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Speed of response to treatment
In the Revlimid maintenance article today it mentions that more aggressive disease responds faster to treatment but relapses faster. Does this mean even if your cytogenetics are for low risk disease your prognosis is worse if you respond quickly to treatment??
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blair77 - Who do you know with myeloma?: My husband
- When were you/they diagnosed?: April 2013
- Age at diagnosis: 43
Re: Speed of response to treatment
I read the article and it sounds like patients were given only Revlimid and dex during the study. So I'm assuming that for anyone taking something in addition to Revlimid and dex, the same conclusions could not be made. So for example, if someone took Revlimid, dex and Velcade there wouldn't be any way to draw the same conclusions. Any ideas on this?
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DallasGG - Name: Kent
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: 6/20/2013
- Age at diagnosis: 56
Re: Speed of response to treatment
Hi blair77,
Going to CR early in disease course is definitely NOT a bad sign. I think you read more into that retrospective study than what was there. It is a well established principle in myeloma and other blood cancers that patients that go to CR early in disease course and than lose it sooner than most patients have a poor prognosis. That does not mean that everyone/majority that gets an early CR will lose it early. The best outcomes in myeloma come from patients that attain an early CR and than maintain it for a long period. Another group of patients that can do very well in myeloma are patients that are low risk (had MGUS/smoldering) disease that goes back to a MGUS like state that never achieve CR. Those patients can be slow responders to therapy. UAMS showed this in some of their Total Therapy trials.
"Superseding the adverse effects of cytogenetic abnormalities and other standard prognostic parameters, both failure to achieve CR (non-CR) and, especially, loss of CR (los-CR) were independently associated with inferior survival in TT1, TT2, and TT3 protocols. In the context of gene array–defined risk, available in TT2 and TT3 subsets, both los-CR and non-CR terms were retained in the survival model as dominant adverse variables, stressing the prognostic importance of sustaining CR status, especially in high-risk disease."
"In addressing the fallacies of CR,7 we noted that a fraction of 10-year survivors had never achieved CR,8 which was attributed to myeloma evolving from a smoldering phase9 or having gene expression profiling (GEP) characteristics of monoclonal gammopathy of undetermined significance (MGUS).10 Conversely, high CR rates, especially in GEP-defined high-risk myeloma, were critical to extended survival.11 In the context of TT2, the median survival of the 15% with high-risk myeloma was only 2 years as opposed to longer than 10 years in the remainder.12 Sustaining CR status for at least 3 years (sus-CR) was associated with superior survival versus not achieving CR (non-CR) and especially attaining and losing CR (los-CR)."
"Figure 1 depicts survival outcomes according to CR categories from a 3-year landmark after initiation of TT1 (Figure 1A), TT2 (Figure 1B), and TT3 protocols (Figure 1C). In all 3 trials, survival was particularly poor in the los-CR category, and non-CR was significantly inferior to sus-CR in TT2 and TT3."
"We have previously addressed the issue of prognostic implications of CR in myeloma. CR was not critical to the outcomes of patients with a documented preceding course of smoldering disease25 or with an MGUS-like GEP signature,18 but was of great prognostic importance in the setting of GEP-defined high-risk myeloma.11 The topic was also the subject of 2 Inside Blood commentaries7,26 and a letter to the editor of Leukemia.27 Here we have addressed, for the first time, the importance not only of attaining CR per se but also the issues of timing of onset and duration of CR. Applying time-dependent variable methodology permitted the inclusion of all trial subjects. Independent of traditional prognostic baseline parameters (CA, LDH, B2M, albumin) and even GEP-defined high-risk designation, SUVIVAL WAS DOMINANTLY FAVORABLY AFFECTED BOTH BY ACHIEVING CR EARLY IN THE TREATMENT COURSE AND BY SUSTAINING SUCH STATUS FOR PROLONGED TIME DURATIONS."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727409/
I hope that helps put your mind at ease.
Mark
Going to CR early in disease course is definitely NOT a bad sign. I think you read more into that retrospective study than what was there. It is a well established principle in myeloma and other blood cancers that patients that go to CR early in disease course and than lose it sooner than most patients have a poor prognosis. That does not mean that everyone/majority that gets an early CR will lose it early. The best outcomes in myeloma come from patients that attain an early CR and than maintain it for a long period. Another group of patients that can do very well in myeloma are patients that are low risk (had MGUS/smoldering) disease that goes back to a MGUS like state that never achieve CR. Those patients can be slow responders to therapy. UAMS showed this in some of their Total Therapy trials.
"Superseding the adverse effects of cytogenetic abnormalities and other standard prognostic parameters, both failure to achieve CR (non-CR) and, especially, loss of CR (los-CR) were independently associated with inferior survival in TT1, TT2, and TT3 protocols. In the context of gene array–defined risk, available in TT2 and TT3 subsets, both los-CR and non-CR terms were retained in the survival model as dominant adverse variables, stressing the prognostic importance of sustaining CR status, especially in high-risk disease."
"In addressing the fallacies of CR,7 we noted that a fraction of 10-year survivors had never achieved CR,8 which was attributed to myeloma evolving from a smoldering phase9 or having gene expression profiling (GEP) characteristics of monoclonal gammopathy of undetermined significance (MGUS).10 Conversely, high CR rates, especially in GEP-defined high-risk myeloma, were critical to extended survival.11 In the context of TT2, the median survival of the 15% with high-risk myeloma was only 2 years as opposed to longer than 10 years in the remainder.12 Sustaining CR status for at least 3 years (sus-CR) was associated with superior survival versus not achieving CR (non-CR) and especially attaining and losing CR (los-CR)."
"Figure 1 depicts survival outcomes according to CR categories from a 3-year landmark after initiation of TT1 (Figure 1A), TT2 (Figure 1B), and TT3 protocols (Figure 1C). In all 3 trials, survival was particularly poor in the los-CR category, and non-CR was significantly inferior to sus-CR in TT2 and TT3."
"We have previously addressed the issue of prognostic implications of CR in myeloma. CR was not critical to the outcomes of patients with a documented preceding course of smoldering disease25 or with an MGUS-like GEP signature,18 but was of great prognostic importance in the setting of GEP-defined high-risk myeloma.11 The topic was also the subject of 2 Inside Blood commentaries7,26 and a letter to the editor of Leukemia.27 Here we have addressed, for the first time, the importance not only of attaining CR per se but also the issues of timing of onset and duration of CR. Applying time-dependent variable methodology permitted the inclusion of all trial subjects. Independent of traditional prognostic baseline parameters (CA, LDH, B2M, albumin) and even GEP-defined high-risk designation, SUVIVAL WAS DOMINANTLY FAVORABLY AFFECTED BOTH BY ACHIEVING CR EARLY IN THE TREATMENT COURSE AND BY SUSTAINING SUCH STATUS FOR PROLONGED TIME DURATIONS."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727409/
I hope that helps put your mind at ease.
Mark
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Mark
Re: Speed of response to treatment
Thanks Mark!!! This information helped ALOT!!!
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blair77 - Who do you know with myeloma?: My husband
- When were you/they diagnosed?: April 2013
- Age at diagnosis: 43
Re: Speed of response to treatment
Hi blair77,
I forgot to mention another study I had seen recently. It is a retrospective study so it does not carry the significance of a randomized trial. It is in the era of "old drugs" - no IMIDs or proteasome inhibitors (Velcade, Kyprolis). The patients received VAD induction and an auto. It really shows how important a CR is in myeloma. Only 19% of the patients got to CR so this stat only applies to a small percentage of the patients. PFS is progression free survival, meaning no relapse, and OS is overall survival meaning that the patient is still alive.
"Responses were clustered in 3 main categories, ie, CR, nCR + VGPR + PR, and SD. The respective 10-year PFS and OS values were 58% and 70% for CR, 15% and 18% for nCR + VGPR + PR, and 0% and 0% for SD."
"The achievement of depth and prolonged response represents the most important prognostic factor. The relapse rate is low for patients in CR after 10 years of follow-up, possibly signifying a cure."
http://www.ncbi.nlm.nih.gov/pubmed/24417912
A 10 year Progression Free Survival rate of 58% is outstanding. That is with no maintenance. Definitely gives some hope for standard risk patients that attain CR status after an auto.
Mark
I forgot to mention another study I had seen recently. It is a retrospective study so it does not carry the significance of a randomized trial. It is in the era of "old drugs" - no IMIDs or proteasome inhibitors (Velcade, Kyprolis). The patients received VAD induction and an auto. It really shows how important a CR is in myeloma. Only 19% of the patients got to CR so this stat only applies to a small percentage of the patients. PFS is progression free survival, meaning no relapse, and OS is overall survival meaning that the patient is still alive.
"Responses were clustered in 3 main categories, ie, CR, nCR + VGPR + PR, and SD. The respective 10-year PFS and OS values were 58% and 70% for CR, 15% and 18% for nCR + VGPR + PR, and 0% and 0% for SD."
"The achievement of depth and prolonged response represents the most important prognostic factor. The relapse rate is low for patients in CR after 10 years of follow-up, possibly signifying a cure."
http://www.ncbi.nlm.nih.gov/pubmed/24417912
A 10 year Progression Free Survival rate of 58% is outstanding. That is with no maintenance. Definitely gives some hope for standard risk patients that attain CR status after an auto.
Mark
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Mark
Re: Speed of response to treatment
Hi Blair,
Thanks for your question. We're glad you asked, because we agree that the information in the article about speed of response is certainly worth discussing/pursuing further. That's one reason we highlighted it at the beginning of the article.
We're going to focus for now for passing along exactly what the authors said about this point in their article, and the references they gave as a basis for what they said.
This should allow some of the others to poke around in the references and report back what they find. We can then decide whether it's worth pursuing further.
Before we do anything else, however, we do want to agree with Mark that study after study has demonstrated that depth of response is a key predictor of how long a myeloma patient is likely to stay in remission after treatment.
On average, newly diagnosed patients who achieve a complete response have longer remissions than patients who achieve, say, a partial response.
That doesn't mean that a patient who achieves a partial response can't have an extremely extended remission. Remember, we're talking averages. Each patient is unique.
That said, the authors of the paper covered in our news article write the following:
"previous observations ... suggest that chemosensitive plasma cell clones tend to behave more aggressively in that, although they respond faster to treatment, they are also more likely to relapse earlier"
The two references they give as support for this statement are the following:
"High serum-free light chain levels and their rapid reduction in response to therapy
define an aggressive multiple myeloma subtype with poor prognosis", Blood, 2007
http://bloodjournal.hematologylibrary.org/content/110/3/827.full.pdf (full text), and
"Early responder myeloma: kinetic studies identify a patient subgroup characterized by very poor prognosis", Journal of Clinical Oncology, 1989
http://jco.ascopubs.org/content/7/1/119.abstract (abstract only)
We'll note straight off the bat that the second study is quite old, from a time when novel myeloma treatments, such as Revlimid and Velcade, were not yet available. So one can raise questions about how relevant its results are.
Why don't we all look these papers over and see if we can come up with any additional insights relevant to your (Blair's) question?
Perhaps there are other papers out there that we can find that bear on the issue?
One thing to bear in mind, however. The statement in the original paper is about time to best response. This is a somewhat different concept than speed of response, at least as myeloma specialists usually think of it.
As best we can tell, "speed of response" usually refers to how quickly a patient's M-spike declines in response to treatment.
This is likely to be related to time to best response, but they are not completely identical concepts.
One patient's M-spike might decline very quickly and achieve best response in a short time.
Another patient's M-spike might decline basically just as quickly at first, but continue declining a bit further, so that patient's time to best response would be longer than the first patient's.
In any case ... thanks again for the question Blair!
Thanks for your question. We're glad you asked, because we agree that the information in the article about speed of response is certainly worth discussing/pursuing further. That's one reason we highlighted it at the beginning of the article.
We're going to focus for now for passing along exactly what the authors said about this point in their article, and the references they gave as a basis for what they said.
This should allow some of the others to poke around in the references and report back what they find. We can then decide whether it's worth pursuing further.
Before we do anything else, however, we do want to agree with Mark that study after study has demonstrated that depth of response is a key predictor of how long a myeloma patient is likely to stay in remission after treatment.
On average, newly diagnosed patients who achieve a complete response have longer remissions than patients who achieve, say, a partial response.
That doesn't mean that a patient who achieves a partial response can't have an extremely extended remission. Remember, we're talking averages. Each patient is unique.
That said, the authors of the paper covered in our news article write the following:
"previous observations ... suggest that chemosensitive plasma cell clones tend to behave more aggressively in that, although they respond faster to treatment, they are also more likely to relapse earlier"
The two references they give as support for this statement are the following:
"High serum-free light chain levels and their rapid reduction in response to therapy
define an aggressive multiple myeloma subtype with poor prognosis", Blood, 2007
http://bloodjournal.hematologylibrary.org/content/110/3/827.full.pdf (full text), and
"Early responder myeloma: kinetic studies identify a patient subgroup characterized by very poor prognosis", Journal of Clinical Oncology, 1989
http://jco.ascopubs.org/content/7/1/119.abstract (abstract only)
We'll note straight off the bat that the second study is quite old, from a time when novel myeloma treatments, such as Revlimid and Velcade, were not yet available. So one can raise questions about how relevant its results are.
Why don't we all look these papers over and see if we can come up with any additional insights relevant to your (Blair's) question?
Perhaps there are other papers out there that we can find that bear on the issue?
One thing to bear in mind, however. The statement in the original paper is about time to best response. This is a somewhat different concept than speed of response, at least as myeloma specialists usually think of it.
As best we can tell, "speed of response" usually refers to how quickly a patient's M-spike declines in response to treatment.
This is likely to be related to time to best response, but they are not completely identical concepts.
One patient's M-spike might decline very quickly and achieve best response in a short time.
Another patient's M-spike might decline basically just as quickly at first, but continue declining a bit further, so that patient's time to best response would be longer than the first patient's.
In any case ... thanks again for the question Blair!
Re: Speed of response to treatment
I read the more recent study, in Blood 2007, and my reaction is that the results are extraordinarily nuanced in a way that makes generalizations dangerous. For example, just take a look at Figure 3 and you will see that that the results are, at least in part, influenced by how high the the light chains were at diagnosis.
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goldmine848 - Name: Andrew
- When were you/they diagnosed?: June 2013
- Age at diagnosis: 60
Re: Speed of response to treatment
I think it's worthwhile to bring up Dr. Rajkumar's earlier cautions wrt interpreting the importance of CR in these earlier studies...
https://myelomabeacon.org/news/2013/08/10/complete-response-multiple-myeloma-treatment/
https://myelomabeacon.org/news/2013/08/10/complete-response-multiple-myeloma-treatment/
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
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