Hi Gary,
Did you actually read the paper Dr. Mehta took the time to write? If you had you would not have made such an obvious error in your analysis of the “total therapy 2” clinical trial.
You wrote:
“How do we define CURE? What total death rate would be considered cure? Using the death rate as a measure, how might we definition cure? If I were to have a go at it, I would say that it might be if the average myeloma patient lives as long or longer than the average American of the same age. So if you were at the age of the average myeloma patient or 70 years of age, you would want to live another 16 years to 86, as calculated by the Social Security actuarial death rate tables. The table of deaths for the UAMS TT2 multiple myeloma protocol that is being discussed here is for 12 years and is as follows:”
Why would you compare the patients in TT2 to 70 year olds? In Dr. Mehta’s well written analysis on page 11 he gave us information about the patients in the TT2 trial.
“Figure 3 is important in refuting natural causes related to old age as a possible explanation for unknown deaths: Deaths related to old age would be expected to be uncommon early on, and would increase with time. In contrast, as the orange curve in the figure shows, deaths from “unknown” causes are spread evenly over time in TT2. Additionally, only 20% of TT2 patients were aged 65 years or more; a proportion that is not sufficient to account for deaths from old age.”
One of the main points of Dr. Mehta’s paper was:
“If a death occurring as a result of cancer is misclassified as being from “unknown”causes, it makes the treatment seem more effective by making the failure rate of the treatment appear lower than it is. If a death occurring as a result of adverse effects of the treatment is misclassified as being from “unknown” causes, it makes the treatment seem safer by making the serious toxicity rate of the treatment to be small.”
Thanks for showing us another way to use statistics to make a therapy seem safer and more effective than it may really be!
Mark
Forums
Re: Report on Myeloma Trials at UAMS / Arkansas
Hi Mark!
Your write:
One of the main points of Dr. Mehta’s paper was:
“If a death occurring as a result of cancer is misclassified as being from “unknown”causes, it makes the treatment seem more effective by making the failure rate of the treatment appear lower than it is. If a death occurring as a result of adverse effects of the treatment is misclassified as being from “unknown” causes, it makes the treatment seem safer by making the serious toxicity rate of the treatment to be small.”
Precisely!!
Your write:
One of the main points of Dr. Mehta’s paper was:
“If a death occurring as a result of cancer is misclassified as being from “unknown”causes, it makes the treatment seem more effective by making the failure rate of the treatment appear lower than it is. If a death occurring as a result of adverse effects of the treatment is misclassified as being from “unknown” causes, it makes the treatment seem safer by making the serious toxicity rate of the treatment to be small.”
Precisely!!
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Report on Myeloma Trials at UAMS / Arkansas
Hi Mark,
Just wanted to follow up on your commentary with the history of chemotherapy in treating multiple myeloma.
Let's look at the evolutionary history of multiple myeloma therapy to underscore the point regarding HDT:
In 1962 they use melphan and prednisone.
In 1983 they used high dose melphlan without success
Then in 1983 Barlogie introduced VAD (vincristine/adriamycin/dexamethosone) plus ASCT.
At this point there was still over 50% failure, along with high mortality, with VAD that necessitated ASCT.(TT1-2)
So, in 1986 they used hi-dose dexamethasone...still poor results.
Conventional therapeutic doses of toxic chemotherapy were unsuccessful...thus began the use of high dose chemotherapy (HDT) that required salvage/rescue ASCT, following MIRT results.
Then in 1996 Berenson used HDT and ASCT with bisphosphonates.
In 1999, we had the introduction of thalidomide and that new agent produced far better results,( higher CR) than the 30 year history of HDT, including TT1-2.
It is important to note that even though high dose chemotherapy (HDT) necessitated the ASCT, the HDT with resultant toxicity from VAD had NOT produced results (high CR rates) even with ASCT.
What this tells us is that over a 30 year period, conventional nor high dose chemotherapy which required ASCT resulted in less than 50% efficacy for multiple myeloma.
I want to repeat for emphasis, that following THIRTY years of barely effective therapy thalidomide was introduced and the results were significantly superior than the tandem HDT with ASCT.
All of which is significant clinical evidence to reasonably conclude that HDT is NOT the most effective therapeutic option, even if it is tandem, and has become standard therapy,that requires ASCT.
When we look at TT1-3 we see precisely that. TT1-2 had high failure rates. What MIRT did was simply add the new agents to the old highly toxic chemotherapy for TT3-4. IOW's throw the kitchen sink at patients of every available highly toxic chemotherapy non-specific to multiple myeloma out there with the addition of new ones. Well, we know the new agents without VAD or melphalan or cyclophosphamide ARE producing far higher rates of CR. Which is why the kitchen sink of highly toxic chemo is seriously questionable scientifically and unsubstantiated clinically as evidence of effective let alone being considered the standard of therapy!!!
All of which says, you need not undergo the most toxic chemo in order to get CR. The regimen at MIRT however, continues to include the most toxic agents despite them not having been shown to be highly efficacious. Thus, my viewpoint that the therapeutic regimen at MIRT is so toxic that you are lucky to leave ALIVE!!!
That is the issue, along with the high mortality which ensues from the use of those highly toxic agents at doses that are so high and toxic they necissitate an ASCT.
Having said that,each patient should choose therapy they believe will work for them, but let's not labor under the false impression that the MIRT regimen is somehow a 'superior' therapeutic regimen.
The data simply does not support that.
IMHO
P.S.
I would love to see the data for SPM (solid & liquid) for all those tandem HDT patients from MIRT!! I suspect it will be unacceptably high...given how high it is for those who recieve only one cycle of HDT, for non-myeloma cancers, let alone back to back HDT for myeloma as myeloma patients are the vast majority of HDT patients, despite comprising only 1% of all cancers.
Just wanted to follow up on your commentary with the history of chemotherapy in treating multiple myeloma.
Let's look at the evolutionary history of multiple myeloma therapy to underscore the point regarding HDT:
In 1962 they use melphan and prednisone.
In 1983 they used high dose melphlan without success
Then in 1983 Barlogie introduced VAD (vincristine/adriamycin/dexamethosone) plus ASCT.
At this point there was still over 50% failure, along with high mortality, with VAD that necessitated ASCT.(TT1-2)
So, in 1986 they used hi-dose dexamethasone...still poor results.
Conventional therapeutic doses of toxic chemotherapy were unsuccessful...thus began the use of high dose chemotherapy (HDT) that required salvage/rescue ASCT, following MIRT results.
Then in 1996 Berenson used HDT and ASCT with bisphosphonates.
In 1999, we had the introduction of thalidomide and that new agent produced far better results,( higher CR) than the 30 year history of HDT, including TT1-2.
It is important to note that even though high dose chemotherapy (HDT) necessitated the ASCT, the HDT with resultant toxicity from VAD had NOT produced results (high CR rates) even with ASCT.
What this tells us is that over a 30 year period, conventional nor high dose chemotherapy which required ASCT resulted in less than 50% efficacy for multiple myeloma.
I want to repeat for emphasis, that following THIRTY years of barely effective therapy thalidomide was introduced and the results were significantly superior than the tandem HDT with ASCT.
All of which is significant clinical evidence to reasonably conclude that HDT is NOT the most effective therapeutic option, even if it is tandem, and has become standard therapy,that requires ASCT.
When we look at TT1-3 we see precisely that. TT1-2 had high failure rates. What MIRT did was simply add the new agents to the old highly toxic chemotherapy for TT3-4. IOW's throw the kitchen sink at patients of every available highly toxic chemotherapy non-specific to multiple myeloma out there with the addition of new ones. Well, we know the new agents without VAD or melphalan or cyclophosphamide ARE producing far higher rates of CR. Which is why the kitchen sink of highly toxic chemo is seriously questionable scientifically and unsubstantiated clinically as evidence of effective let alone being considered the standard of therapy!!!
All of which says, you need not undergo the most toxic chemo in order to get CR. The regimen at MIRT however, continues to include the most toxic agents despite them not having been shown to be highly efficacious. Thus, my viewpoint that the therapeutic regimen at MIRT is so toxic that you are lucky to leave ALIVE!!!
That is the issue, along with the high mortality which ensues from the use of those highly toxic agents at doses that are so high and toxic they necissitate an ASCT.
Having said that,each patient should choose therapy they believe will work for them, but let's not labor under the false impression that the MIRT regimen is somehow a 'superior' therapeutic regimen.
The data simply does not support that.
IMHO
P.S.
I would love to see the data for SPM (solid & liquid) for all those tandem HDT patients from MIRT!! I suspect it will be unacceptably high...given how high it is for those who recieve only one cycle of HDT, for non-myeloma cancers, let alone back to back HDT for myeloma as myeloma patients are the vast majority of HDT patients, despite comprising only 1% of all cancers.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
What is the role of high-dose therapy and autotransplantatio
Just a reminder that this is a discussion on adequate monitoring of clinical trials, and accurate and complete disclosure of trial data. It is not a debate on the utility of intensive therapy.
I am a firm believer in the utility of high-dose therapy and autotransplantation – including tandem transplantation in appropriate patients.
Here is a very short and simplified summary – as I see it:
In the pre-novel agent era:
- Single autograft better than no autograft
- Tandem autograft better than single autograft – at least in patients not achieving VGPR or better
- Overall survival same with early or late transplantation, but quality of life better with early transplantation
In the novel agent era:
- No published direct comparison of autograft versus no autograft
- The ECOG lenalidomide-dexamethasone study showed that patients who underwent an autograft (which was optional) did better in terms of overall and progression-free survival
- A Mayo Clinic presentation at ASH in 2009 showed that patients who were in CR after induction and underwent an autograft did better than those who were in CR and did not undergo an autograft
- High-risk patients fare worse than lower-risk patients irrespective of the therapy given
- High-risk patients will do better with more effective therapy (compared to high-risk patients who get less effective therapy)
- What the magical "effective therapy" is for high-risk patients remains undefined, but as far as I know, incontrovertible evidence that high-dose chemotherapy is ineffective in high-risk patients (which would be identical outcome of high-risk patients with and without transplantation) is lacking
- Novel agents can be used with good tolerance and reasonable effect in extensively pre-treated patients (e.g. after an early transplant), whereas tolerability (and effectiveness) of transplantation declines significantly with advanced disease (e.g. delayed transplantation – especially when delayed beyond second-line)
My belief is that early transplantation is beneficial in most patients aged 65 or under, some patients aged 66-70, and in selected patients over the age of 70.
I am a firm believer in the utility of high-dose therapy and autotransplantation – including tandem transplantation in appropriate patients.
Here is a very short and simplified summary – as I see it:
In the pre-novel agent era:
- Single autograft better than no autograft
- Tandem autograft better than single autograft – at least in patients not achieving VGPR or better
- Overall survival same with early or late transplantation, but quality of life better with early transplantation
In the novel agent era:
- No published direct comparison of autograft versus no autograft
- The ECOG lenalidomide-dexamethasone study showed that patients who underwent an autograft (which was optional) did better in terms of overall and progression-free survival
- A Mayo Clinic presentation at ASH in 2009 showed that patients who were in CR after induction and underwent an autograft did better than those who were in CR and did not undergo an autograft
- High-risk patients fare worse than lower-risk patients irrespective of the therapy given
- High-risk patients will do better with more effective therapy (compared to high-risk patients who get less effective therapy)
- What the magical "effective therapy" is for high-risk patients remains undefined, but as far as I know, incontrovertible evidence that high-dose chemotherapy is ineffective in high-risk patients (which would be identical outcome of high-risk patients with and without transplantation) is lacking
- Novel agents can be used with good tolerance and reasonable effect in extensively pre-treated patients (e.g. after an early transplant), whereas tolerability (and effectiveness) of transplantation declines significantly with advanced disease (e.g. delayed transplantation – especially when delayed beyond second-line)
My belief is that early transplantation is beneficial in most patients aged 65 or under, some patients aged 66-70, and in selected patients over the age of 70.
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jmehta - Name: Jayesh Mehta MD
Re: Report on Myeloma Trials at UAMS / Arkansas
Thanks, everyone, for the additional postings you've all made to this interesting -- and valuable -- discussion.
Just to repeat a point that Dr. Mehta just made: This is not a thread for debating whether or not stem cell transplantation (HDT+autologous stem cell transplant) is a beneficial therapy for multiple myeloma patients.
If you'd like to debate that point, you are free to start another thread specifically for that purpose, or add to the discussions which already have been started about stem cell transplantation. (For a list of those discussions, see here: bit.ly/QETL2e .)
All the best,
Boris.
Just to repeat a point that Dr. Mehta just made: This is not a thread for debating whether or not stem cell transplantation (HDT+autologous stem cell transplant) is a beneficial therapy for multiple myeloma patients.
If you'd like to debate that point, you are free to start another thread specifically for that purpose, or add to the discussions which already have been started about stem cell transplantation. (For a list of those discussions, see here: bit.ly/QETL2e .)
All the best,
Boris.
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Boris Simkovich - Name: Boris Simkovich
Founder
The Myeloma Beacon
Re: Report on Myeloma Trials at UAMS / Arkansas
Mark, Yes I did, and it is just noise in the BIG PICTURE of patient survival. I rest my case! Gary
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Gary P
Re: Report on Myeloma Trials at UAMS / Arkansas
Thanks Suzie and Dr. Mehta for very informative posts.
Sometimes I get so excited reading about this stuff that I forget I'm a patient and find myself thinking "I can't wait to try that". This research is very interesting. Stann
Sometimes I get so excited reading about this stuff that I forget I'm a patient and find myself thinking "I can't wait to try that". This research is very interesting. Stann
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stann
Re: Report on Myeloma Trials at UAMS / Arkansas
It is interesting that Suzierose mentions the following:
"Then in 1996 Berenson used HDT and ASCT with bisphosphonates."
Today Berenson is one of the staunchest advocates against ASCT, typically explaining that it destroys the soil in the bone marrow. And I think he has a point: I have read of many instances of patients receiving ASCT where all blood counts remain low, a problem that gets even worse if they receive another ASCT. This is also reflected in several blogs, gravely describing their marrow as a wasteland.
This also underscores a personal gripe I have: there is simply not enough appreciation of the diverse presentation of multiple myeloma. Some patients are low risk and can remain fine for years - if not decades -- with minimal treatment. In others, yes: they require drastic and intense therapy.
By what is clear is that one size does not fit all. And this endless push for ASCT personally strikes me as a scare tactic lacking any nuanced approach to a patient's individual situation. Sure: take two months off from work or retire with no money; become a full-time cancer patient; end whatever normalcy you ever had. Submit to the endless spiral of more and more drugs and then more drugs to treat the side effects of the first drugs.
We are not the test tubes of oncologists. And yet the silent mantra seems to be this: you are screwed; you are on death's door, so you better be scared and submit to whatever I say.
"Then in 1996 Berenson used HDT and ASCT with bisphosphonates."
Today Berenson is one of the staunchest advocates against ASCT, typically explaining that it destroys the soil in the bone marrow. And I think he has a point: I have read of many instances of patients receiving ASCT where all blood counts remain low, a problem that gets even worse if they receive another ASCT. This is also reflected in several blogs, gravely describing their marrow as a wasteland.
This also underscores a personal gripe I have: there is simply not enough appreciation of the diverse presentation of multiple myeloma. Some patients are low risk and can remain fine for years - if not decades -- with minimal treatment. In others, yes: they require drastic and intense therapy.
By what is clear is that one size does not fit all. And this endless push for ASCT personally strikes me as a scare tactic lacking any nuanced approach to a patient's individual situation. Sure: take two months off from work or retire with no money; become a full-time cancer patient; end whatever normalcy you ever had. Submit to the endless spiral of more and more drugs and then more drugs to treat the side effects of the first drugs.
We are not the test tubes of oncologists. And yet the silent mantra seems to be this: you are screwed; you are on death's door, so you better be scared and submit to whatever I say.
-
My Rant
Re: Report on Myeloma Trials at UAMS / Arkansas
Hi RAnt.
I agree with you.
I gave the history of HDT & mentioned Berenson to show how he evolved from the use of HDT.
thirty years later he no longer supports that therapeutic modality.
The mortality rates & how they have failed to be reported are directly related to HDT given in tandem..
The history of multiple myeloma shows that clearly. & should not be mistaken for a debate on ASCT since without HDT. Patients don't need 2 be salvage and there wouldnot be an issue about how deaths are reported.
I agree with you.
I gave the history of HDT & mentioned Berenson to show how he evolved from the use of HDT.
thirty years later he no longer supports that therapeutic modality.
The mortality rates & how they have failed to be reported are directly related to HDT given in tandem..
The history of multiple myeloma shows that clearly. & should not be mistaken for a debate on ASCT since without HDT. Patients don't need 2 be salvage and there wouldnot be an issue about how deaths are reported.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Report on Myeloma Trials at UAMS / Arkansas
Hi Dr. Mehta,
You write:
" a discussion on adequate monitoring of clinical trials, and accurate and complete disclosure of trial data. It is not a debate on the utility of intensive therapy."
While I do have the background to discuss how data is reported in clinical trials, its clear to me that how deaths are reported are highly indicative of therapeutic efficacy...thus I chose to give the history of (not debate) how HDT evolved.
As you know all things in life are connected, like the green of the leaves depending on the intensity of the sun, or the way the thigh bone is connected to the hip bone and how the blood from our marrow courses through us nourishing all cellular lifelong in our bodies...such that any discussion on the complete disclosure of deaths in a clinical trial are connected as well to the therapeutic regimen. Especially one which obliterates the very marrow that perpetuates our lives.
I also understand relative risk reduction vs absolute risk reduction and how deaths are reported clearly determine if a therapeutic regimen is an effective risk.
Such that, I truly admire your integrity and you having the courage of your convictions when it comes to disclosure of trial data being accurate and complete. I suspect many of your medical colleagues have not engaged this discussion due to the politics within the medical community regarding HDT and the tandem HDT as a staple of MIRT. While I am not in the medical community it has been made clear that challenging the rationale for such is not welcome. And when you seek to challenge how deaths have been reported in TT 1-4 it threatens the core therapeutic principles that have become 'standard therapy''... having said that,
Could you please tell me what was unsatisfactory about the response you received from Barlogie here:
https://docs.google.com/viewer?a=v&q=cache:qcNdB45fxXoJ:jco.ascopubs.org/content/29/5/e125.full.pdf+mehta+death+reports+myeloma&hl=en&gl=us&pid=bl&srcid=ADGEESh0rS0L__sPmbVv7ej4SXmUND5pMwpbxJPzH2rg2r0zfdGFKQDSKVy6v83PK3ZOH4j-xgUp31bPQI-1YnMpbz0B3MWpGKRV70An4xkZTiVgDQuDNE040DMWd8sN_2qMax9R-gz6&sig=AHIEtbRRsV2hJhRYdDDB5H78y_sWwhg-sQ
You write:
" a discussion on adequate monitoring of clinical trials, and accurate and complete disclosure of trial data. It is not a debate on the utility of intensive therapy."
While I do have the background to discuss how data is reported in clinical trials, its clear to me that how deaths are reported are highly indicative of therapeutic efficacy...thus I chose to give the history of (not debate) how HDT evolved.
As you know all things in life are connected, like the green of the leaves depending on the intensity of the sun, or the way the thigh bone is connected to the hip bone and how the blood from our marrow courses through us nourishing all cellular lifelong in our bodies...such that any discussion on the complete disclosure of deaths in a clinical trial are connected as well to the therapeutic regimen. Especially one which obliterates the very marrow that perpetuates our lives.
I also understand relative risk reduction vs absolute risk reduction and how deaths are reported clearly determine if a therapeutic regimen is an effective risk.
Such that, I truly admire your integrity and you having the courage of your convictions when it comes to disclosure of trial data being accurate and complete. I suspect many of your medical colleagues have not engaged this discussion due to the politics within the medical community regarding HDT and the tandem HDT as a staple of MIRT. While I am not in the medical community it has been made clear that challenging the rationale for such is not welcome. And when you seek to challenge how deaths have been reported in TT 1-4 it threatens the core therapeutic principles that have become 'standard therapy''... having said that,
Could you please tell me what was unsatisfactory about the response you received from Barlogie here:
https://docs.google.com/viewer?a=v&q=cache:qcNdB45fxXoJ:jco.ascopubs.org/content/29/5/e125.full.pdf+mehta+death+reports+myeloma&hl=en&gl=us&pid=bl&srcid=ADGEESh0rS0L__sPmbVv7ej4SXmUND5pMwpbxJPzH2rg2r0zfdGFKQDSKVy6v83PK3ZOH4j-xgUp31bPQI-1YnMpbz0B3MWpGKRV70An4xkZTiVgDQuDNE040DMWd8sN_2qMax9R-gz6&sig=AHIEtbRRsV2hJhRYdDDB5H78y_sWwhg-sQ
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
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