tell you, in my own personal practice, we tend to watch a patient who presents with biochemical relapse and see what the progression of that protein is. And the reason that’s important is that if you can hold off therapy for 6 months or 12 months—in 1 case, I had a patient for whom we waited 8 years before we started therapy—then that’s more time for us to get additional agents and to learn the results of larger studies to understand how to optimally treat that patient.

If a patient, however, has rapid progress—so escalation of the protein quickly—or has high-risk disease where I know they’re more likely to progress quickly, I may not wait for symptomatic progression in those patients.

The third thing that we do differently now than we did a few years ago is to look at imaging. So it’s not uncommon for patients to have a very low-level protein. But when you do a PET/CT [positron emission tomography/computed tomography scan] to see bone lesions that light up—in those patients, I’ll initiate therapy as well. So if I’m going to watch somebody, I will typically do more advanced bone imaging to make sure that that watchful waiting is a reasonable thing to do.

When it comes to other factors that may influence the decisions on biochemical versus symptomatic treatment, comorbidities don’t typically factor in a lot for me. In fact, they would tend to push me toward watchful waiting as opposed to early intervention. Age is not necessarily a factor unless I’m concerned about offering a transplant in somebody who delayed transplant. And if they’re in their mid-to late 70s, you may want to err on the side of doing it sooner rather than later so that you don’t lose performance status. But in most cases, it’s really slope of the rise of the protein and…the genetic risk of the myeloma that guide that treatment decision.

How a patient tolerates their initial therapy doesn’t necessarily influence whether I treat it as symptomatic or biochemical relapse. And I think the main reason for that is—in fact, if anything, it would cause you to want to delay and keep them on watchful waiting. Most patients, I find, want to hold off on treatment as long as they can. There are some anxious patients who want to do something immediately, but I think in the grand scheme of things, if you can go a period of time and not have to change therapy, that’s longer that you can perhaps get benefit out of that second drug.

Ajai Chari, MD: When we talk about risk for a patient, historically we again look at the initial risk stratification by, for example, the ISS [International Staging System] stage.

But there’s another way of looking at risk, which is really the response to therapy. And there patients can fragment into 2 categories—those who…never respond to initial therapy, so-called primary refractory, versus those who had a response and then relapsed. And those do differ. Historically, primary refractory is uncommon, and with the efficacy of novel agents, it’s even becoming less common. And it usually portends terrible disease. I think these patients should be enrolled in clinical trials if at all possible because if you’re progressing on a triplet regimen like bortezomib/lenalidomide/dexamethasone, that’s very concerning because the response rate should be upward of 90% or 95%. And if somebody is progressing on that, that usually portends badness, and that patient might be served with, for example, 96-hour chemotherapy regimens like VDT PACE [bortezomib/dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide] to try to debulk the disease, consolidate with transplant, do aggressive maintenance, and then really, again, consider clinical trials given the ominous warnings of primary refractory disease.

In general, when we think about the different options that we have for relapsed and refractory disease, I would bucket them into 3 categories. Again, we have host factors. So, for example, cardiac function, renal function, blood counts. Those are all important features. Patient preference, of course, we need to consider. We have so many choices in terms of oral versus parenteral drugs. Age of the patient, frailty. So those are host factors. And then we have disease factors like the burden, the biology, the rate of progression, symptomatic relapse versus biochemical. And lastly, we have prior therapy, which is an important consideration in relapsed settings that isn’t so prevalent, obviously, in newly diagnosed patients.

But within that prior therapy, we want to know how a patient [tolerated] previous therapy. Did they have toxicities? How efficacious was it? How long did it take to relapse? And when we integrate all those 3 buckets, there is not going to be 1 right answer. And I think that’s part of the complexity of managing myeloma, and it really is the art of managing patients with myeloma. And it really, again, emphasizes the importance of collaboration with academic centers to really identify for a given patient what might be the best regimen for salvage.

Transcript Edited for Clarity 
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Transcript: 

Ajai Chari, MD: In terms of the type of relapse that patients can have, they’re basically broken down into biochemical relapses and symptomatic relapses. Biochemical would be defined as somebody whose paraproteins are increasing versus the clinical relapse, where they’re actually getting hypercalcemia, renal failure, anemia, bone disease, hyperviscosity, something that’s causing problems to the patient. And the question is: What type of relapse gets treated with which drugs?

In contrast to a biochemical relapse, the symptomatic relapse really demands urgent therapy. We know that in the relapsed setting, combination therapy, study after study has shown triplets are better than doublets, and we want to use active drugs and change the backbone as well. So, for example, if somebody is again progressing on lenalidomide and they’re having a clinical relapse, we may want to consider changing that up, maybe adding a monoclonal antibody, adding a proteasome inhibitor, possibly switching the lenalidomide to pomalidomide. So those are some strategies to consider rather than just keeping the same drug going that you might use for a biochemical relapse.

When we think about the approach to a relapsed patient, the urgency in a biochemical relapse typically would be perceived as less. Therefore, we may want to use drugs perhaps that are not necessarily as toxic or aggressive but perhaps have been shown to be very well tolerated. So an example of this might be elotuzumab, where it has no single-agent activity, its approval is only with lenalidomide, and perhaps coming forward soon with pomalidomide, but in our program, we have found that the elotuzumab/Revlimid/dexamethasone regimen is very well tolerated. So in somebody who has progression on low-dose lenalidomide 10 mg—again, this is not supported by clinical trial data, and I think that’s a data gap where somebody who progresses on [lenalidomide] maintenance technically is not eligible for a lot of phase III studies that are currently there.

But [elotuzumab] might be an example of a drug that you would not use in a very aggressive relapse because, again, it has no single-agent activity, but it might be something you could do in a biochemical relapse. Certainly you could also add, up-titrate the drug like lenalidomide to full dose and add steroids, although, again, we don’t know how long those remissions last. And the last point I would make is that we really need to distinguish when to pull the trigger. So when somebody goes from immunofixation negative to positive, that’s not an immediate crisis. And in fact, in the future what we’re going to have to worry about is when somebody becomes MRD [minimal residual disease] negative previously becomes MRD positive, does that require an immediate change in therapy?

So as we get more and more sensitive with our detection limits, we may be picking up these relapses earlier and earlier. And deciding when to initiate therapy is difficult. But as a general rule, I would say that you want to make sure that you at least have some measurable disease, with an M spike of 0.5, a light chain of 100 mg per liter, or a Bence Jones protein of more than 200. And that way you’ll feel confident that if you do make a treatment change, it’s not just the disease ebbing and flowing, but the treatment is actually having an impact.

Sagar Lonial, MD: Progression is defined by the International Myeloma Working Group as not only an increase in the M protein or the free light chain but as also associated with symptoms. So recurrence of those CRAB [hypercalcemia, renal failure, anemia, bone lesions] criteria that we used in the diagnosis to say somebody is symptomatic versus smoldering. Now, practically speaking, many clinicians, many patients, and many clinical trials have not held to those same CRAB criteria for the development of progression.

I will tell you, in my own personal practice, we tend to watch a patient who presents with biochemical relapse and see what the progression of that protein is. And the reason that’s important is that if you can hold off therapy for 6 months or 12 months—in 1 case, I had a patient for whom we waited 8 years before we started therapy—then that’s more time for us to get additional agents and to learn the results of larger studies to understand how to optimally treat that patient.

If a patient, however, has rapid progress—so escalation of the protein quickly—or has high-risk disease where I know they’re more likely to progress quickly, I may not wait for symptomatic progression in those patients.

The third thing that we do differently now than we did a few years ago is to look at imaging. So it’s not uncommon for patients to have a very low-level protein. But when you do a PET/CT [positron emission tomography/computed tomography scan] to see bone lesions that light up—in those patients, I’ll initiate therapy as well. So if I’m going to watch somebody, I will typically do more advanced bone imaging to make sure that that watchful waiting is a reasonable thing to do.

When it comes to other factors that may influence the decisions on biochemical versus symptomatic treatment, comorbidities don’t typically factor in a lot for me. In fact, they would tend to push me toward watchful waiting as opposed to early intervention. Age is not necessarily a factor unless I’m concerned about offering a transplant in somebody who delayed transplant. And if they’re in their mid-to late 70s, you may want to err on the side of doing it sooner rather than later so that you don’t lose performance status. But in most cases, it’s really slope of the rise of the protein and…the genetic risk of the myeloma that guide that treatment decision.

How a patient tolerates their initial therapy doesn’t necessarily influence whether I treat it as symptomatic or biochemical relapse. And I think the main reason for that is—in fact, if anything, it would cause you to want to delay and keep them on watchful waiting. Most patients, I find, want to hold off on treatment as long as they can. There are some anxious patients who want to do something immediately, but I think in the grand scheme of things, if you can go a period of time and not have to change therapy, that’s longer that you can perhaps get benefit out of that second drug.

Ajai Chari, MD: When we talk about risk for a patient, historically we again look at the initial risk stratification by, for example, the ISS [International Staging System] stage.

But there’s another way of looking at risk, which is really the response to therapy. And there patients can fragment into 2 categories—those who…never respond to initial therapy, so-called primary refractory, versus those who had a response and then relapsed. And those do differ. Historically, primary refractory is uncommon, and with the efficacy of novel agents, it’s even becoming less common. And it usually portends terrible disease. I think these patients should be enrolled in clinical trials if at all possible because if you’re progressing on a triplet regimen like bortezomib/lenalidomide/dexamethasone, that’s very concerning because the response rate should be upward of 90% or 95%. And if somebody is progressing on that, that usually portends badness, and that patient might be served with, for example, 96-hour chemotherapy regimens like VDT PACE [bortezomib/dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide] to try to debulk the disease, consolidate with transplant, do aggressive maintenance, and then really, again, consider clinical trials given the ominous warnings of primary refractory disease.

In general, when we think about the different options that we have for relapsed and refractory disease, I would bucket them into 3 categories. Again, we have host factors. So, for example, cardiac function, renal function, blood counts. Those are all important features. Patient preference, of course, we need to consider. We have so many choices in terms of oral versus parenteral drugs. Age of the patient, frailty. So those are host factors. And then we have disease factors like the burden, the biology, the rate of progression, symptomatic relapse versus biochemical. And lastly, we have prior therapy, which is an important consideration in relapsed settings that isn’t so prevalent, obviously, in newly diagnosed patients.

But within that prior therapy, we want to know how a patient [tolerated] previous therapy. Did they have toxicities? How efficacious was it? How long did it take to relapse? And when we integrate all those 3 buckets, there is not going to be 1 right answer. And I think that’s part of the complexity of managing myeloma, and it really is the art of managing patients with myeloma. And it really, again, emphasizes the importance of collaboration with academic centers to really identify for a given patient what might be the best regimen for salvage.

Transcript Edited for Clarity 
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