Interesting single-center Italian study. The point of the study is to show the value of this particular flow cytometry test for minimal residual disease (MRD), There are no overall survival stats given, but the progression-free survival (PFS) stats are impressive for the group that is MRD negative by this test. The 5 year PFS is 70% for the MRD-negative group vs 5% for the MRD positive group. This is not a study to compare treatments and they do not mention maintenance, but I do not think maintenance was used since they describe the percentage of patients MRD negative at different time intervals during treatment and there is no mention of maintenance. Seems like this is a worthwhile flow test.
Excerpts from article:
"In this study we evaluated the minimal residual disease (MRD) in 50 consecutive multiple myeloma patients who underwent an up-front tandem ASCT in our center, using a single-tube six-colors flow cytometry assay (FC) based on intra-cytoplasmic immunoglobulin (cy-Ig) light chains ratio evaluated on patient-specific plasma cells (PC) immune profile, in a real-life setting."
"A significant decrease of clonal-PC was observed between induction and first transplant (63 % vs 5 %; P < 0.0001), but not between first and second ASCT (5 % vs 1 %; P = 0.412). Treatment response by standard and FC criteria, according to check point of the therapeutic program, is shown in Fig. 2. Compared to conventional CR, a lower rate of immunophenotypic CR (flow MRD-negative) was documented in all check-points of the therapeutic program (28 % vs 16 % after induction, 54 % vs 32 % after fist and 66 % vs 48 % after second ASCT). The 5ys-PFS of flow MRD-negative patients after second transplant was significantly better compared to MRD-positive (5ys-PFS 70 % vs 5 %, respectively; P < 0.0001, Fig. 3a). According to flow MRD assessment, patients in conventional CR showed a significant difference in 5ys-PFS after second transplant (5ys-PFS 67 % vs 0 % for MRD-positive and MRD-negative patients, respectively; P < 0.0001, Fig. 3b). After induction, we found a significant higher rate of conventional CR and flow MRD-negative cases in patients who received a novel agents-based treatment compared with those treated with VAD regimen (10/27, 37 % vs 4/23, 17.4 %; P = 0.042 and 6/27, 22.2 % vs 2/23, 8.7 %; P = 0.039, respectively). Interestingly, this difference was also evident, but not statistically significant, after first and second transplant. Moreover, 5-ys-PFS curves of MRD-negative patients were absolutely similar among patients who received novel agents vs VAD as induction treatment prior first ASCT (data not shown)."
Full reference information for study (note that the full text of the study can be read without a subscription):
I Cordone et al, "Flow cytometry remission by Ig light chains ratio is a powerful marker of outcome in multiple myeloma after tandem autologous transplant: a real-life study," Journal of Experimental & Clinical Cancer Research, March 2016 (full text of article)
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Re: Italian minimal residual disease study
Thanks for posting about this, Mark.
I believe you are correct that the main benefit of this study is that it shows the feasibility and benefit of the particular MRD test that the authors used. It also confirms what most studies show, which is that patients who achieve a deep response to treatment typically have longer progression-free survival (and usually overall survival, as well).
What's unfortunate about these sorts of studies is that lots of people draw the wrong conclusion from them. From postings you've made in the past, I don't think you do this; I think you know enough about statistics to understand the difference between correlation and causation. However, lots of people – even a lot of myeloma specialists – see results like these and think they prove that you should treat myeloma patients as intensively as possible, and for as long as possible, to ensure they get the deepest response possible.
Instead, what studies like this show is something really simple: Patients who respond best to treatment live the longest.
Most of the studies like this one involve giving a group of patients the same identical treatment. Then the researchers look at how patients responded to the treatment, and how long they survived. Most of the time, the researchers find that patients who respond best to the treatment live the longest.
Wow. What. A. Surprise.
I think most of us here could have told the researchers that ahead of time. You don't need a Nobel prize to know that patients who respond better to treatment will probably live longer than patients who don't respond well to treatment.
Yet you'll find supposedly intelligent people saying things like "Well, studies show that myeloma patients who have the deepest response to treatment live the longest. This means that we should treat myeloma patients with as many drugs as they can tolerate, for as long as they can tolerate them, because that will get them to the deepest possible response."
What's worse, you'll find supposedly intelligent people buying this sort of argument uncritically, often because they believe that if a myeloma specialist makes such a statement, it must be right.
That's why I appreciate this forum and its emphasis on critical discussion of actual research results rather than subjective opinion.
I believe you are correct that the main benefit of this study is that it shows the feasibility and benefit of the particular MRD test that the authors used. It also confirms what most studies show, which is that patients who achieve a deep response to treatment typically have longer progression-free survival (and usually overall survival, as well).
What's unfortunate about these sorts of studies is that lots of people draw the wrong conclusion from them. From postings you've made in the past, I don't think you do this; I think you know enough about statistics to understand the difference between correlation and causation. However, lots of people – even a lot of myeloma specialists – see results like these and think they prove that you should treat myeloma patients as intensively as possible, and for as long as possible, to ensure they get the deepest response possible.
Instead, what studies like this show is something really simple: Patients who respond best to treatment live the longest.
Most of the studies like this one involve giving a group of patients the same identical treatment. Then the researchers look at how patients responded to the treatment, and how long they survived. Most of the time, the researchers find that patients who respond best to the treatment live the longest.
Wow. What. A. Surprise.
I think most of us here could have told the researchers that ahead of time. You don't need a Nobel prize to know that patients who respond better to treatment will probably live longer than patients who don't respond well to treatment.
Yet you'll find supposedly intelligent people saying things like "Well, studies show that myeloma patients who have the deepest response to treatment live the longest. This means that we should treat myeloma patients with as many drugs as they can tolerate, for as long as they can tolerate them, because that will get them to the deepest possible response."
What's worse, you'll find supposedly intelligent people buying this sort of argument uncritically, often because they believe that if a myeloma specialist makes such a statement, it must be right.
That's why I appreciate this forum and its emphasis on critical discussion of actual research results rather than subjective opinion.
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JimNY
Re: Italian minimal residual disease study
Thank you for posting this, Mark, and your insightful comment, JimNY. I have recently read a lot on the topic of MRD. I find it of great interest and thought I would chime in.
My takeaway on that is that the main issue is that MRD negative is good. It does not mean you are cured. In the future, however, it is expected that the state of the art can improve the sensitivity of the test (today it is about one in a million cells) by a factor of 10 or 100. At that level of sensitivity, it may still not measure a cure level, but it may indicate that a patient would have reached a stage where they safely could go on a low level of maintenance, or no treatment; and by monitoring it, restart treatment before it came back strong, keeping it at bay. In other words, it could also be used as a tool not only to indicate where more aggressive treatment is required, but also as a tool to dial back treatment, and not to over-treat, that is to "right size" the level of treatment.
I think that JimNY's point on response is very valid, that a good response typically means that you have a treatable, manageable condition that should do relatively well, where poor response for the most part could indicate a difficult, more aggressive condition. This begs the question as to whether throwing more treatment in a mediocre or poor response setting does any good at all.
But here is my question at this stage. On another thread, I briefly discussed the results for the Univ of Chicago (Dr. Jakubowiak's) regimen for Kyprolis, Revlimid, dexamethasone (KRD) induction; autologous stem cell transplant (ASCT); KRD consolidation; and KRD maintenance. Present standard of care for transplant eligible patients (Revlimid, Velcade, dexamethasone plus ASCT) brings a complete response (CR) rate of about 45% to 50%. The Univ of Chicago (yes, the study size is relatively small) is about 85% stringent CR (sCR) response (if you look it up, the sCR and MRD- rate is only slightly off for that study).
For the people who took longer to reach MRD-, but eventually reached it, the last 35% or 40%, those patients presumably would have been very good partial response (VGPR), or even a couple of partial responses (PR) under the existing standard of care. For those people, their response was not as quick or robust as the fast responders, but reached the MRD- response later; will their PFS turn out to be like the MRD- cohort in the Italian study?? If the answer is yes, then that would be a good result for the state of the art, as reaching MRD- would overcome initial poor or mediocre response, even if it took a little longer. If the later responders in the Univ of Chicago study relapsed like that MRD+ cohort, that would conversely be bad, in that they took a lot of extra treatment for no effect.
I am rooting of course for the first case. My suspicion, however, is that it would turn out somewhere in the middle, where it's better to have a very good response. However, even if you don't, there may turn out to be some benefit to reaching MRD-, eventually. The Univ of Chicago study was published last year at ASCO, and had response data, but not yet PFS data, median follow up was only 9 months. I think it would take about two years for preliminary PFS data to become available, based on a reasonable guess of expected response.
My takeaway on that is that the main issue is that MRD negative is good. It does not mean you are cured. In the future, however, it is expected that the state of the art can improve the sensitivity of the test (today it is about one in a million cells) by a factor of 10 or 100. At that level of sensitivity, it may still not measure a cure level, but it may indicate that a patient would have reached a stage where they safely could go on a low level of maintenance, or no treatment; and by monitoring it, restart treatment before it came back strong, keeping it at bay. In other words, it could also be used as a tool not only to indicate where more aggressive treatment is required, but also as a tool to dial back treatment, and not to over-treat, that is to "right size" the level of treatment.
I think that JimNY's point on response is very valid, that a good response typically means that you have a treatable, manageable condition that should do relatively well, where poor response for the most part could indicate a difficult, more aggressive condition. This begs the question as to whether throwing more treatment in a mediocre or poor response setting does any good at all.
But here is my question at this stage. On another thread, I briefly discussed the results for the Univ of Chicago (Dr. Jakubowiak's) regimen for Kyprolis, Revlimid, dexamethasone (KRD) induction; autologous stem cell transplant (ASCT); KRD consolidation; and KRD maintenance. Present standard of care for transplant eligible patients (Revlimid, Velcade, dexamethasone plus ASCT) brings a complete response (CR) rate of about 45% to 50%. The Univ of Chicago (yes, the study size is relatively small) is about 85% stringent CR (sCR) response (if you look it up, the sCR and MRD- rate is only slightly off for that study).
For the people who took longer to reach MRD-, but eventually reached it, the last 35% or 40%, those patients presumably would have been very good partial response (VGPR), or even a couple of partial responses (PR) under the existing standard of care. For those people, their response was not as quick or robust as the fast responders, but reached the MRD- response later; will their PFS turn out to be like the MRD- cohort in the Italian study?? If the answer is yes, then that would be a good result for the state of the art, as reaching MRD- would overcome initial poor or mediocre response, even if it took a little longer. If the later responders in the Univ of Chicago study relapsed like that MRD+ cohort, that would conversely be bad, in that they took a lot of extra treatment for no effect.
I am rooting of course for the first case. My suspicion, however, is that it would turn out somewhere in the middle, where it's better to have a very good response. However, even if you don't, there may turn out to be some benefit to reaching MRD-, eventually. The Univ of Chicago study was published last year at ASCO, and had response data, but not yet PFS data, median follow up was only 9 months. I think it would take about two years for preliminary PFS data to become available, based on a reasonable guess of expected response.
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JPC - Name: JPC
Re: Italian minimal residual disease study
Thanks for the well thought out responses.
When I was reading JimNY's post I was going to discuss something JPC also mentioned. Jim's comment:
Here is what JPC wrote:
My own experience as a high risk patient is that, by using MRD testing, I did not over treat. Since I was MRD negative after my allo, I decided not to use any maintenance. That decision was based on 2 small studies that showed patients who did allo transplants that achieved a molecular response after their transplant could just be monitored since they are in the group that is least likely to relapse. Patients that are MRD negative are a subgroup that an individual patient could be in after completing their therapy. MRD testing can be used to indicate what patients do not need additional consolidation/maintenance therapy.
I also want to point out that, while this is a flow cytometry test, it was done in a slightly different way than many flow tests are done. Being able to put patients into 2 groups, one with a 95% chance of relapsing in 5 years, and the other with a 30% chance of relapsing, is an impressive test, IMO. If you look at other studies using flow cytometry, they show a PFS advantage for MRD negative patients but not to the extent this study did. The point of this study was to show how accurate this test was, not to show that patients who are MRD negative do better than patients that are MRD positive.
I know from personal experience that using MRD testing when making therapy decisions made me very confident with the treatment decisions I made. I also used it as the goal of my therapy and I do not feel that I over treated. I feel I was treated with the exact amount of therapy that was necessary given my goal of having a long term drug free remission / cure and my individual presentation at diagnosis.
When I was reading JimNY's post I was going to discuss something JPC also mentioned. Jim's comment:
This means that we should treat myeloma patients with as many drugs as they can tolerate, for as long as they can tolerate them, because that will get them to the deepest possible response.
Here is what JPC wrote:
In other words, it could also be used as a tool not only to indicate where more aggressive treatment is required, but also as a tool to dial back treatment, and not to over-treat, that is to "right size" the level of treatment.
My own experience as a high risk patient is that, by using MRD testing, I did not over treat. Since I was MRD negative after my allo, I decided not to use any maintenance. That decision was based on 2 small studies that showed patients who did allo transplants that achieved a molecular response after their transplant could just be monitored since they are in the group that is least likely to relapse. Patients that are MRD negative are a subgroup that an individual patient could be in after completing their therapy. MRD testing can be used to indicate what patients do not need additional consolidation/maintenance therapy.
I also want to point out that, while this is a flow cytometry test, it was done in a slightly different way than many flow tests are done. Being able to put patients into 2 groups, one with a 95% chance of relapsing in 5 years, and the other with a 30% chance of relapsing, is an impressive test, IMO. If you look at other studies using flow cytometry, they show a PFS advantage for MRD negative patients but not to the extent this study did. The point of this study was to show how accurate this test was, not to show that patients who are MRD negative do better than patients that are MRD positive.
I know from personal experience that using MRD testing when making therapy decisions made me very confident with the treatment decisions I made. I also used it as the goal of my therapy and I do not feel that I over treated. I feel I was treated with the exact amount of therapy that was necessary given my goal of having a long term drug free remission / cure and my individual presentation at diagnosis.
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Mark11
Re: Italian minimal residual disease study
Thank you for posting this study. I've seen similar info coming out of Mayo Clinic and other sources.
I also have seen similar questions about cause versus effect. My humble opinion is that it's both.
We tailored her induction to start and stop her RVD in stages. By accident on their part, on purpose on my part
The primary reason is that I know how Janet responds to unknown issues. We've heard the adage about how to boil a frog. I know that sounds harsh, but this allowed her to stay focused and work hard at each stage.
She is on Day 13 on the transplant schedule and will be going home today.
We are hopeful since she was MRD negative prior to starting the auto transplant procedure.
Best regards to everyone!
I also have seen similar questions about cause versus effect. My humble opinion is that it's both.
We tailored her induction to start and stop her RVD in stages. By accident on their part, on purpose on my part
The primary reason is that I know how Janet responds to unknown issues. We've heard the adage about how to boil a frog. I know that sounds harsh, but this allowed her to stay focused and work hard at each stage.She is on Day 13 on the transplant schedule and will be going home today.
We are hopeful since she was MRD negative prior to starting the auto transplant procedure.
Best regards to everyone!
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JohnBoy5456 - Name: John
- Who do you know with myeloma?: Janet
- When were you/they diagnosed?: 6/15/15
- Age at diagnosis: 64
Re: Italian minimal residual disease study
Hi JohnBoy,
Hopefully your wife is home as scheduled. You never appreciate home quite like that first day after being away while doing a transplant!
That is great news that your wife was MRD negative prior to doing the auto. Sounds like you think like I do - use effective therapies early while the patient is responding well. There are some patients that do autos as part of their upfront therapy that never relapse. Let's hope your wife is one of them.
Mark
Hopefully your wife is home as scheduled. You never appreciate home quite like that first day after being away while doing a transplant!
That is great news that your wife was MRD negative prior to doing the auto. Sounds like you think like I do - use effective therapies early while the patient is responding well. There are some patients that do autos as part of their upfront therapy that never relapse. Let's hope your wife is one of them.
Mark
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Mark11
Re: Italian minimal residual disease study
Thank you Mark,
Yes, Janet has been home for 3 days now and is doing fairly well (by her definition; amazingly well by my definition!)
On release from the hospital, her immunoglobulin numbers are almost normal and her blood counts are recovering nicely.
Interestingly, she is still showing a very slight M-spike of 0.2.
I think I read somewhere that with IgG type myeloma, the M-spike can hang around for a 100 days even when you've achieved MRD-negative status.
Thank you for all you do for these forums!
John
Yes, Janet has been home for 3 days now and is doing fairly well (by her definition; amazingly well by my definition!)
On release from the hospital, her immunoglobulin numbers are almost normal and her blood counts are recovering nicely.
Interestingly, she is still showing a very slight M-spike of 0.2.
I think I read somewhere that with IgG type myeloma, the M-spike can hang around for a 100 days even when you've achieved MRD-negative status.
Thank you for all you do for these forums!
John
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JohnBoy5456 - Name: John
- Who do you know with myeloma?: Janet
- When were you/they diagnosed?: 6/15/15
- Age at diagnosis: 64
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