Has it really been established that getting a deeper response to treatment – e.g., whether a complete response (CR) or stringent complete response (sCR) – "typically means longer overall survival" (as TerryH wrote in a recent forum posting)?
In his August, 2013 article for the Beacon,
"Should Myeloma Patients Panic If They Do Not Achieve A Complete Response?"
Dr. Rajkumar seems to be demurring on this point. My reading of his position is that, while there is evidence in some studies that patients with a deeper response (to an autologous stem cell transplant) do show longer overall survival, it does not follow from this that intensifying therapy to achieve a CR will result in longer overall survival.
Have there been newer studies that more conclusively tie going after and achieving deeper responses to achieving longer overall survival?
There are many cases of patients that achieve a CR that unfortunately has weak durability, and that as a consequence confer no benefit in overall survival. Several have posted on this forum.
Forums
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MrPotatohead - Name: MrPotatohead
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: March, 2015
- Age at diagnosis: 65
Re: Does a deeper response mean longer overall survival?
Mr. PH,
Very good question, and one I discussed with my doctor a while back while I was on maintenance therapy. I'll try to recount it as best I can.
He indicated researchers are investigating whether reaching and maintaining a stable response may in some cases be comparable, or even preferable, to trying to reach a complete response.
To understand, first realize there are many, many different mutations of multiple myeloma coexisting in our body, ranging from relatively benign to very aggressive. The benign versions are generally easier to treat and retain in remission, while the aggressive versions are more difficult to treat and relapse more quickly.
Evidence suggests that at any given time, only one mutation is dominant and may tend to keep the rest at bay. If that particular mutation is treated and beaten into submission, upon relapse a different mutation may become dominant.
Therefore, if the dominant mutation is relatively benign, logic suggests it might be better to keep it in place rather than have a more aggressive version replace it. Conversely, if an aggressive version is dominant, it would be preferable to knock that into remission and hope a less aggressive version replaces it.
So, if the dominant form is relatively benign, would it be better to reach and maintain a low- level stable response rather than a complete response?
I haven't come across any subsequent findings on this research, but then I haven't looked very hard either.
More food for thought,
Kevin.
Very good question, and one I discussed with my doctor a while back while I was on maintenance therapy. I'll try to recount it as best I can.
He indicated researchers are investigating whether reaching and maintaining a stable response may in some cases be comparable, or even preferable, to trying to reach a complete response.
To understand, first realize there are many, many different mutations of multiple myeloma coexisting in our body, ranging from relatively benign to very aggressive. The benign versions are generally easier to treat and retain in remission, while the aggressive versions are more difficult to treat and relapse more quickly.
Evidence suggests that at any given time, only one mutation is dominant and may tend to keep the rest at bay. If that particular mutation is treated and beaten into submission, upon relapse a different mutation may become dominant.
Therefore, if the dominant mutation is relatively benign, logic suggests it might be better to keep it in place rather than have a more aggressive version replace it. Conversely, if an aggressive version is dominant, it would be preferable to knock that into remission and hope a less aggressive version replaces it.
So, if the dominant form is relatively benign, would it be better to reach and maintain a low- level stable response rather than a complete response?
I haven't come across any subsequent findings on this research, but then I haven't looked very hard either.
More food for thought,
Kevin.
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Kevin J - Name: Kevin J
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: Jan 2011
- Age at diagnosis: 52
Re: Does a deeper response mean longer overall survival?
Hi MrP,
As you may have noticed, I was very careful in the way I worded the reply that you quoted in your post up above. I think the evidence is relatively clear that, for a given treatment regimen, administered for an equal length of time and with equal doses to patients at a very similar point in their myeloma journey -- for example, newly diagnosed patients -- a deeper response usually signals longer overall survival.
Now, even though a deeper response is associated with longer overall survival, that doesn't mean there won't be outliers. You will get patients who don't get deep responses, but who will have long overall survival. And, unfortunately, you'll also get the opposite.
Also -- and this is so often misunderstood -- just because deep responses are associated with longer overall survival, this doesn't mean that getting as deep a response as possible should be the goal of therapy.
There is one set of circumstances where targeting a deep response makes sense. It's when you're having a patient do induction therapy prior to an allogeneic transplant. As Mark has cogently pointed out here in the forum many times, the evidence is close to conclusive that the deeper the response a patient has achieved prior to an allo transplant, the better the long-term outcome of the allo transplant.
But setting aside allo transplantation, most of the arguments that people make in favor of targeting depth of response in myeloma patients rest on extrapolations from datasets that did not in any way test the targeting-response hypothesis. People -- even seemingly educated people -- will say things like "Well, patients who had deeper responses in trials X, Y, and Z lived the longest, so this means you should treat patients until you get the deepest response possible."
You'll also see variations of this argument, like "Well, patients who reached MRD negativity in trials X, Y, and Z lived the longest, so we should treat patients until they are MRD negative."
Yet, as doctors and others here in the forum have pointed out many times, all those results really say is that patients who have responded the best to a given treatment were likely to live the longest.
And there's nothing surprising about that.
Kevin makes a very interesting argument up above as to why treating for depth of response may not make sense. You can come up with similar arguments once you start thinking about the clonal nature of myeloma and how the disease is interdependent on the bone marrow microenvironment.
In general, even though it's not the "in" view these days, I don't think it makes sense to routinely treat for depth of response. I'm not saying "Never treat for depth of response." I just don't think it makes sense as a general strategy for all patients.
Finally, as Mark also has suggested in one or two other discussions in the forum similar to this one, this topic is related to what has been called the "cure vs. control" debate. I sometimes think our still limited understanding of multiple myeloma makes that debate into a kind of religious argument, where it's difficult to decide who is right based purely on facts and data.
As you may have noticed, I was very careful in the way I worded the reply that you quoted in your post up above. I think the evidence is relatively clear that, for a given treatment regimen, administered for an equal length of time and with equal doses to patients at a very similar point in their myeloma journey -- for example, newly diagnosed patients -- a deeper response usually signals longer overall survival.
Now, even though a deeper response is associated with longer overall survival, that doesn't mean there won't be outliers. You will get patients who don't get deep responses, but who will have long overall survival. And, unfortunately, you'll also get the opposite.
Also -- and this is so often misunderstood -- just because deep responses are associated with longer overall survival, this doesn't mean that getting as deep a response as possible should be the goal of therapy.
There is one set of circumstances where targeting a deep response makes sense. It's when you're having a patient do induction therapy prior to an allogeneic transplant. As Mark has cogently pointed out here in the forum many times, the evidence is close to conclusive that the deeper the response a patient has achieved prior to an allo transplant, the better the long-term outcome of the allo transplant.
But setting aside allo transplantation, most of the arguments that people make in favor of targeting depth of response in myeloma patients rest on extrapolations from datasets that did not in any way test the targeting-response hypothesis. People -- even seemingly educated people -- will say things like "Well, patients who had deeper responses in trials X, Y, and Z lived the longest, so this means you should treat patients until you get the deepest response possible."
You'll also see variations of this argument, like "Well, patients who reached MRD negativity in trials X, Y, and Z lived the longest, so we should treat patients until they are MRD negative."
Yet, as doctors and others here in the forum have pointed out many times, all those results really say is that patients who have responded the best to a given treatment were likely to live the longest.
And there's nothing surprising about that.
Kevin makes a very interesting argument up above as to why treating for depth of response may not make sense. You can come up with similar arguments once you start thinking about the clonal nature of myeloma and how the disease is interdependent on the bone marrow microenvironment.
In general, even though it's not the "in" view these days, I don't think it makes sense to routinely treat for depth of response. I'm not saying "Never treat for depth of response." I just don't think it makes sense as a general strategy for all patients.
Finally, as Mark also has suggested in one or two other discussions in the forum similar to this one, this topic is related to what has been called the "cure vs. control" debate. I sometimes think our still limited understanding of multiple myeloma makes that debate into a kind of religious argument, where it's difficult to decide who is right based purely on facts and data.
Re: Does a deeper response mean longer overall survival?
Thank you very much, Kevin J and TerryH.
Kevin J,
I have had similar thoughts. In my case, I was diagnosed with kappa light chain myeloma, and my response was tracked by the free light chain assay which, on a regimen of Cytoxan (cyclophosphamide), Kyprolis (carfilzomib), and dexamethasone, showed a complete response after about four months (one monthly test showed a stringent complete response). However, a PET/CT scan showed numerous active myeloma lesions avidly taking up FDG at the same time.
Reading various articles on the Beacon and elsewhere, I mused that perhaps the kappa free light chain myeloma was responsible for some of my CRAB symptoms, but that the continuing bone destruction may be the result of a completely oligosecretory strain distinct from the kappa version.
I have also read of cases where induction and/or an autologous transplant achieved a complete response, but when relapse occurred, progression was rapid and overwhelming, suggesting the presence of a much more aggressive strain than what appeared to be dominant at diagnosis.
It is hard to know what to do when confronted with these kinds of ambiguities. What are the implications for treatment decisions if it may be the case that maintaining stable disease is superior to trying to wipe it all out? How would one do that? The tools just don't exist.
Thanks again, Kevin.
TerryH,
You were indeed very careful in how you stated the "typical" overall survival advantage of a deeper response. Moreover, I think that the dominant guiding principle in current practice is to achieve as deep a response as possible, assuming that doing so will result in better outcomes, including prolonged survival. But, as you also say, just because patients survive longer when, all other variables such as treatment type, length of treatment, etc., are equal, they have a deeper response, it does not follow that tweaking one's regimen to achieve a deeper response will necessarily prolong survival.
As you suggest, I also think that the reason for this may be related to the points Kevin J makes – namely, that if you have multiple strains of myeloma in one patient and a benign version is dominant, keeping more aggressive strains that may also be present at bay, manipulating the therapeutic protocol to wipe out the dominant strain may lead to the more aggressive (and deadlier) strain becoming dominant, thereby shortening overall survival.
I am not familiar enough with Mark11's posts, nor with allogenic transplants, to comment on what he says on the topic of deep responses in preparation for an allo transplant. It is clear to me, however, based on Mark's posts that I have read, that he is very knowledgeable and has done some deep thinking and research on these issues.
As for the control versus cure debate, I think a lot more fundamental research needs to be done on the underlying nature and mechanisms of multiple myeloma before that can be settled. My feeling is that, despite the very real and impressive progress that has been made in treatment, we are a very long way off from resolving that issue.
Thanks again, Terry.
Kevin J,
I have had similar thoughts. In my case, I was diagnosed with kappa light chain myeloma, and my response was tracked by the free light chain assay which, on a regimen of Cytoxan (cyclophosphamide), Kyprolis (carfilzomib), and dexamethasone, showed a complete response after about four months (one monthly test showed a stringent complete response). However, a PET/CT scan showed numerous active myeloma lesions avidly taking up FDG at the same time.
Reading various articles on the Beacon and elsewhere, I mused that perhaps the kappa free light chain myeloma was responsible for some of my CRAB symptoms, but that the continuing bone destruction may be the result of a completely oligosecretory strain distinct from the kappa version.
I have also read of cases where induction and/or an autologous transplant achieved a complete response, but when relapse occurred, progression was rapid and overwhelming, suggesting the presence of a much more aggressive strain than what appeared to be dominant at diagnosis.
It is hard to know what to do when confronted with these kinds of ambiguities. What are the implications for treatment decisions if it may be the case that maintaining stable disease is superior to trying to wipe it all out? How would one do that? The tools just don't exist.
Thanks again, Kevin.
TerryH,
You were indeed very careful in how you stated the "typical" overall survival advantage of a deeper response. Moreover, I think that the dominant guiding principle in current practice is to achieve as deep a response as possible, assuming that doing so will result in better outcomes, including prolonged survival. But, as you also say, just because patients survive longer when, all other variables such as treatment type, length of treatment, etc., are equal, they have a deeper response, it does not follow that tweaking one's regimen to achieve a deeper response will necessarily prolong survival.
As you suggest, I also think that the reason for this may be related to the points Kevin J makes – namely, that if you have multiple strains of myeloma in one patient and a benign version is dominant, keeping more aggressive strains that may also be present at bay, manipulating the therapeutic protocol to wipe out the dominant strain may lead to the more aggressive (and deadlier) strain becoming dominant, thereby shortening overall survival.
I am not familiar enough with Mark11's posts, nor with allogenic transplants, to comment on what he says on the topic of deep responses in preparation for an allo transplant. It is clear to me, however, based on Mark's posts that I have read, that he is very knowledgeable and has done some deep thinking and research on these issues.
As for the control versus cure debate, I think a lot more fundamental research needs to be done on the underlying nature and mechanisms of multiple myeloma before that can be settled. My feeling is that, despite the very real and impressive progress that has been made in treatment, we are a very long way off from resolving that issue.
Thanks again, Terry.
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MrPotatohead - Name: MrPotatohead
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: March, 2015
- Age at diagnosis: 65
Re: Does a deeper response mean longer overall survival?
This is an interesting article on maintenance which also touches on the point that KevinJ raised earlier:
Nooka, AK, and Lonial, S, "Is Maintenance Therapy for Everyone," Clinical Lymphoma, Myeloma, and Leukemia, Aug 2016 (abstract, PDF of full article)
Excerpt:
"However,certain considerations need to be well thought-out while planning on initiating maintenance therapy. First, it is quite uncertain which patient phenotype benefits the most. Secondly, there is a theoretical concern for development of resistant clones on prolonged exposure to the maintenance agent."
Nooka, AK, and Lonial, S, "Is Maintenance Therapy for Everyone," Clinical Lymphoma, Myeloma, and Leukemia, Aug 2016 (abstract, PDF of full article)
Excerpt:
"However,certain considerations need to be well thought-out while planning on initiating maintenance therapy. First, it is quite uncertain which patient phenotype benefits the most. Secondly, there is a theoretical concern for development of resistant clones on prolonged exposure to the maintenance agent."
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: Does a deeper response mean longer overall survival?
Hi Mr. Potatohead,
Thanks for posting that article. This has been like "back to the future" week since we are discussing a lot of topics we discussed back when I started posting back in 2010-11. As much as people say things are changing rapidly in myeloma therapy, it seems we keep discussing the same topics.
With respect to the article, if you read the one study that Dr. Rajkumar references, it is a study on patients that used upfront tandem auto transplants. Obviously that study does not suggest that patients should use less aggressive therapy. It was a study to show the ability of gene expression profiling (GEP) to identify patients at a high risk of relapse. What you see are a group of patients that used aggressive therapy that did well despite not achieving a CR. Note some of the comments in the paper:
"Our observation that a second transplant benefits especially patients already in CR after the first transplant is at variance with results reported by the Intergroupe Francophone du Myelome in their IFM94 trial, showing such benefit only among patients not yet in CR at the time of the second transplant. Thus, as in other malignancies, further tumor cytoreduction beyond the level of clinical CR seems to be beneficial. "
"Unlike traditional SPF with HR values not exceeding 2, the 70-gene model captured a truly high-risk subset with unprecedented high HR values in patients not achieving CR. In this setting, early onset of CR (reflecting marked sensitivity to the treatment used) is of critical importance to prolonged disease control and survival. We postulate that, as had been the case in non-Hodgkin lymphoma with the advent of doxorubicin (20), patients with high-risk multiple myeloma are more likely candidates for curative therapy, whereas those with low-risk multiple myeloma may require prolonged or repeated treatment to achieve a chronic disease status. In the case of MGUS-like multiple myeloma, high-dose therapy seems be incapable of eliminating dormant MGUS-precursor plasma cells so that a MGUS-like condition is reestablished, which explains the lower CR rate observed in this setting and yet a superior survival (10, 11)."
Do patients that use less aggressive therapy potentially return to a MGUS like state? I do not know. I know when I asked patients in the past if a study existed that showed patients that did not do a transplant returning to an MGUS phase, no one replied with one. Maybe one exists, but all I know from the study is that patients that do early transplants that do not achieve CR can have an excellent outcome given that they are low risk as defined by GEP.
You wrote:
I disagree that there is a move toward more aggressive therapy. The only 2 therapies that appear to have the ability to help achieve a deep enough response that patients can enjoy a long term drug free remission are autologous and allogeneic transplants. Allos are almost never used on newly diagnosed patients and the rate of patients doing an early auto is also very low (see this related forum, "Autologous stem cell transplants in the United States").
In my opinion, the novel agents alone do not get patients a deep response, and both the doctors and patients know that they do not based on their actions While they claim they got a deep response because they are minimal residual disease (MRD) negative based on a test, they keep their patients on never ending cycles of drugs I have a deep response to my therapy. I know that because I was a high-risk patient that has been in a drug free remission for over 5 years. Beacon Columnist Sean Murray had a deep response from Total Therapy because he has been in a drug free remission for around 4 years. I know someone that did an auto 9 years ago, used no maintenance, and remains in complete response. I know she had a deep response to her treatment.
What makes you think there is a move toward more aggressive therapy and that patients achieve a deep response based on the actions of the doctors and patients, as opposed to what they say, for example, in interviews or other platforms that are not peer-reviewed?
Mark
Thanks for posting that article. This has been like "back to the future" week since we are discussing a lot of topics we discussed back when I started posting back in 2010-11. As much as people say things are changing rapidly in myeloma therapy, it seems we keep discussing the same topics.
With respect to the article, if you read the one study that Dr. Rajkumar references, it is a study on patients that used upfront tandem auto transplants. Obviously that study does not suggest that patients should use less aggressive therapy. It was a study to show the ability of gene expression profiling (GEP) to identify patients at a high risk of relapse. What you see are a group of patients that used aggressive therapy that did well despite not achieving a CR. Note some of the comments in the paper:
"Our observation that a second transplant benefits especially patients already in CR after the first transplant is at variance with results reported by the Intergroupe Francophone du Myelome in their IFM94 trial, showing such benefit only among patients not yet in CR at the time of the second transplant. Thus, as in other malignancies, further tumor cytoreduction beyond the level of clinical CR seems to be beneficial. "
"Unlike traditional SPF with HR values not exceeding 2, the 70-gene model captured a truly high-risk subset with unprecedented high HR values in patients not achieving CR. In this setting, early onset of CR (reflecting marked sensitivity to the treatment used) is of critical importance to prolonged disease control and survival. We postulate that, as had been the case in non-Hodgkin lymphoma with the advent of doxorubicin (20), patients with high-risk multiple myeloma are more likely candidates for curative therapy, whereas those with low-risk multiple myeloma may require prolonged or repeated treatment to achieve a chronic disease status. In the case of MGUS-like multiple myeloma, high-dose therapy seems be incapable of eliminating dormant MGUS-precursor plasma cells so that a MGUS-like condition is reestablished, which explains the lower CR rate observed in this setting and yet a superior survival (10, 11)."
Do patients that use less aggressive therapy potentially return to a MGUS like state? I do not know. I know when I asked patients in the past if a study existed that showed patients that did not do a transplant returning to an MGUS phase, no one replied with one. Maybe one exists, but all I know from the study is that patients that do early transplants that do not achieve CR can have an excellent outcome given that they are low risk as defined by GEP.
You wrote:
Moreover, I think that the dominant guiding principle in current practice is to achieve as deep a response as possible, assuming that doing so will result in better outcomes, including prolonged survival.
I disagree that there is a move toward more aggressive therapy. The only 2 therapies that appear to have the ability to help achieve a deep enough response that patients can enjoy a long term drug free remission are autologous and allogeneic transplants. Allos are almost never used on newly diagnosed patients and the rate of patients doing an early auto is also very low (see this related forum, "Autologous stem cell transplants in the United States").
In my opinion, the novel agents alone do not get patients a deep response, and both the doctors and patients know that they do not based on their actions While they claim they got a deep response because they are minimal residual disease (MRD) negative based on a test, they keep their patients on never ending cycles of drugs I have a deep response to my therapy. I know that because I was a high-risk patient that has been in a drug free remission for over 5 years. Beacon Columnist Sean Murray had a deep response from Total Therapy because he has been in a drug free remission for around 4 years. I know someone that did an auto 9 years ago, used no maintenance, and remains in complete response. I know she had a deep response to her treatment.
What makes you think there is a move toward more aggressive therapy and that patients achieve a deep response based on the actions of the doctors and patients, as opposed to what they say, for example, in interviews or other platforms that are not peer-reviewed?
Mark
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Mark11
Re: Does a deeper response mean longer overall survival?
Here is a recent article on reaching MRD negative, the most stringent measurement as of this time, from Dr. Langren:
Landgren, O., et al, "Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis," Bone Marrow Transplantation, Sep 6, 2016 (abstract)
I did not have access to the full article, only the abstract. Based on my understanding of the term of "hazard ratio", it looks to be that when comparing minimal residual disease (MRD) negative to MRD positive, that the advantage to MRD negative in terms of progression-free survival (PFS) is a factor of 3, and in overall survival (OS), a factor of 2.
So with respect to deepening response, I think it's very valid to say that if the expectation is to get a slightly better very good partial response (VGPR), or a slightly better partial response (PR), additional treatment is probably not worth the additional toxicities (that's a gross generalization, and may not be true in all individual cases). However, if you are near MRD negative, but not yet there yet, I think that the recent data strongly suggests that it could be worth it to try and jump that hurdle.
Good luck to all.
Here's the abstract for the paper:
Driven by access to better drugs, on average, newly diagnosed multiple myeloma patients have over 10 years overall survival. Using modern combination therapies – with or without the addition of high-dose melphalan and autologous stem cell transplantation – up to 80% of patients reach a complete response. As a logical and necessary step forward, clinical studies have explored strategies to detect minimal residual disease (MRD) and its correlation with clinical outcomes. In this context, MRD has been proposed as a regulatory end point for drug approval in newly diagnosed multiple myeloma. To better define the role of MRD negativity in relation to clinical outcomes, we undertook a meta-analysis including published clinical trials of newly diagnosed multiple myeloma patients. We applied a random effects model which weighted studies using the inverse–variance method. Studies were combined on the scale of the logarithm of the hazard ratio (HR) and the corresponding s.d. We found that MRD negativity (versus positivity) was associated with better PFS (HR=0.35; 95% confidence interval (CI) 0.27–0.46; P<0.001) and overall survival (HR=0.48; 95% CI 0.33–0.70; P<0.001). Our results show that MRD negativity is a strong predictor of clinical outcomes, supportive of MRD becoming a regulatory end point for drug approval in newly diagnosed multiple myeloma.
Landgren, O., et al, "Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis," Bone Marrow Transplantation, Sep 6, 2016 (abstract)
I did not have access to the full article, only the abstract. Based on my understanding of the term of "hazard ratio", it looks to be that when comparing minimal residual disease (MRD) negative to MRD positive, that the advantage to MRD negative in terms of progression-free survival (PFS) is a factor of 3, and in overall survival (OS), a factor of 2.
So with respect to deepening response, I think it's very valid to say that if the expectation is to get a slightly better very good partial response (VGPR), or a slightly better partial response (PR), additional treatment is probably not worth the additional toxicities (that's a gross generalization, and may not be true in all individual cases). However, if you are near MRD negative, but not yet there yet, I think that the recent data strongly suggests that it could be worth it to try and jump that hurdle.
Good luck to all.
Here's the abstract for the paper:
Driven by access to better drugs, on average, newly diagnosed multiple myeloma patients have over 10 years overall survival. Using modern combination therapies – with or without the addition of high-dose melphalan and autologous stem cell transplantation – up to 80% of patients reach a complete response. As a logical and necessary step forward, clinical studies have explored strategies to detect minimal residual disease (MRD) and its correlation with clinical outcomes. In this context, MRD has been proposed as a regulatory end point for drug approval in newly diagnosed multiple myeloma. To better define the role of MRD negativity in relation to clinical outcomes, we undertook a meta-analysis including published clinical trials of newly diagnosed multiple myeloma patients. We applied a random effects model which weighted studies using the inverse–variance method. Studies were combined on the scale of the logarithm of the hazard ratio (HR) and the corresponding s.d. We found that MRD negativity (versus positivity) was associated with better PFS (HR=0.35; 95% confidence interval (CI) 0.27–0.46; P<0.001) and overall survival (HR=0.48; 95% CI 0.33–0.70; P<0.001). Our results show that MRD negativity is a strong predictor of clinical outcomes, supportive of MRD becoming a regulatory end point for drug approval in newly diagnosed multiple myeloma.
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JPC - Name: JPC
Re: Does a deeper response mean longer overall survival?
PH
Kevin J writes:
This is the first time I have ever heard such a statement, and therefore I hadn't thought about it. Sure, I can see where a del13 or a t(4,14) 'could be' two different mutations in a 'specific' patient.
I don't know that 'many different mutations of multiple myeloma' coexist in my body. Am I to assume healthy people also have "many, many different mutations of multiple myeloma coexisting in their body, ranging from relatively benign to very aggressive," but myeloma is kept in check by a properly operating immune system?
I do think (without any scientific data whatsoever) that the more myeloma cells a patient has in his system – whether it be 1, 1,000, or 1,000,000 – the chances that a mutation could develop and become resistant to a treatment plan is greater the more myeloma cells there are. Just a guess.
I don't know if I can accept Kevin's claim, partially because I might be in healthy denial that it could be true.
Kevin J writes:
To understand, first realize there are many, many different mutations of multiple myeloma coexisting in our body, ranging from relatively benign to very aggressive.
This is the first time I have ever heard such a statement, and therefore I hadn't thought about it. Sure, I can see where a del13 or a t(4,14) 'could be' two different mutations in a 'specific' patient.
I don't know that 'many different mutations of multiple myeloma' coexist in my body. Am I to assume healthy people also have "many, many different mutations of multiple myeloma coexisting in their body, ranging from relatively benign to very aggressive," but myeloma is kept in check by a properly operating immune system?
I do think (without any scientific data whatsoever) that the more myeloma cells a patient has in his system – whether it be 1, 1,000, or 1,000,000 – the chances that a mutation could develop and become resistant to a treatment plan is greater the more myeloma cells there are. Just a guess.
I don't know if I can accept Kevin's claim, partially because I might be in healthy denial that it could be true.
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blueblood - Name: Craig
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: March 2014
- Age at diagnosis: 54
Re: Does a deeper response mean longer overall survival?
Hi Craig,
The overall concept that KevinJ related has been around for a number of years. You may want to read through these articles:
Morgan, GJ, "Evolution, Intra-Clonal Heterogeneity, And Multiple Myeloma," The Myeloma Beacon, Nov 3, 2014
Bahlis, NJ, "Darwinian evolution and tiding clones in multiple myeloma," Blood, 2012 (full text of article)
The overall concept that KevinJ related has been around for a number of years. You may want to read through these articles:
Morgan, GJ, "Evolution, Intra-Clonal Heterogeneity, And Multiple Myeloma," The Myeloma Beacon, Nov 3, 2014
Bahlis, NJ, "Darwinian evolution and tiding clones in multiple myeloma," Blood, 2012 (full text of article)
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: Does a deeper response mean longer overall survival?
Just saw a meta-analysis of studies looking progression free survival (PFS) and overall survival (OS) in patients getting to minimal residual disease (MRD) negative status vs. those only reaching complete response (CR) status. It's at the link listed below and it's (believe it or not) free!
One of the aspects that I found particularly intriguing was the flattening of the Kaplan-Meier curves at around 6 - 7 years for both those getting to MRD negative and those getting to CR. I've seen some speculation that this indicates that some individuals are being functionally cured.
Of course, there's another article in the same issue (also free: "Minimal Residual Disease as a Potential Surrogate End Point – Lingering Questions") looking at some of the questions that remain regarding measurement of MRD status and how to treat that information. It's always more complicated than it initially seems to be.
Reference:
Munshi, NC, et al, "Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis," JAMA Oncology, Sep 15, 2016 (full text of article)
Abstract:
Importance: Numerous studies have evaluated the prognostic value of minimal residual disease (MRD) in patients with multiple myeloma (multiple myeloma). Most studies were small and varied in terms of patient population, treatment, and MRD assessment methods.
Objective: To evaluate the utility of MRD detection in patients with newly diagnosed multiple myeloma.
Data Sources: A Medline search was conducted for articles published in English between January 1990 and January 2016.
Study Selection: Eligible studies reported MRD status and progression-free survival (PFS) or overall survival (OS) in 20 or more patients following treatment. Among 405 articles identified, 21 met the initial eligibility criteria and were included in the analysis.
Data Extraction and Synthesis: Information on patient characteristics, treatment, MRD assessment, and outcomes were extracted using a standard form.
Main Outcomes and Measures: The impact of MRD status on PFS and OS was assessed by pooling data from relevant trials. Data were adjusted to allow for different proportions of patients with MRD in different studies, and analyzed using the Peto method. Forest plots were created based on Cox model analysis. Other prespecified research questions were addressed qualitatively.
Results: Fourteen studies (n = 1273) provided data on the impact of MRD on PFS, and 12 studies (n = 1100) on OS. Results were reported specifically in patients who had achieved conventional complete response (CR) in 5 studies for PFS (n = 574) and 6 studies for OS (n = 616). An MRD-negative status was associated with significantly better PFS overall (hazard ratio [HR], 0.41; 95% CI, 0.36-0.48; P < .001) and in studies specifically looking at CR patients (HR, 0.44; 95% CI, 0.34-0.56; P < .001). Overall survival was also favorable in MRD-negative patients overall (HR, 0.57; 95% CI, 0.46-0.71; P < .001) and in CR patients (HR, 0.47; 95% CI, 0.33-0.67; P < .001). Tests of heterogeneity found no significant differences among the studies for PFS and OS.
Conclusions and Relevance: Minimal residual disease-negative status after treatment for newly diagnosed multiple myeloma is associated with long-term survival. These findings provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of multiple myeloma.
One of the aspects that I found particularly intriguing was the flattening of the Kaplan-Meier curves at around 6 - 7 years for both those getting to MRD negative and those getting to CR. I've seen some speculation that this indicates that some individuals are being functionally cured.
Of course, there's another article in the same issue (also free: "Minimal Residual Disease as a Potential Surrogate End Point – Lingering Questions") looking at some of the questions that remain regarding measurement of MRD status and how to treat that information. It's always more complicated than it initially seems to be.
Reference:
Munshi, NC, et al, "Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis," JAMA Oncology, Sep 15, 2016 (full text of article)
Abstract:
Importance: Numerous studies have evaluated the prognostic value of minimal residual disease (MRD) in patients with multiple myeloma (multiple myeloma). Most studies were small and varied in terms of patient population, treatment, and MRD assessment methods.
Objective: To evaluate the utility of MRD detection in patients with newly diagnosed multiple myeloma.
Data Sources: A Medline search was conducted for articles published in English between January 1990 and January 2016.
Study Selection: Eligible studies reported MRD status and progression-free survival (PFS) or overall survival (OS) in 20 or more patients following treatment. Among 405 articles identified, 21 met the initial eligibility criteria and were included in the analysis.
Data Extraction and Synthesis: Information on patient characteristics, treatment, MRD assessment, and outcomes were extracted using a standard form.
Main Outcomes and Measures: The impact of MRD status on PFS and OS was assessed by pooling data from relevant trials. Data were adjusted to allow for different proportions of patients with MRD in different studies, and analyzed using the Peto method. Forest plots were created based on Cox model analysis. Other prespecified research questions were addressed qualitatively.
Results: Fourteen studies (n = 1273) provided data on the impact of MRD on PFS, and 12 studies (n = 1100) on OS. Results were reported specifically in patients who had achieved conventional complete response (CR) in 5 studies for PFS (n = 574) and 6 studies for OS (n = 616). An MRD-negative status was associated with significantly better PFS overall (hazard ratio [HR], 0.41; 95% CI, 0.36-0.48; P < .001) and in studies specifically looking at CR patients (HR, 0.44; 95% CI, 0.34-0.56; P < .001). Overall survival was also favorable in MRD-negative patients overall (HR, 0.57; 95% CI, 0.46-0.71; P < .001) and in CR patients (HR, 0.47; 95% CI, 0.33-0.67; P < .001). Tests of heterogeneity found no significant differences among the studies for PFS and OS.
Conclusions and Relevance: Minimal residual disease-negative status after treatment for newly diagnosed multiple myeloma is associated with long-term survival. These findings provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of multiple myeloma.
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Mike F - Name: Mike F
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: May 18, 2012
- Age at diagnosis: 53
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