Hi Ricardo,
I always enjoy your commentary as well.
Frankly, I must admit to narrowly focusing on the parameters Mark orginally set out when comparing survival outcomes i.e. Berenson vs. Barlogie
While MIRT has had outstanding results..there have been no comparative trials with other regimens. The decision to enter into comparative RCT is a decision that would come from Barlogie.
Berenson does participate as you noted in numerous clinical trials.
I do not know if Berenson has done RCT, that could be labelled his 'unique clinical protocol" given the focus was on Barlogie vs. Berenson, survival outcomes I did not look to see. Perhaps, that was an oversight on my part, driven by knowing that was not feasible as a comparator given how Barlogie has declined RCT and Berenson is not a proponent of SCT.
So, couldn't possibly see how there would be trials of that nature run by Berenson to compare to Barlogie's TT1-3 tandem transplant approach.
I also think it is telling that despite Barlogie's aggressive approach he has not increased overall survival for multiple myeloma patients.
However, more importantly, I have not located any head to head clinical trials where TT1-3 was a randomized arm vs. another regimen in the over 20 years Barlogie has run MIRT.
Let me know if you are more successful than I.
Suzierose
Forums
Re: Berenson 5 Year OS Data Superior to UAMS
Hi, Suzierose:
With the broad spectrum of treatment options available, from the most conservative to the most aggressive, patients tend to subscribe to one or another set of philosophies. Their life at stake, few patients would be willing to surrender their right to choose to a computer program. That might be the basis of the tremendous difficulty in setting up the randomized trials you mentioned. In the "Cure" debate between him and Dr. Barlogie, Dr. Rajkumar also expressed the same understanding of the difficulty inherent in such circumstances.
Gleaning from some of the blog entries of UAMS patients, I also happen to think that Dr. Barlogie has a very strong belief in his treatment regimens. One can agree or disgagree with him on the effect/toxicity balance of his protocols, it would indeed be difficult for someone to consent to place some of his patients into a treatment he thinks is clearly inferior.
Ben
With the broad spectrum of treatment options available, from the most conservative to the most aggressive, patients tend to subscribe to one or another set of philosophies. Their life at stake, few patients would be willing to surrender their right to choose to a computer program. That might be the basis of the tremendous difficulty in setting up the randomized trials you mentioned. In the "Cure" debate between him and Dr. Barlogie, Dr. Rajkumar also expressed the same understanding of the difficulty inherent in such circumstances.
Gleaning from some of the blog entries of UAMS patients, I also happen to think that Dr. Barlogie has a very strong belief in his treatment regimens. One can agree or disgagree with him on the effect/toxicity balance of his protocols, it would indeed be difficult for someone to consent to place some of his patients into a treatment he thinks is clearly inferior.
Ben
-
Ben S.
Re: Berenson 5 Year OS Data Superior to UAMS
Suzierose,
Thank you for your very informative response. It is very obvious that you have immersed yourself in getting as much information about multiple myeloma as possible. Although I try to stay informed I by no means have your level of eduction on the subject.
I do however wish to respond on a couple of your points.
You started your post with the following:
"If relapse were not inevitable, then multiple myeloma is not incurable, no?"
- Not if someone has to stay on combination maintenance therapy for the rest of their lives. At least IMO. Diabetics must take insulin all of their lives. If they do so they can hold of progression of that disease but it does not mean they are cured of diabetes. The same is true with HIV patients.
"Resistance can be minimized with combination therapy and multiple myeloma patients with out negative cytogenetic profiles can have a longer progression free survival. These patients appear to comprise 75% of what is called conventional multiple myeloma patients. However, even they relapse"
. - I don't think that the RVD used in combination has been around long enough to say "even they relapse". So far I have not, that does not mean I won't, but as an initial treatment RVD in combination has not been around for very long.. There are others like me that have been in a remissive state for 2-3 years. What I will acknowedgle is that if removed from the drugs, I probably will relapse. The novel agents were not even approved except to treat relapsed and refractory paitients until the 2007 - 2008 time frame. The combination of the drugs was started even later. Patients that received ASCT, until very recently ,were not put on a maintainence protocal that included combination of novel agents. So I don't think enough time has gone by to say that "all will relpase".
Besides, I think as a cancer patient, you have to be optomistic and not fatalistic.
I do enjoy your posts and your informitive discussions.
Ron
Thank you for your very informative response. It is very obvious that you have immersed yourself in getting as much information about multiple myeloma as possible. Although I try to stay informed I by no means have your level of eduction on the subject.
I do however wish to respond on a couple of your points.
You started your post with the following:
"If relapse were not inevitable, then multiple myeloma is not incurable, no?"
- Not if someone has to stay on combination maintenance therapy for the rest of their lives. At least IMO. Diabetics must take insulin all of their lives. If they do so they can hold of progression of that disease but it does not mean they are cured of diabetes. The same is true with HIV patients.
"Resistance can be minimized with combination therapy and multiple myeloma patients with out negative cytogenetic profiles can have a longer progression free survival. These patients appear to comprise 75% of what is called conventional multiple myeloma patients. However, even they relapse"
. - I don't think that the RVD used in combination has been around long enough to say "even they relapse". So far I have not, that does not mean I won't, but as an initial treatment RVD in combination has not been around for very long.. There are others like me that have been in a remissive state for 2-3 years. What I will acknowedgle is that if removed from the drugs, I probably will relapse. The novel agents were not even approved except to treat relapsed and refractory paitients until the 2007 - 2008 time frame. The combination of the drugs was started even later. Patients that received ASCT, until very recently ,were not put on a maintainence protocal that included combination of novel agents. So I don't think enough time has gone by to say that "all will relpase".
Besides, I think as a cancer patient, you have to be optomistic and not fatalistic.
I do enjoy your posts and your informitive discussions.
Ron
-
Ron Harvot - Name: Ron Harvot
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: Feb 2009
- Age at diagnosis: 56
Re: Berenson 5 Year OS Data Superior to UAMS
Hi Ben,
I absolutely agree with you about therapeutic choices being highly personal.
I do not believe Barlogie is knowingly treating patients with inferior therapy either. He simply doesn't make his protocol available in a trial setting that could demonstrate if it is more toxic than other effective therapies vs. being more effective. We do know Barlogie has not decreased multiple myeloma mortality anymore so than other effective therapies available despite the grueling toxicity of TT1-3.
In terms of the comparator trials though, what would have happened is that we would have had randomized trials of effective therapies. Not one arm is a loser and the other could be highly effective. Rather it would have been an older effective therapy (such as alklylators/dex) vs a newer "effective" therapy such as VAD TT1-2 followed by tandem SCT. Comparative induction effective therapies. Those would not be hard choices. It would be unethical to design a trial for multiple myeloma therapy at this juncture which was not challenging efficacy vs. more efficacy. Who is the best NYGiants or NEPatriots? Which one wins. Both teams are great..now let's have the SuperBowl and determine the champions.
The only trial comparisons out there are between TT1 vs. TT2 vs. TT3..nicely convenient for Barlogie.
Why aren't there head to head comparator trials of any of the T1-3 trials with any other multiple myeloma therapy that has been shown to be effective? Randomization into such trials would not be allowing a computer choice. Rather, the patient is doing precisely what we do presently which is electing a proven clinically effective therapy. However, the outcome would show us which therapy demonstrates the greatest efficacy. VD-Pace is most toxic stuff on the market and like throwing the kitchen sink at multiple myeloma. We already know it is highly toxic, the question is it highly effective over and beyond other EFFECTIVE drug regimens for multiple myeloma.
To me that is highly desirable. Toxic aggresive therapy is not the same as most effective therapy.
Here is a very valid peer criticism of TT2 from a peer-reviewed journal:
"Another weakness is the lack of direct information on fatal treatment-related toxicity in any of the published articles that report on the Total Therapy 2 trial. Figure 2B in the article by Barlogie et al1 shows that a total of 287 patients have died, and Figure 2D shows that 159 patients have died after experiencing disease progression. This suggests that 128 of 668 patients (19%) died as a result of nonrelapse causes. If true, this indicates that the treatment approach is prohibitively toxic. If the 19% estimate that I derived on the basis of available data is incorrect, the entire analysis and data set need to be revisited for possible inaccuracies, not only for this article but for all publications pertaining to the Total Therapy 2 trial.
Because of the complexity of the data and the piecemeal presentation of the study outcomes in several different manuscripts published during the last several years, Barlogie et al should make deidentified primary data, including detailed karyotype information, available to interested readers in an appropriate form so that the contribution of GEP in multiple myeloma and the extent of treatment-related mortality associated with the approach used in the Total Therapy 2 trial can be evaluated independently."
http://jco.ascopubs.org/content/29/5/e124.full
I absolutely agree with you about therapeutic choices being highly personal.
I do not believe Barlogie is knowingly treating patients with inferior therapy either. He simply doesn't make his protocol available in a trial setting that could demonstrate if it is more toxic than other effective therapies vs. being more effective. We do know Barlogie has not decreased multiple myeloma mortality anymore so than other effective therapies available despite the grueling toxicity of TT1-3.
In terms of the comparator trials though, what would have happened is that we would have had randomized trials of effective therapies. Not one arm is a loser and the other could be highly effective. Rather it would have been an older effective therapy (such as alklylators/dex) vs a newer "effective" therapy such as VAD TT1-2 followed by tandem SCT. Comparative induction effective therapies. Those would not be hard choices. It would be unethical to design a trial for multiple myeloma therapy at this juncture which was not challenging efficacy vs. more efficacy. Who is the best NYGiants or NEPatriots? Which one wins. Both teams are great..now let's have the SuperBowl and determine the champions.
The only trial comparisons out there are between TT1 vs. TT2 vs. TT3..nicely convenient for Barlogie.
Why aren't there head to head comparator trials of any of the T1-3 trials with any other multiple myeloma therapy that has been shown to be effective? Randomization into such trials would not be allowing a computer choice. Rather, the patient is doing precisely what we do presently which is electing a proven clinically effective therapy. However, the outcome would show us which therapy demonstrates the greatest efficacy. VD-Pace is most toxic stuff on the market and like throwing the kitchen sink at multiple myeloma. We already know it is highly toxic, the question is it highly effective over and beyond other EFFECTIVE drug regimens for multiple myeloma.
To me that is highly desirable. Toxic aggresive therapy is not the same as most effective therapy.
Here is a very valid peer criticism of TT2 from a peer-reviewed journal:
"Another weakness is the lack of direct information on fatal treatment-related toxicity in any of the published articles that report on the Total Therapy 2 trial. Figure 2B in the article by Barlogie et al1 shows that a total of 287 patients have died, and Figure 2D shows that 159 patients have died after experiencing disease progression. This suggests that 128 of 668 patients (19%) died as a result of nonrelapse causes. If true, this indicates that the treatment approach is prohibitively toxic. If the 19% estimate that I derived on the basis of available data is incorrect, the entire analysis and data set need to be revisited for possible inaccuracies, not only for this article but for all publications pertaining to the Total Therapy 2 trial.
Because of the complexity of the data and the piecemeal presentation of the study outcomes in several different manuscripts published during the last several years, Barlogie et al should make deidentified primary data, including detailed karyotype information, available to interested readers in an appropriate form so that the contribution of GEP in multiple myeloma and the extent of treatment-related mortality associated with the approach used in the Total Therapy 2 trial can be evaluated independently."
http://jco.ascopubs.org/content/29/5/e124.full
-
suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Berenson 5 Year OS Data Superior to UAMS
Hi, Suzierose:
You are absolutely right that a randomized trial has to be between two seemingly equally effecitve treatment regimens so irrelevant factors can be excluded and more effective of the two can emerge. To judge the effectiveness of a treatment, one has to have solid, large sample based stattistics. This is where problems may arise. UAMS has been meticulously maintaining historical data related to its treatment protocols from way back. But I have not seen any large sample statistics published by other major treatment centers or small offices alike. Remember in this setting, trials involving small number of patients such as 25 are hardly meaningful. This might also be the place where the statistics published by offices such as that of Dr. Berenson's would need more looking into. I am not sure those statistics were derived by independent medical statisticians and audited by "independent, nationally accredited reviewers", as stated in the reply by UAMS to Mehta.
Rather than the 19% treatment-related mortality as stated in Mehta's critique, UAMS' reply stated that the actual treatment-related mortality is 51/688, or 7.6%. If you consider the number includes both the older and the younger, that mortality might need to be adjusted depending on the age of the person who is interested. But the 19% number seems to be out of line.
Ben
You are absolutely right that a randomized trial has to be between two seemingly equally effecitve treatment regimens so irrelevant factors can be excluded and more effective of the two can emerge. To judge the effectiveness of a treatment, one has to have solid, large sample based stattistics. This is where problems may arise. UAMS has been meticulously maintaining historical data related to its treatment protocols from way back. But I have not seen any large sample statistics published by other major treatment centers or small offices alike. Remember in this setting, trials involving small number of patients such as 25 are hardly meaningful. This might also be the place where the statistics published by offices such as that of Dr. Berenson's would need more looking into. I am not sure those statistics were derived by independent medical statisticians and audited by "independent, nationally accredited reviewers", as stated in the reply by UAMS to Mehta.
Rather than the 19% treatment-related mortality as stated in Mehta's critique, UAMS' reply stated that the actual treatment-related mortality is 51/688, or 7.6%. If you consider the number includes both the older and the younger, that mortality might need to be adjusted depending on the age of the person who is interested. But the 19% number seems to be out of line.
Ben
-
Ben S.
Re: Berenson 5 Year OS Data Superior to UAMS
Hi Ben,
Thanks so much for delineating about sample size of data. Another frustration about MIRT.
ICAM about Berenson's relative sample sizes...sigh...even greater frustration. But that also leads back to TerryH's original comment regarding why those comparative survival outcomes were misleading as posted by Ron.
Had not seen MIRT's reply...thanks for that update, as well.
Was it a typo in the data that Mehta read?
Suzierose.
Thanks so much for delineating about sample size of data. Another frustration about MIRT.
ICAM about Berenson's relative sample sizes...sigh...even greater frustration. But that also leads back to TerryH's original comment regarding why those comparative survival outcomes were misleading as posted by Ron.
Had not seen MIRT's reply...thanks for that update, as well.
Was it a typo in the data that Mehta read?
Suzierose.
-
suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Berenson 5 Year OS Data Superior to UAMS
Hi Ron,
We each learn about multiple myeloma based on our starting points, I happened to have a jump start somewhat, based on my educational and professional background. Over time you too, will know far more than you ever wanted to know, lol.
I completely agree with you about AIDS & diabetes becoming chronic INCURABLE diseases, thanks to maintenance therapy.
Unfortunately RVD has been around long enough to see relapse in patients. In fact one of the Beacon columnists, who also happens to be an M.D., has written about his personal experience:
"It has been almost six years since my diagnosis. At various times during the course of treatment for multiple relapses, I have been on Revlimid, thalidomide, Velcade, and several combinations of these. I have tried pomalidomide in a clinical trial.
All of these drugs worked for a period of time and have allowed me good quality of life during that time.
One year ago, after a bad relapse, I underwent a salvage second stem cell transplant, which I had written about in an earlier post.
Initially, the results were very good. However, after about 10 months on maintenance therapy with thalidomide and Velcade following the transplant, my M spike started going up again and I am now back in full relapse mode.
So now what?"
https://myelomabeacon.org/headline/2012/01/10/arnies-rebounding-world-multiple-myeloma-on-the-ropes-really/
Regarding combination therapy for multiple myeloma. Combos such as vincristine/adriamycin/doxurubcin (VAD) have been around for a long time prior to thalidomide being introduced ... just like most cancers regimens since the 50s. Combination were a staple of chemotherapy. In fact this is just what I was discussing with Ben about comparator trials.
The superiority of thalidomide and dex was demonstrated in head to head comparisons with VAD Randomized trials compared VAD with thalidomide plus dexamethasone ; thalidomide and doxorubicin plus dexamethasone ; and thalidomide plus VAD in order for thalidomide to become first line therapy.
The same types of randomized trials were used for lenalidomide, bortezomib as well as carfilzomib.We do not have this type date from MIRT"s TT1-3 regimens.
I enjoy great discussions too Ron.
I am optimistic that you and I are going to have many new effective therapies which will result in us having the same chronic disease state as diabetes and AIDS, or perhaps even something better is on the horizon...dare we use the word... Cure or eradication?.
Those microRNA's sound quite interesting...so does the new research out of UPenn where your own Tcells are infused with stealth killing genetically modified markers that specifically target multiple myeloma stem cells and results in our own body making up more Tcells to fight the disease on is own. I believe that is most promising, to have our own personalized drones, for hitting those pugnacious taliban stem cells gone wild. LOL
http://www.evaluatepharma.com/Universal/View.aspx?type=Story&id=247869
YAY!!
suzierose
We each learn about multiple myeloma based on our starting points, I happened to have a jump start somewhat, based on my educational and professional background. Over time you too, will know far more than you ever wanted to know, lol.
I completely agree with you about AIDS & diabetes becoming chronic INCURABLE diseases, thanks to maintenance therapy.
Unfortunately RVD has been around long enough to see relapse in patients. In fact one of the Beacon columnists, who also happens to be an M.D., has written about his personal experience:
"It has been almost six years since my diagnosis. At various times during the course of treatment for multiple relapses, I have been on Revlimid, thalidomide, Velcade, and several combinations of these. I have tried pomalidomide in a clinical trial.
All of these drugs worked for a period of time and have allowed me good quality of life during that time.
One year ago, after a bad relapse, I underwent a salvage second stem cell transplant, which I had written about in an earlier post.
Initially, the results were very good. However, after about 10 months on maintenance therapy with thalidomide and Velcade following the transplant, my M spike started going up again and I am now back in full relapse mode.
So now what?"
https://myelomabeacon.org/headline/2012/01/10/arnies-rebounding-world-multiple-myeloma-on-the-ropes-really/
Regarding combination therapy for multiple myeloma. Combos such as vincristine/adriamycin/doxurubcin (VAD) have been around for a long time prior to thalidomide being introduced ... just like most cancers regimens since the 50s. Combination were a staple of chemotherapy. In fact this is just what I was discussing with Ben about comparator trials.
The superiority of thalidomide and dex was demonstrated in head to head comparisons with VAD Randomized trials compared VAD with thalidomide plus dexamethasone ; thalidomide and doxorubicin plus dexamethasone ; and thalidomide plus VAD in order for thalidomide to become first line therapy.
The same types of randomized trials were used for lenalidomide, bortezomib as well as carfilzomib.We do not have this type date from MIRT"s TT1-3 regimens.
I enjoy great discussions too Ron.
I am optimistic that you and I are going to have many new effective therapies which will result in us having the same chronic disease state as diabetes and AIDS, or perhaps even something better is on the horizon...dare we use the word... Cure or eradication?.
Those microRNA's sound quite interesting...so does the new research out of UPenn where your own Tcells are infused with stealth killing genetically modified markers that specifically target multiple myeloma stem cells and results in our own body making up more Tcells to fight the disease on is own. I believe that is most promising, to have our own personalized drones, for hitting those pugnacious taliban stem cells gone wild. LOL
http://www.evaluatepharma.com/Universal/View.aspx?type=Story&id=247869
YAY!!
suzierose
-
suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Berenson 5 Year OS Data Superior to UAMS
This is a great discussion.
I haven't read everything so far, but there is one point I think everyone needs to remember.
Arguing about whether UAMS or Berenson have the better approach to treating myeloma is a lot like arguing whether fascism or Communism is a better way to run a society.
In reality, the choice isn't just between those two extremes, and the best option is probably somewhere in between.
I haven't read everything so far, but there is one point I think everyone needs to remember.
Arguing about whether UAMS or Berenson have the better approach to treating myeloma is a lot like arguing whether fascism or Communism is a better way to run a society.
In reality, the choice isn't just between those two extremes, and the best option is probably somewhere in between.
-
TerryH
Re: Berenson 5 Year OS Data Superior to UAMS
Hi TerryH
just cut to the chase why don't you? lol
hahahaa
snicker
we gotta have some fun discussing something that gets our minds off multiple myeloma..we can't change the world...but we sure can engage it, lol
just cut to the chase why don't you? lol
hahahaa
snicker
we gotta have some fun discussing something that gets our minds off multiple myeloma..we can't change the world...but we sure can engage it, lol
-
suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Berenson 5 Year OS Data Superior to UAMS
Hello back Suzie Rose
I enjoy your energy, comments, and insights. While I think that I have stable, smoldering myeloma, I don't know for sure. But if I do remain stable, I am reminded of a comment by Dr. Brian Durie that was quoted elsewhere on this site: namely, that if your myeloma is stable, it really means that the myeloma cells are asleep (in a quiescent or dormant )and will not respond to the toxic arsenal of drugs, such as Velcade. And so such treatment should me minimized.
Indeed, one of the many horrible aspects of this disease is that improper treatment early on may well accelerate progression by removing the "quiet" pre-malignant myeloma cells and selecting for malignant precursors or providing an environment for the creation and propagation of such maligant cells.
But who knows for sure? And that uncertainty is also part of the challenge, complexity, and frustration in deciding which course of action is best. Regarding the HIV analogy, if knew that there was at least a 50 percent probability of cure, I would readily endure a highly toxic treatment. But until then, I view the current treatment regimens as a slippery slope that must be approached with caution and eyes wide open.
And I also think that because this nasty disease is currently incurable, many doctors are more than willing to dispense toxic treatments. Thank goodness for those physicians who recognize that treatment must consider quality of life.
Until then, I am taking curcumin in the hopes of keeping this disease incurable but stable -- for now.
I enjoy your energy, comments, and insights. While I think that I have stable, smoldering myeloma, I don't know for sure. But if I do remain stable, I am reminded of a comment by Dr. Brian Durie that was quoted elsewhere on this site: namely, that if your myeloma is stable, it really means that the myeloma cells are asleep (in a quiescent or dormant )and will not respond to the toxic arsenal of drugs, such as Velcade. And so such treatment should me minimized.
Indeed, one of the many horrible aspects of this disease is that improper treatment early on may well accelerate progression by removing the "quiet" pre-malignant myeloma cells and selecting for malignant precursors or providing an environment for the creation and propagation of such maligant cells.
But who knows for sure? And that uncertainty is also part of the challenge, complexity, and frustration in deciding which course of action is best. Regarding the HIV analogy, if knew that there was at least a 50 percent probability of cure, I would readily endure a highly toxic treatment. But until then, I view the current treatment regimens as a slippery slope that must be approached with caution and eyes wide open.
And I also think that because this nasty disease is currently incurable, many doctors are more than willing to dispense toxic treatments. Thank goodness for those physicians who recognize that treatment must consider quality of life.
Until then, I am taking curcumin in the hopes of keeping this disease incurable but stable -- for now.
-
Dan D
43 posts
• Page 3 of 5 • 1, 2, 3, 4, 5