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Goals of Therapy for Relapsed Myeloma

Insights From:Jatin P. Shah, MD, MD Anderson Cancer Center;Ivan Marques Borrello, MD, Johns Hopkins University;James R. Berenson, MD, Institute for Myeloma and Bone Cancer Research
Published Online: Saturday, Sep 17, 2016



Transcript:

James R. Berenson, MD:
What is the treatment approach to patients with a rapid versus a more smoldering or slower relapse? Well, in those patients with a rapid relapse in which they may be going down the tubes very quickly, you want to get a rapid response. So, you may want to be using more drugs. And, as I say, you don’t want to blow it. Because, if you do, you may not get the opportunity to try again. Those patients may require three and four, even five, drugs combined together. And those can be quite effective and durable. Whereas patients with slower relapses, in which the protein’s just slowly rising, you can even watch many of these folks. If you intervene, you want to intervene with less-toxic drugs, such as the antibodies, which are very well tolerated.

Jatin P. Shah, MD: We measure response to therapy traditionally based on overall response rate. And so, that’s using our M protein, or our paraprotein, both in the serum or the urine, as a first key indicator for response to therapy in terms of disease control. And that also includes free light-chain and free light-chain ratio, as well. Those are important assessments of initial response to therapy. However, importantly, we also talk about progression-free survival, as well. And those are classic key endpoints that we look at to understand the activity of a combination or activity of a certain drug.

However, I think that there are a couple of things that are changing that we need to start embracing—and number-one is using minimal residual disease (MRD). Importantly, we talk about MRD because we’re able to achieve MRD now in patients, which we were never able to achieve before. So, now that we’re able to achieve MRD with combinations like carfilzomib/lenalidomide/dexamethasone, that’s an important endpoint that we need to embrace. However, at the end of the day, it becomes challenging to look at MRD because this is not a uniform response that we have. It’s done differently at every major academic center, and it’s not uniformly available. But, importantly, if we step back and say, “Why are we measuring MRD?”, it’s ultimately to understand the depth of response. Because it’s important as we move towards a cure, but also, it’s a surrogate for long-term disease control, as well. And so, I think that’s the key point here: that patients who become MRD-negative have good long-term disease control.

The other response to therapy that we also now need to start thinking about, in addition to overall response rates and progression-free survival, which we classically think about—and now we’re starting to think about MRD—is long-term disease control. And so, for example, let’s look at 3-year PFS, or 4-year PFS, and look at that as long-term disease control, as another marker of therapy, as well. We’re starting to see that, for example, in non-Hodgkin’s Lymphoma, as well as for our patients with follicular lymphoma, we can identify an 18-month PFS, translating out to overall survival benefit. So, I think that’s important, that we need to start thinking about that in myeloma, as well; to go beyond our response rates, go beyond our median PFS, and now think about MRD. But also think about, now, long-term disease control, and identify what’s your 5-year PFS, for example. And I think that becomes critically important to really understand the benefit of each therapy.

Ivan Marques Borrello, MD: Pseudoprogression is an interesting phenomenon that’s been observed in solid tumors. So much so that the RECIST criteria, which are currently used to determine overall response rates in solid tumors, have been modified to what are now known as immune RECIST criteria. And this is really attributable to the observation that an early immune response is associated with a huge influx of inflammatory responses in the tumor. This, as one can imagine, translates into an increase in the overall diameter of the tumor mass itself, followed by a subsequent reduction.

And that has been the definition of a pseudoprogression that is often seen in many solid tumors. I think in a disease like myeloma, where obviously there’s no mass that we can measure, but we’re measuring a protein in the serum, this whole concept may be a little bit more difficult to understand. However, the advice that I would give to clinicians using many of these immunotherapeutic approaches is to not necessarily discount what appears like relapse and therefore discontinue or change therapy early on if the patient is otherwise relatively asymptomatic. Because that can be followed by a very nice and potentially even deeper response to therapy as that immunotherapeutic intervention is continued.

Obviously, as an M-spike goes up with the first cycle of treatment and continues to go up, that’s a very different scenario than somebody’s M-spike that goes up and then comes down, the first case being progression and the second case being pseudoprogression. But, this can only be effectively determined post facto. And so, persistence in the absence of symptoms is a very important point to take home.

James R. Berenson, MD: What is the potential for using minimal residual disease as an endpoint in myeloma? Well, it’s really unknown at this point. The problem is that there are so many different ways to measure it, there’s no consistent assay. So, one lab may show one thing using one technique, another lab may show something else. There’s no uniformity, so it makes it very hard to compare data across different laboratories or, again, through different studies.

And also, what do you do with the data that you find? Nobody has ever showed that you can act differently for the patient who has minimal residual disease versus the one that doesn’t. For example, say I’m going to stop therapy, you have nothing left. And whether that works for the patient with MRD versus the one that doesn’t get that far, we don’t know; we have no data. You’d have to do a real study to show that continuing treatment in one group versus another group matters. So, at this point you can go, “Wow, we can’t measure it.” But there are a lot of problems with the assay. There are laboratories that find no MRD, but there’s still gross protein, which means the assay didn’t work very well.

I’m not real enamored right now with MRD assays. We did a lot of early work on that when we were looking at purging of bone marrows and determining whether we got rid of myeloma. It’s very complicated, and it really hasn’t been well worked out.

Transcript Edited for Clarity
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Transcript:

James R. Berenson, MD:
What is the treatment approach to patients with a rapid versus a more smoldering or slower relapse? Well, in those patients with a rapid relapse in which they may be going down the tubes very quickly, you want to get a rapid response. So, you may want to be using more drugs. And, as I say, you don’t want to blow it. Because, if you do, you may not get the opportunity to try again. Those patients may require three and four, even five, drugs combined together. And those can be quite effective and durable. Whereas patients with slower relapses, in which the protein’s just slowly rising, you can even watch many of these folks. If you intervene, you want to intervene with less-toxic drugs, such as the antibodies, which are very well tolerated.

Jatin P. Shah, MD: We measure response to therapy traditionally based on overall response rate. And so, that’s using our M protein, or our paraprotein, both in the serum or the urine, as a first key indicator for response to therapy in terms of disease control. And that also includes free light-chain and free light-chain ratio, as well. Those are important assessments of initial response to therapy. However, importantly, we also talk about progression-free survival, as well. And those are classic key endpoints that we look at to understand the activity of a combination or activity of a certain drug.

However, I think that there are a couple of things that are changing that we need to start embracing—and number-one is using minimal residual disease (MRD). Importantly, we talk about MRD because we’re able to achieve MRD now in patients, which we were never able to achieve before. So, now that we’re able to achieve MRD with combinations like carfilzomib/lenalidomide/dexamethasone, that’s an important endpoint that we need to embrace. However, at the end of the day, it becomes challenging to look at MRD because this is not a uniform response that we have. It’s done differently at every major academic center, and it’s not uniformly available. But, importantly, if we step back and say, “Why are we measuring MRD?”, it’s ultimately to understand the depth of response. Because it’s important as we move towards a cure, but also, it’s a surrogate for long-term disease control, as well. And so, I think that’s the key point here: that patients who become MRD-negative have good long-term disease control.

The other response to therapy that we also now need to start thinking about, in addition to overall response rates and progression-free survival, which we classically think about—and now we’re starting to think about MRD—is long-term disease control. And so, for example, let’s look at 3-year PFS, or 4-year PFS, and look at that as long-term disease control, as another marker of therapy, as well. We’re starting to see that, for example, in non-Hodgkin’s Lymphoma, as well as for our patients with follicular lymphoma, we can identify an 18-month PFS, translating out to overall survival benefit. So, I think that’s important, that we need to start thinking about that in myeloma, as well; to go beyond our response rates, go beyond our median PFS, and now think about MRD. But also think about, now, long-term disease control, and identify what’s your 5-year PFS, for example. And I think that becomes critically important to really understand the benefit of each therapy.

Ivan Marques Borrello, MD: Pseudoprogression is an interesting phenomenon that’s been observed in solid tumors. So much so that the RECIST criteria, which are currently used to determine overall response rates in solid tumors, have been modified to what are now known as immune RECIST criteria. And this is really attributable to the observation that an early immune response is associated with a huge influx of inflammatory responses in the tumor. This, as one can imagine, translates into an increase in the overall diameter of the tumor mass itself, followed by a subsequent reduction.

And that has been the definition of a pseudoprogression that is often seen in many solid tumors. I think in a disease like myeloma, where obviously there’s no mass that we can measure, but we’re measuring a protein in the serum, this whole concept may be a little bit more difficult to understand. However, the advice that I would give to clinicians using many of these immunotherapeutic approaches is to not necessarily discount what appears like relapse and therefore discontinue or change therapy early on if the patient is otherwise relatively asymptomatic. Because that can be followed by a very nice and potentially even deeper response to therapy as that immunotherapeutic intervention is continued.

Obviously, as an M-spike goes up with the first cycle of treatment and continues to go up, that’s a very different scenario than somebody’s M-spike that goes up and then comes down, the first case being progression and the second case being pseudoprogression. But, this can only be effectively determined post facto. And so, persistence in the absence of symptoms is a very important point to take home.

James R. Berenson, MD: What is the potential for using minimal residual disease as an endpoint in myeloma? Well, it’s really unknown at this point. The problem is that there are so many different ways to measure it, there’s no consistent assay. So, one lab may show one thing using one technique, another lab may show something else. There’s no uniformity, so it makes it very hard to compare data across different laboratories or, again, through different studies.

And also, what do you do with the data that you find? Nobody has ever showed that you can act differently for the patient who has minimal residual disease versus the one that doesn’t. For example, say I’m going to stop therapy, you have nothing left. And whether that works for the patient with MRD versus the one that doesn’t get that far, we don’t know; we have no data. You’d have to do a real study to show that continuing treatment in one group versus another group matters. So, at this point you can go, “Wow, we can’t measure it.” But there are a lot of problems with the assay. There are laboratories that find no MRD, but there’s still gross protein, which means the assay didn’t work very well.

I’m not real enamored right now with MRD assays. We did a lot of early work on that when we were looking at purging of bone marrows and determining whether we got rid of myeloma. It’s very complicated, and it really hasn’t been well worked out.

Transcript Edited for Clarity
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