MRD literature indicates a wide variance in the sample size and MRD negative definition. Believe the most stringent testing in the U.S. uses a sample size of approximately 4,000,000 cells with MRD negative being defined as less than 0.002% myeloma cells (20 cells in 1,000,000).
Question #1: Which medical facilities currently use the most stringent testing (largest sample size with lowest MRD negative cutoff)?
Question #2: What is the best average sensitivity that can be routinely achieved, i.e. can tests show one myeloma cell in a 4,000,000 cell sample?
Question #3: Why have a MRD negative definition higher than what is reliably achievable, i.e does an MRD negative cutoff of 0.01% provide any benefit over a 0.002% cutoff or whatever the lowest reliably obtainable value?
Question #4: What does it really mean to be MRD negative, if the test shows you have myeloma cells at a lower level than the cutoff?
My current assumptions are (1) patients should demand/seek the most stringent testing, (2) MRD negative doesn't mean a whole lot and (3) as long as the test show any myeloma cells continued maintenance needs to be carefully considered.
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Re: Minimal residual disease (MRD) testing - some questions
Hi baegerter,
Sounds like you have been reading about using flow cytometry for checking for MRD. I believe ASO-PCR is still considered the most sensitive technique for checking for MRD in myeloma. This is a recent paper written by the doctors from Spain that are considered the leaders in using Flow. Note that I have read that the standardized 8 color flow being discussed can cost in the area of $100 while the molecular testing I had last year cost over $11,000, which makes the flow test much more attractive. It took a while to get my insurance to approve the molecular testing.
"Regarding the different methods which are currently available for MRD detection, flow-based MRD, compared to molecular methods, shows a clear higher applicability (e.g. it can currently be applied to >95% vs 70-75% of all myeloma patients) and specificity, with a sensitivity of between 10-4 and 10-5 (slightly lower than that of PCR-based molecular methods (10-4 to 10-6); in addition, it is a fast and easy to perform test which is widely available in most clinical diagnostic laboratories where myeloma patients are treated and it provides information not only about the myeloma plasma cell compartment but also about the other cellular compartments in the sample."
http://www.sah.org.ar/revista/numeros/vol17.n.extra.118.119.pdf
The weakness of both tests is that they are just a sample from one spot on your body. Myeloma is a "patchy" disease, so these tests can miss localized disease. While the studies are small, in my opinion it is hard to argue with the importance of being MRD negative via molecular testing in the allo setting. Obviously, few myeloma patients do allos as part of their upfront therapy when it can cure patients, but it was very important for my "mental QOL" to be MRD negative after my allo.
"Of these 48 patients, 16 (33%) attained durable PCR-negativity after transplantation, whereas 13 (27%) remained persistently PCR-positive and 19 (40%) showed a mixed pattern. The cumulative risk of relapse at 5 years was 0% for PCR-negative patients, 33% for PCR-mixed patients, and 100% for PCR-positive patients. Within the group studied it was not possible to identify any clinical feature predictive of durable PCR-negativity. We believe that these findings could prompt the design of prospective studies to evaluate if the treatment of molecular disease can extend remission duration and survival."
http://bloodjournal.hematologylibrary.org/content/102/5/1927.long
"The study underlines the importance of the depth of remission and shows that achieving molecular remission as determined by myeloma-specific IgH gene rearrangements and plasma cell chimerism is associated with long-term freedom from disease and potential cure of multiple myeloma in an auto-/allo SCT approach."
https://ash.confex.com/ash/2011/webprogram/Paper42900.html
Here is a molecular study in the non-allo setting. Achieving MRD negativity is certainly not indicative of a cure, but it does push relapse back compared to those who did not achieve it. Check the graphs at the bottom. Without the immunotherapy of the donor immune system, the remissions are not as durable, but it still seems like a positive thing to achieve it in the non-allo setting. It could depend on the patients goal of therapy.
https://ash.confex.com/ash/2013/webprogram/Paper59332.html
The specific (great) questions you ask can only be answered via trials. That is what the Black Swan initiative is for - to find answers to the questions you are asking by using a standardized MRD test (slightly less sensitive 8 color flow test).
Molecular responses/MRD negative was checked in European studies because that level of remission was possible in the allo setting since the 1990's, so there is long term follow up. MRD negativity was rarely seen in the non-allo setting prior to novel agents being available as part of upfront therapy.
As much as we all wish we had the answers now while we are making our therapy decisions, we are going to have to wait for the results of the trials to answer them.
Mark
Sounds like you have been reading about using flow cytometry for checking for MRD. I believe ASO-PCR is still considered the most sensitive technique for checking for MRD in myeloma. This is a recent paper written by the doctors from Spain that are considered the leaders in using Flow. Note that I have read that the standardized 8 color flow being discussed can cost in the area of $100 while the molecular testing I had last year cost over $11,000, which makes the flow test much more attractive. It took a while to get my insurance to approve the molecular testing.
"Regarding the different methods which are currently available for MRD detection, flow-based MRD, compared to molecular methods, shows a clear higher applicability (e.g. it can currently be applied to >95% vs 70-75% of all myeloma patients) and specificity, with a sensitivity of between 10-4 and 10-5 (slightly lower than that of PCR-based molecular methods (10-4 to 10-6); in addition, it is a fast and easy to perform test which is widely available in most clinical diagnostic laboratories where myeloma patients are treated and it provides information not only about the myeloma plasma cell compartment but also about the other cellular compartments in the sample."
http://www.sah.org.ar/revista/numeros/vol17.n.extra.118.119.pdf
The weakness of both tests is that they are just a sample from one spot on your body. Myeloma is a "patchy" disease, so these tests can miss localized disease. While the studies are small, in my opinion it is hard to argue with the importance of being MRD negative via molecular testing in the allo setting. Obviously, few myeloma patients do allos as part of their upfront therapy when it can cure patients, but it was very important for my "mental QOL" to be MRD negative after my allo.
"Of these 48 patients, 16 (33%) attained durable PCR-negativity after transplantation, whereas 13 (27%) remained persistently PCR-positive and 19 (40%) showed a mixed pattern. The cumulative risk of relapse at 5 years was 0% for PCR-negative patients, 33% for PCR-mixed patients, and 100% for PCR-positive patients. Within the group studied it was not possible to identify any clinical feature predictive of durable PCR-negativity. We believe that these findings could prompt the design of prospective studies to evaluate if the treatment of molecular disease can extend remission duration and survival."
http://bloodjournal.hematologylibrary.org/content/102/5/1927.long
"The study underlines the importance of the depth of remission and shows that achieving molecular remission as determined by myeloma-specific IgH gene rearrangements and plasma cell chimerism is associated with long-term freedom from disease and potential cure of multiple myeloma in an auto-/allo SCT approach."
https://ash.confex.com/ash/2011/webprogram/Paper42900.html
Here is a molecular study in the non-allo setting. Achieving MRD negativity is certainly not indicative of a cure, but it does push relapse back compared to those who did not achieve it. Check the graphs at the bottom. Without the immunotherapy of the donor immune system, the remissions are not as durable, but it still seems like a positive thing to achieve it in the non-allo setting. It could depend on the patients goal of therapy.
https://ash.confex.com/ash/2013/webprogram/Paper59332.html
The specific (great) questions you ask can only be answered via trials. That is what the Black Swan initiative is for - to find answers to the questions you are asking by using a standardized MRD test (slightly less sensitive 8 color flow test).
Molecular responses/MRD negative was checked in European studies because that level of remission was possible in the allo setting since the 1990's, so there is long term follow up. MRD negativity was rarely seen in the non-allo setting prior to novel agents being available as part of upfront therapy.
As much as we all wish we had the answers now while we are making our therapy decisions, we are going to have to wait for the results of the trials to answer them.
Mark
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Mark
Re: Minimal residual disease (MRD) testing - some questions
Hi baegerter,
I just saw this recent small study looking at patients that were MRD negative using ASO-PCR after auto. Increased PFS (progression free survival) but no increase in OS (overall survival).
"The aim was to evaluate prospectively the impact of MRD, assessed with qASO-PCR, on progression free (PFS) and overall survival (OS) in patients with multiple myeloma who had attained CR/nCR (paraprotein not visible in electrophoresis but immunofixation positive) within six months after upfront ASCT performed in the time period from Oct. 1997 to Sept. 2010. From a total of 43 patients who were randomly selected for molecular analysis, 25 had reached low/negative MRD status, and 18 had high MRD. The groups were otherwise well balanced but in the MRDhigh group the proportion of nCR patients was higher, 8 out of 18, while the respective figure in the MRDlow/neg group was two out of 25. MRD was measured with a patient specific qASO-PCR, the method of which has been described earlier1. Allele-specific primers could successfully be designed for 90 % of patients. The median sensitivity of the PCR assay for those by whom the PCR target was not detectable was < 0.002 %. Kaplan-Mayer curves for PFS and OS for the MRDlow/negative and MRD high groups were produced."
"The median PFS for the MRDlow/neg and MRDhigh groups were 38 and 26 months (p=0.013), respectively. However, no significant difference was seen in OS (53 vs 52 months)."
"Negative or low MRD is associated with a prolonged PFS but seems not to lead to a statistically significant benefit in OS when compared to high MRD in patients with a good response (CR or nCR) after upfront ASCT for multiple myeloma. The most apparent cause for non-benefit in OS is probably the use of novel drugs, viz. bortezomib and lenalidomide, and late transplantations in the salvage protocols; they level off the early PFS benefit from upfront ASCT. Prospective studies are needed to work out how to maintain low or negative MRD status and translate this into a prolonged survival in multiple myeloma."
https://b-com.mci-group.com/Abstract/Statistics/AbstractStatisticsViewPage.aspx?AbstractID=188561
Mark
I just saw this recent small study looking at patients that were MRD negative using ASO-PCR after auto. Increased PFS (progression free survival) but no increase in OS (overall survival).
"The aim was to evaluate prospectively the impact of MRD, assessed with qASO-PCR, on progression free (PFS) and overall survival (OS) in patients with multiple myeloma who had attained CR/nCR (paraprotein not visible in electrophoresis but immunofixation positive) within six months after upfront ASCT performed in the time period from Oct. 1997 to Sept. 2010. From a total of 43 patients who were randomly selected for molecular analysis, 25 had reached low/negative MRD status, and 18 had high MRD. The groups were otherwise well balanced but in the MRDhigh group the proportion of nCR patients was higher, 8 out of 18, while the respective figure in the MRDlow/neg group was two out of 25. MRD was measured with a patient specific qASO-PCR, the method of which has been described earlier1. Allele-specific primers could successfully be designed for 90 % of patients. The median sensitivity of the PCR assay for those by whom the PCR target was not detectable was < 0.002 %. Kaplan-Mayer curves for PFS and OS for the MRDlow/negative and MRD high groups were produced."
"The median PFS for the MRDlow/neg and MRDhigh groups were 38 and 26 months (p=0.013), respectively. However, no significant difference was seen in OS (53 vs 52 months)."
"Negative or low MRD is associated with a prolonged PFS but seems not to lead to a statistically significant benefit in OS when compared to high MRD in patients with a good response (CR or nCR) after upfront ASCT for multiple myeloma. The most apparent cause for non-benefit in OS is probably the use of novel drugs, viz. bortezomib and lenalidomide, and late transplantations in the salvage protocols; they level off the early PFS benefit from upfront ASCT. Prospective studies are needed to work out how to maintain low or negative MRD status and translate this into a prolonged survival in multiple myeloma."
https://b-com.mci-group.com/Abstract/Statistics/AbstractStatisticsViewPage.aspx?AbstractID=188561
Mark
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Mark
Re: Minimal residual disease (MRD) testing - some questions
It's not standardized, yet. My doctor won't do it because of the false positives/false negatives. Until all centers do it exactly the same, I won't bother with it.
BTW, my doctor is at Mt. Sinai in NYC, and is well known in the myeloma world. He's declared me in sCR. No transplant. Just Velcade, 15mg Revlimid and low-dose prednisone. Been at this level for 6 months. Just on maintenance, now
BTW, my doctor is at Mt. Sinai in NYC, and is well known in the myeloma world. He's declared me in sCR. No transplant. Just Velcade, 15mg Revlimid and low-dose prednisone. Been at this level for 6 months. Just on maintenance, now
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Stan W. - Name: Stan
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: SMM-April 2012
- Age at diagnosis: 58
Re: Minimal residual disease (MRD) testing - some questions
What is your maintenance regimen, Stan?
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goldmine848 - Name: Andrew
- When were you/they diagnosed?: June 2013
- Age at diagnosis: 60
Re: Minimal residual disease (MRD) testing - some questions
<<"MRD literature indicates a wide variance in the sample size and MRD negative definition. Believe the most stringent testing in the U.S. uses a sample size of approximately 4,000,000 cells with MRD negative being defined as less than 0.002% myeloma cells (20 cells in 1,000,000). >>"
I too would like to know which centers currently use the most stringent testing. I would imagine those that do not will eventually modify and conform to the more reliable testing parameters so the value of MRD testing as proposed by the IMF's BSRI can be established and in turn, support the reasons behind its use.
I believe the value of MRD status as a treatment decision endpoint is what needs to be established. Trying to standardized testing may lead to the right clinical trials to prove its usefulness. I still see it in its research phase with no clear answers how the data should or should not be interpreted, a work in progress.
I believe if your multiple myeloma center or specialist were already using the most stringent testing in the U.S. regardless if it is or is not yet standardized, the information would be of value, but a value yet to be determined.
Best to all,
Dana H.
I too would like to know which centers currently use the most stringent testing. I would imagine those that do not will eventually modify and conform to the more reliable testing parameters so the value of MRD testing as proposed by the IMF's BSRI can be established and in turn, support the reasons behind its use.
I believe the value of MRD status as a treatment decision endpoint is what needs to be established. Trying to standardized testing may lead to the right clinical trials to prove its usefulness. I still see it in its research phase with no clear answers how the data should or should not be interpreted, a work in progress.
I believe if your multiple myeloma center or specialist were already using the most stringent testing in the U.S. regardless if it is or is not yet standardized, the information would be of value, but a value yet to be determined.
Best to all,
Dana H.
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DanaH - Who do you know with myeloma?: Myself, SMM as of 1/2012
- When were you/they diagnosed?: 1/2012
- Age at diagnosis: 54
Re: Minimal residual disease (MRD) testing - some questions
goldmine848 asked: "What is your maintenance regime Stan?"
I've been on the same 15mg of Revlimid. Starting next month, it'll be 10mg. I got to CR after 4 cycles. The first two were Cytoxan and Velcade with prednisone. Every one after that was with Revlimid instead of Cytoxan.
I've been on the same 15mg of Revlimid. Starting next month, it'll be 10mg. I got to CR after 4 cycles. The first two were Cytoxan and Velcade with prednisone. Every one after that was with Revlimid instead of Cytoxan.
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Stan W. - Name: Stan
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: SMM-April 2012
- Age at diagnosis: 58
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