For those interested, here is an update with long-term follow up from the Arkansas (UAMS) Total Therapy trials. I only have access to the abstract and I was a bit confused by what the stats were showing, so I was hoping someone could help me out. Here is the abstract:
B Barlogie et al, "Curing myeloma at last: defining criteria and providing the evidence," Blood, Oct 7, 2014.
Abstract:
"We examine whether the historical dogma of multiple myeloma being incurable still holds true. The genomic chaos and resulting resistance to apoptosis of myeloma, long considered an obstacle to cure, formed the basis of the Arkansas Total Therapy (TT) program. The TT approach employs all myeloma-active drugs up-front to target drug-resistant sub-clones during initial treatment to prevent later relapse.
Long-term follow up of altogether 1202 patients enrolled (TT1: n=231, median follow up: 21yr; TT2: 668, median follow up: 12yr; TT3a: n=303, median follow up: 9yr) permitted investigation of whether progression-free survival (PFS) and complete response (CR) duration were consistent with curability, i.e. observation of plateaus in Kaplan-Meier plots for PFS and CR duration.
In the subset of 627 patients with plasma cell gene expression profiling data, cure plateaus were apparent at 5 years in the 14% with high-risk myeloma compared to 10 years in the remainder with low-risk disease.
A parametric model based on PFS and CR duration supported an increase in curability with successive trials. Thus, 10-yr PFS and CR estimates increased from 8.8% / 17.9% in TT1 to 15.5% / 28.2% in TT2's control arm to 25.1% / 35.6% in TT2's thalidomide arm and to 32.9 / 48.8% in TT3a.
Toward developing novel therapies, we recommend a concerted focus on patients with high-risk myeloma whose outcome has not been advanced."
> Here's my question:
Using TT3a, for example, it shows 10 year PFS as 32.9% and CR estimate at 48.8%. Does that mean that 48.8% got to CR and that 32.9% of those patients held CR for 10 years?
For example, if 100 patients did TT3a, 48 got to CR and a third of those (16 patients) held CR for 10 years. Or is it saying something else entirely?
Thanks in advance for any help. Maybe it is clearer with full access to the article.
Mark
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Re: Latest Total Therapy long-term survival results
Hi Mark-
I read the article yesterday. I saw your post but was hoping someone else would chime in as I'm still trying to really understand some aspects of it. There is an awful lot of information in there. The best I can do to summarize a few key points (which is fairly lame) is as follows:
I will be very curious to hear the response to this from the rest of the doctors and researchers in the field.
I read the article yesterday. I saw your post but was hoping someone else would chime in as I'm still trying to really understand some aspects of it. There is an awful lot of information in there. The best I can do to summarize a few key points (which is fairly lame) is as follows:
- Each evolution of the Total Therapy procedure has resulted in improved complete remission and progression free survival stats. No surprise there.
- The numbers referred to in the abstract (which you mention in your post) represent the "progression-free survival cure-fraction estimates" and the "complete response duration cure-fraction estimates.
As mentioned in the abstract, the "cure" percentage refers to a point at which the Kaplan-Meier survival curves plateau, meaning that there's a certain percentage of patients who just keep going with no disease progression or who maintain complete response. (I think. There is a fair amount of statistical stuff in the article that's beyond me).
So I guess those percentages refer to the percentage of patients who can be expected to live the rest of their lives with in complete response or with no disease progression.
I don't understand why the PFS percentage is lower than the Complete Response Duration (CRD) percentage. It seems to me that the former should include the latter plus others, but there's n = 303 for the PFS number and n = 189 for the CRD number, so there's something going on there that I'm clearly missing. They make the point that a minimum ten year followup is needed to develop these statistics.
- High risk myeloma is a different beast from standard and low risk and the Total Therapy approach has yet to be as successful with it. The overall cure rates based on CRD at baseline and at 5 years after were 50 and 75% for TT3a, but only 15% at 5 years for high risk patients.
- They believe that melphalan conditioning with stem cell transplant(s) is still the best approach and urge caution with the idea that we can just go with novel agent therapy to start. That seems to apply whether you're going with the Total Therapy approach or not.
- They believe that better "surrogate endpoints" for cure are needed, particularly for low risk patients. They list a couple of potential techniques for this, including flow cytometry combined with genetic expression profiling of bone marrow cells and micro-RNA analysis in blood.
I will be very curious to hear the response to this from the rest of the doctors and researchers in the field.
-
Mike F - Name: Mike F
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: May 18, 2012
- Age at diagnosis: 53
Re: Latest Total Therapy long-term survival results
Hi Mike F,
Thanks for the info.
I might (and I stress might!) have figured out what they are referring to based on your post. I had seen in a previous abstract that 62% of patients in Total Therapy 3 had got to CR. See Figure C at this link.
"I don't understand why the PFS percentage is lower than the Complete Response Duration (CRD) percentage. It seems to me that the former should include the latter plus others, but there's n = 303 for the PFS number and n = 189 for the CRD number, so there's something going on there that I'm clearly missing."
189 divided by 303 is 62.3%.
For Total Therapy 3A, the 48.8% in the abstract is the complete response duration (189 patients that achieved a complete response and are expected to hold it for 10 years). The 32.9% refers to the progression free survival of the entire group (303), including the 38% that did not get to CR.
Instead of what I originally thought in my post above, maybe the number of patients for every 100 patients doing Total Therapy 3A that get to CR and maintain it for 10 years would be more like 30-31. It would be 62 (62% CR rate) times the 48.8% complete response duration equals 30.25.
I did not take into account the 14% of high risk patients, so the number per 100 of standard risk patients would be a little higher than 30-31.
It would have been a lot easier for us if they just gave a percentage like they did for the high risk patients. Hopefully I was accurate on that.
If anyone else has any ideas or read the paper, I think it could be beneficial for a newly diagnosed standard risk patient to know what their chance of 10 year plus progression free survival if they did a Total Therapy type treatment plan.
Mark
Thanks for the info.
I might (and I stress might!) have figured out what they are referring to based on your post. I had seen in a previous abstract that 62% of patients in Total Therapy 3 had got to CR. See Figure C at this link.
"I don't understand why the PFS percentage is lower than the Complete Response Duration (CRD) percentage. It seems to me that the former should include the latter plus others, but there's n = 303 for the PFS number and n = 189 for the CRD number, so there's something going on there that I'm clearly missing."
189 divided by 303 is 62.3%.
For Total Therapy 3A, the 48.8% in the abstract is the complete response duration (189 patients that achieved a complete response and are expected to hold it for 10 years). The 32.9% refers to the progression free survival of the entire group (303), including the 38% that did not get to CR.
Instead of what I originally thought in my post above, maybe the number of patients for every 100 patients doing Total Therapy 3A that get to CR and maintain it for 10 years would be more like 30-31. It would be 62 (62% CR rate) times the 48.8% complete response duration equals 30.25.
I did not take into account the 14% of high risk patients, so the number per 100 of standard risk patients would be a little higher than 30-31.
It would have been a lot easier for us if they just gave a percentage like they did for the high risk patients. Hopefully I was accurate on that.
If anyone else has any ideas or read the paper, I think it could be beneficial for a newly diagnosed standard risk patient to know what their chance of 10 year plus progression free survival if they did a Total Therapy type treatment plan.
Mark
-
Mark11
Re: Latest Total Therapy long-term survival results
Yeah, that makes sense, Mark. Thanks.
As I said, it will be interesting to see how the rest of the community of doctors and researchers responds to this. It would also be interesting to know if anyone else has this level of data on patients from a single institution using other types of therapy. As you say, this kind of info is good stuff for newly diagnosed patients.
As I said, it will be interesting to see how the rest of the community of doctors and researchers responds to this. It would also be interesting to know if anyone else has this level of data on patients from a single institution using other types of therapy. As you say, this kind of info is good stuff for newly diagnosed patients.
-
Mike F - Name: Mike F
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: May 18, 2012
- Age at diagnosis: 53
Re: Latest Total Therapy long-term survival results
For those interested here is a link to the full paper.
http://m.bloodjournal.org/content/124/20/3043.full
If reading this paper I think it is good to read Dr. Morgan's excellent Beacon column again. The information compliments what is in the paper and he is a co-author of the paper above.
https://myelomabeacon.org/news/2014/11/03/evolution-intra-clonal-heterogeneity-multiple-myeloma/
Some points that I thought were important in the paper. This is not unexpected, but post relapse survival is shorter when using more agents as part of upfront therapy.
"Thus, although increased use of all available therapeutic tools upfront shortened postrelapse survival, the gap between OS and PFS narrowed toward increasing cure fractions."
This point has been mentioned before but I think it is worth noting again. Patients on TT that do not achieve CR do not necessarily have worse outcomes than those that get to CR. There are long term survivors that do not achieve CR. Poor outcomes tend to come from those that attain an early CR and lose it within 3 years.
"Although most investigators consider CR a prerequisite for long-term PFS and cure,46⇓⇓⇓⇓⇓-52 we reported previously that PFS and OS were not compromised by lack of CR in patients with documented preceding AMM53 and those with MGUS-like CMM based on GEP.54,55 However, CR was crucial for long-term PFS and OS in high-risk CMM.56 We also addressed the importance of a critical duration of CR for PFS durability.57 Best outcomes were observed when CR was sustained beyond a 3-year landmark. Those failing to achieve CR but remaining progression-free during this time frame fared better than patients attaining and losing CR. With long-term follow-up available in TT1 and TT2 trials, we examined the role of CR for long-term prognosis from a 2-year landmark (Figure 6). Although PFS was superior in patients remaining in CR at 2 years, plateaus were also apparent among non-CR patients. Thus, although a critical early event in terms of the degree of tumor mass reduction, CR is not essential for long-term disease control in all cases."
CMM stands for clinical multiple myeloma. This paragraph discuses using metronomic therapy for high risk patients. Metronomic therapy is using much lower doses of therapy for longer periods/more often. Total therapy type of approaches for myeloma tend to be more effective for standard risk patients as opposed to high risk patients.
"Our data show that for patients with high-risk CMM, novel therapies are needed. Even with TT approaches, median PFS of these patients is only 2 years although a small cure fraction of ∼15% does emerge at 5 years. Work is in progress to determine whether earlier disease progression in high-risk CMM may be linked to a lower depth of CR as judged by sensitive MRD detection strategies.
In reflecting on the failure of our TT approach to advance clinical outcomes in high-risk multiple myeloma, we considered the role of “cytokine storms” ensuing after chemotherapy or autologous transplants for steady-state normal hematopoiesis to be established. By exerting stimulatory effects also on multiple myeloma cells, such cytokine release may contribute to multiple myeloma survival and disease escape. Our recently published metronomic therapy using low doses of cytotoxic agents (doxorubicin, cisplatin) in combination with bortezomib, thalidomide, and dexamethasone was exquisitely devoid of bone marrow toxicity.64 Extending treatment to 28 days, we offered such therapy to 10 transplant-ineligible newly diagnosed patients with high-risk CMM. Treatment was well tolerated and brought about CR in 5 patients at the conclusion of 1 cycle, lasting unmaintained for up to 8 months (B.B., unpublished observations). In light of poor outcomes in high-risk CMM, we are following 1-cycle CR patients closely to determine the length of benefit and especially whether “downgrading” from GEP-defined high to low risk can be demonstrated."
I do agree with this point.
"Recent trials with novel agent combinations have achieved high CR rates comparable to those previously reported only with transplants.18 The quality of comparable rates of CR effectuated by different treatment approaches can be judged by their durability after cessation of treatment."
Interesting paper. While I do not agree with all of it and I am relying on/a believer in immunotherapy as opposed to drugs, I think this paper is a worthwhile read for a newly diagnosed patient making a decision on what type of therapy route to pursue.
http://m.bloodjournal.org/content/124/20/3043.full
If reading this paper I think it is good to read Dr. Morgan's excellent Beacon column again. The information compliments what is in the paper and he is a co-author of the paper above.
https://myelomabeacon.org/news/2014/11/03/evolution-intra-clonal-heterogeneity-multiple-myeloma/
Some points that I thought were important in the paper. This is not unexpected, but post relapse survival is shorter when using more agents as part of upfront therapy.
"Thus, although increased use of all available therapeutic tools upfront shortened postrelapse survival, the gap between OS and PFS narrowed toward increasing cure fractions."
This point has been mentioned before but I think it is worth noting again. Patients on TT that do not achieve CR do not necessarily have worse outcomes than those that get to CR. There are long term survivors that do not achieve CR. Poor outcomes tend to come from those that attain an early CR and lose it within 3 years.
"Although most investigators consider CR a prerequisite for long-term PFS and cure,46⇓⇓⇓⇓⇓-52 we reported previously that PFS and OS were not compromised by lack of CR in patients with documented preceding AMM53 and those with MGUS-like CMM based on GEP.54,55 However, CR was crucial for long-term PFS and OS in high-risk CMM.56 We also addressed the importance of a critical duration of CR for PFS durability.57 Best outcomes were observed when CR was sustained beyond a 3-year landmark. Those failing to achieve CR but remaining progression-free during this time frame fared better than patients attaining and losing CR. With long-term follow-up available in TT1 and TT2 trials, we examined the role of CR for long-term prognosis from a 2-year landmark (Figure 6). Although PFS was superior in patients remaining in CR at 2 years, plateaus were also apparent among non-CR patients. Thus, although a critical early event in terms of the degree of tumor mass reduction, CR is not essential for long-term disease control in all cases."
CMM stands for clinical multiple myeloma. This paragraph discuses using metronomic therapy for high risk patients. Metronomic therapy is using much lower doses of therapy for longer periods/more often. Total therapy type of approaches for myeloma tend to be more effective for standard risk patients as opposed to high risk patients.
"Our data show that for patients with high-risk CMM, novel therapies are needed. Even with TT approaches, median PFS of these patients is only 2 years although a small cure fraction of ∼15% does emerge at 5 years. Work is in progress to determine whether earlier disease progression in high-risk CMM may be linked to a lower depth of CR as judged by sensitive MRD detection strategies.
In reflecting on the failure of our TT approach to advance clinical outcomes in high-risk multiple myeloma, we considered the role of “cytokine storms” ensuing after chemotherapy or autologous transplants for steady-state normal hematopoiesis to be established. By exerting stimulatory effects also on multiple myeloma cells, such cytokine release may contribute to multiple myeloma survival and disease escape. Our recently published metronomic therapy using low doses of cytotoxic agents (doxorubicin, cisplatin) in combination with bortezomib, thalidomide, and dexamethasone was exquisitely devoid of bone marrow toxicity.64 Extending treatment to 28 days, we offered such therapy to 10 transplant-ineligible newly diagnosed patients with high-risk CMM. Treatment was well tolerated and brought about CR in 5 patients at the conclusion of 1 cycle, lasting unmaintained for up to 8 months (B.B., unpublished observations). In light of poor outcomes in high-risk CMM, we are following 1-cycle CR patients closely to determine the length of benefit and especially whether “downgrading” from GEP-defined high to low risk can be demonstrated."
I do agree with this point.
"Recent trials with novel agent combinations have achieved high CR rates comparable to those previously reported only with transplants.18 The quality of comparable rates of CR effectuated by different treatment approaches can be judged by their durability after cessation of treatment."
Interesting paper. While I do not agree with all of it and I am relying on/a believer in immunotherapy as opposed to drugs, I think this paper is a worthwhile read for a newly diagnosed patient making a decision on what type of therapy route to pursue.
-
Mark11
Re: Latest Total Therapy long-term survival results
Thanks, Mark, for your initial post and link to the paper. And thanks, Mike F, for your summary of the paper.
Sounds like important reading. Especially if they are claiming the multiple myeloma is now "curable." That raises the question, of course: how will we really know when multiple myeloma is a curable disease? Is there any standard metric that is applied in the medical profession for "curable"?
I now have some weekend reading material.
Mike B
Sounds like important reading. Especially if they are claiming the multiple myeloma is now "curable." That raises the question, of course: how will we really know when multiple myeloma is a curable disease? Is there any standard metric that is applied in the medical profession for "curable"?
I now have some weekend reading material.
Mike B
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mikeb - Name: mikeb
- Who do you know with myeloma?: self
- When were you/they diagnosed?: 2009 (MGUS at that time)
- Age at diagnosis: 55
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