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Role of MRD Assessment in Multiple Myeloma

Insights From: Kenneth C. Anderson, MD, Dana-Farber Cancer Institute and Harvard Medical School; Rafael Fonseca, MD, Mayo Clinic; Noopur S. Raje, MD, Massachusetts General Hospital Cancer Center
Published: Tuesday, Feb 26, 2019



Transcript:

Rafael Fonseca, MD:
Testing for MRD [minimal residual disease] has now come to the forefront and has been increasingly used in a number of settings—at this point, primarily in academic centers or in centers that practice a stem cell transplantation. We have a number of referral centers where some of our community colleagues would refer their patients. We are doing this as the standard of care. So for my patients where we complete autologous stem cell transplantation, at what’s called a day-100 visit we’re doing testing for MRD status.

Now we do that both through flow cytometry as well as next-generation sequencing to try to determine to a level of 10-6 whether there’s any evidence of residual cells. MRD is defining in my mind the 2 parameters that are most important for the long-term outcome of myeloma patients.

Number 1 is, if you may, on a vertical access, that would be in the y axis, the depth of the response. So we’re trying to get patients into that MRD-negative status. And I think as we go, over time, and we think about strategies for maintenance, we’re going to start using more MRD testing to determine who needs to continue on therapy versus not. And now we use it for a patient who has a durable complete remission, that maybe has been on maintenance for 2 years or 3 years, where that complete remission remained. We actually do MRD testing at that point, not as the sole deciding factor, but bringing it in as a piece of information that we would use in the conversation with patients at that point whether we should continue with maintenance therapy. There are many reasons why you would continue. You could make an argument for that based on some of the clinical trials. But also, there are reasons why a person would want to discontinue therapy. And like every other test that we do, any laboratory test that we do, we have the information for use at the bedside or in our clinical encounters to decide whether we will continue the therapy.

So for us, we’re using it as routine. I personally believe that a threshold of 10-6, however that is determined, is really where we should go, not 10-5. There are approaches that are being explored for novel technologists, including some proteomic assays. But I think really it’s here to stay.

Some recent clinical trial data show that MRD’s really the goal, and it should be all that we aspire to. Now, there are exceptions to this and I won’t go into all of that. There are some patients who I think keep a small molecular protein and do very well. But at the time you start therapy I think the aspiration should be for patients to get to MRD status. In fact, I would refer the listeners to a video where I did a 1-hour interview where some of those details of how we can use MRD testing in the clinic were discussed.

Noopur S. Raje, MD: MRD testing is obviously a new diagnostic and monitoring tool that I think is extremely relevant, specifically in how we are using drugs right now. Given that we’re already talking about 3- and 4-drug combinations, and given that we have seen complete responses of anywhere between 40% and 50%, and if you’re then trying to compare these different quadruplets or triplets, I think using a tool such as MRD testing or looking for molecular remissions is the way forward. So that is the future.

Now how does one define MRD testing? As of right now, what we in the scientific community will accept is MRD testing to the tune of 10-6. That’s how sensitive your test should be—so 1 in a million cells. Whether you use a genotypic-based MRD testing strategy or use a flow-based strategy, it doesn’t really matter. It should be dependent on what’s available at that specific site.

I think the bottom line is the sensitivity, and I’m saying sensitivity of 10-6 right now. Who knows; a year down the line we might say we want it to be even more sensitive. We just don’t have the tools yet. And whether you use a flow-based assay or you use a genotypic-based assay really depends on what is available to you at your site.

Kenneth C. Anderson, MD: The bone marrow microenvironment is extremely important in multiple myeloma. We and others have been studying that for many decades, honestly. And in the microenvironment in patients with myeloma, the fact that myeloma cells bind to the microenvironment extracellular matrix proteins, or accessory cells in the bone marrow, in and of itself confers drug resistance. We also have in the bone marrow, cytokines, TGF [transforming growth factor]-beta, interleukin 10, many others—VEGF—that can confer immunosuppression. And finally, we have cells that are constitutively present like T-regulatory cells, or myeloid-derived suppressor cells, or plasmacytoid dendritic cells. These are cells in the marrow of patients with myeloma that not only help to promote tumor growth, but they are immunosuppressive.

As in solid tumors, the really important concept is that when myeloma cells actually move into the bone marrow microenvironment where they grow in patients, they actually induce T-regulatory cells. They induce myeloid-derived suppressor cells and other mechanisms of immunosuppression. So getting rid of myeloma is really important in achieving MRD negativity, but so is trying to correct this abnormal bone marrow microenvironment, which promotes growth and drug resistance of the cancer but also promotes immunosuppression.

Transcript edited for clarity.
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Transcript:

Rafael Fonseca, MD:
Testing for MRD [minimal residual disease] has now come to the forefront and has been increasingly used in a number of settings—at this point, primarily in academic centers or in centers that practice a stem cell transplantation. We have a number of referral centers where some of our community colleagues would refer their patients. We are doing this as the standard of care. So for my patients where we complete autologous stem cell transplantation, at what’s called a day-100 visit we’re doing testing for MRD status.

Now we do that both through flow cytometry as well as next-generation sequencing to try to determine to a level of 10-6 whether there’s any evidence of residual cells. MRD is defining in my mind the 2 parameters that are most important for the long-term outcome of myeloma patients.

Number 1 is, if you may, on a vertical access, that would be in the y axis, the depth of the response. So we’re trying to get patients into that MRD-negative status. And I think as we go, over time, and we think about strategies for maintenance, we’re going to start using more MRD testing to determine who needs to continue on therapy versus not. And now we use it for a patient who has a durable complete remission, that maybe has been on maintenance for 2 years or 3 years, where that complete remission remained. We actually do MRD testing at that point, not as the sole deciding factor, but bringing it in as a piece of information that we would use in the conversation with patients at that point whether we should continue with maintenance therapy. There are many reasons why you would continue. You could make an argument for that based on some of the clinical trials. But also, there are reasons why a person would want to discontinue therapy. And like every other test that we do, any laboratory test that we do, we have the information for use at the bedside or in our clinical encounters to decide whether we will continue the therapy.

So for us, we’re using it as routine. I personally believe that a threshold of 10-6, however that is determined, is really where we should go, not 10-5. There are approaches that are being explored for novel technologists, including some proteomic assays. But I think really it’s here to stay.

Some recent clinical trial data show that MRD’s really the goal, and it should be all that we aspire to. Now, there are exceptions to this and I won’t go into all of that. There are some patients who I think keep a small molecular protein and do very well. But at the time you start therapy I think the aspiration should be for patients to get to MRD status. In fact, I would refer the listeners to a video where I did a 1-hour interview where some of those details of how we can use MRD testing in the clinic were discussed.

Noopur S. Raje, MD: MRD testing is obviously a new diagnostic and monitoring tool that I think is extremely relevant, specifically in how we are using drugs right now. Given that we’re already talking about 3- and 4-drug combinations, and given that we have seen complete responses of anywhere between 40% and 50%, and if you’re then trying to compare these different quadruplets or triplets, I think using a tool such as MRD testing or looking for molecular remissions is the way forward. So that is the future.

Now how does one define MRD testing? As of right now, what we in the scientific community will accept is MRD testing to the tune of 10-6. That’s how sensitive your test should be—so 1 in a million cells. Whether you use a genotypic-based MRD testing strategy or use a flow-based strategy, it doesn’t really matter. It should be dependent on what’s available at that specific site.

I think the bottom line is the sensitivity, and I’m saying sensitivity of 10-6 right now. Who knows; a year down the line we might say we want it to be even more sensitive. We just don’t have the tools yet. And whether you use a flow-based assay or you use a genotypic-based assay really depends on what is available to you at your site.

Kenneth C. Anderson, MD: The bone marrow microenvironment is extremely important in multiple myeloma. We and others have been studying that for many decades, honestly. And in the microenvironment in patients with myeloma, the fact that myeloma cells bind to the microenvironment extracellular matrix proteins, or accessory cells in the bone marrow, in and of itself confers drug resistance. We also have in the bone marrow, cytokines, TGF [transforming growth factor]-beta, interleukin 10, many others—VEGF—that can confer immunosuppression. And finally, we have cells that are constitutively present like T-regulatory cells, or myeloid-derived suppressor cells, or plasmacytoid dendritic cells. These are cells in the marrow of patients with myeloma that not only help to promote tumor growth, but they are immunosuppressive.

As in solid tumors, the really important concept is that when myeloma cells actually move into the bone marrow microenvironment where they grow in patients, they actually induce T-regulatory cells. They induce myeloid-derived suppressor cells and other mechanisms of immunosuppression. So getting rid of myeloma is really important in achieving MRD negativity, but so is trying to correct this abnormal bone marrow microenvironment, which promotes growth and drug resistance of the cancer but also promotes immunosuppression.

Transcript edited for clarity.
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