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Barlogie-Rajkumar Debate - Part 1 of 5
This video is Part 1 of the debate held on October 13, 2011 between Dr. Bart Barlogie (University of Arkansas) and Dr. Vincent Rajkumar (Mayo Clinic) on the topic "Is Myeloma Curable."
Part 1 is primarily an introduction by Dr.Issam Makhoul of UAMS.
To help other Beacon readers, feel free to post in this thread a summary of what is discussed in this video, or your comments on it.
Please leave general comments or summaries of the debate as a whole at the overall thread for the debate, which is here.
Re: Barlogie-Rajkumar Debate - Part 1 of 5
I suppose it needs to be emphasized that this debate is taking place in Little Rock.
Further, the audience is clearly biased to Barlogie's current therapeutic regimens and is not a neutral site to hold a debate. Given that I should also state that I support Rajkumar's clinical perspective...thus this feedback could be considered a counterbalance to what is presented in the first video.
OTOH, we could say that is the bar being set for Rajkumar, in terms of the debate, to sway a bunch of Barlogie acolytes to a different clinical approach. The problem is that Barlogie long ago stacked the deck against making a scientific and evidence based medical debate by declining to participate in RCT, the gold standard of scientific proof, so there are no definitive comparative clinical trials to demonstrate whether the therapeutic choices and options in LittleRock are indeed statistically significant not to mention clinically significant.
Nevertheless, those are the terms of the debate....so it proceeds
This first video gives a patient case summary and then is followed with questions on therapeutic choices regarding agents of choice for induction along with the question of whether there should be transplantation for the newly diagnosed patient. Which is the first clue about the bias of the audience as they not only select the most toxic agents available for induction but also select a tandem transplant for initial therapy for a high risk patient (17p) when multiple studies show that this type of high risk patient has exceptional poor survival following BSCT and thus it is not recommended.
It is unclear why, based on the labs the patient is dx as smoldering, when he clearly meets the ISS stage I criteria and based on bone lesions meets the CRAB criteria as well as his FLC meets the definition for multiple myeloma, not to mention his cytogenetic profile is hi risk with 17p.
Perhaps, one of our medical advisors could provide better detail on why this case would be considered smoldering vs multiple myeloma.
ETA: my oversight..it says 6 months post SM dx he presents as...sorry
Further, the audience is clearly biased to Barlogie's current therapeutic regimens and is not a neutral site to hold a debate. Given that I should also state that I support Rajkumar's clinical perspective...thus this feedback could be considered a counterbalance to what is presented in the first video.
OTOH, we could say that is the bar being set for Rajkumar, in terms of the debate, to sway a bunch of Barlogie acolytes to a different clinical approach. The problem is that Barlogie long ago stacked the deck against making a scientific and evidence based medical debate by declining to participate in RCT, the gold standard of scientific proof, so there are no definitive comparative clinical trials to demonstrate whether the therapeutic choices and options in LittleRock are indeed statistically significant not to mention clinically significant.
Nevertheless, those are the terms of the debate....so it proceeds
This first video gives a patient case summary and then is followed with questions on therapeutic choices regarding agents of choice for induction along with the question of whether there should be transplantation for the newly diagnosed patient. Which is the first clue about the bias of the audience as they not only select the most toxic agents available for induction but also select a tandem transplant for initial therapy for a high risk patient (17p) when multiple studies show that this type of high risk patient has exceptional poor survival following BSCT and thus it is not recommended.
It is unclear why, based on the labs the patient is dx as smoldering, when he clearly meets the ISS stage I criteria and based on bone lesions meets the CRAB criteria as well as his FLC meets the definition for multiple myeloma, not to mention his cytogenetic profile is hi risk with 17p.
Perhaps, one of our medical advisors could provide better detail on why this case would be considered smoldering vs multiple myeloma.
ETA: my oversight..it says 6 months post SM dx he presents as...sorry
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Suzierose,
Dr. Rajkumar would have to be considered the winner of this debate because Dr. Barlogie made a statement that he knows is false in Part 2 at 2:28. He states that the only chance for cure or long term disease control is with combination therapy (Total Therapy) and he knows that Allogeneic transplants done in an upfront setting have the best chance of long term disease control. Obviously many multiple myeloma patients are not eligible for Allo transplants due to age, etc. This would only apply to younger patients that are blessed with a Matched Donor (related or unrelated).
I will attach a link to a Swiss study at ASH this year relating to Allo transplants. Check out the curves for patients that do Allos as part of planned, upfront therapy. The PFS curve is flat at over 50% for patients at 5 years, suggesting a possible cure. Relapses are not that common in years 5-10 for Allo patients. Also interesting to note that that the OS curve is flat at 77% at year 6 - the same range as the OS curve on both Dr. Rajkumars and Dr. Barlogies OS curves presented at the beginning of Part 5. Note that the patients doing the Allos are younger and more likely to have high risk disease than a normal patient population.
http://ash.confex.com/ash/2011/webprogram/Paper37067.html
You should not have a debate questioning if Myeloma is curable and not discuss the therapy that has likely cured many patients.
Mark
Dr. Rajkumar would have to be considered the winner of this debate because Dr. Barlogie made a statement that he knows is false in Part 2 at 2:28. He states that the only chance for cure or long term disease control is with combination therapy (Total Therapy) and he knows that Allogeneic transplants done in an upfront setting have the best chance of long term disease control. Obviously many multiple myeloma patients are not eligible for Allo transplants due to age, etc. This would only apply to younger patients that are blessed with a Matched Donor (related or unrelated).
I will attach a link to a Swiss study at ASH this year relating to Allo transplants. Check out the curves for patients that do Allos as part of planned, upfront therapy. The PFS curve is flat at over 50% for patients at 5 years, suggesting a possible cure. Relapses are not that common in years 5-10 for Allo patients. Also interesting to note that that the OS curve is flat at 77% at year 6 - the same range as the OS curve on both Dr. Rajkumars and Dr. Barlogies OS curves presented at the beginning of Part 5. Note that the patients doing the Allos are younger and more likely to have high risk disease than a normal patient population.
http://ash.confex.com/ash/2011/webprogram/Paper37067.html
You should not have a debate questioning if Myeloma is curable and not discuss the therapy that has likely cured many patients.
Mark
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Mark
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Dr. Barlogie always believes that a cure is possible eventually, hopefully with his Total Treatment program . There has been tremendous progress with the development of novel agents in recent years and the future looks bright , but all these agents destroy the malignant plasma cells and to my knowledge nothing to date kills the myeloma stem cell. Until the myeloma stem cell can be destroyed, I do not see a cure being possible and we will all relapse. At present, making myeloma a chronic disease appears the goal; I have never heard of anyone being cured of myeloma. Did they die of other causes before the myeloma had an opportunity to have a measurable relapse? Perhaps this site's oncologists could comment.
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bond007
Re: Barlogie-Rajkumar Debate - Part 1 of 5
hi Mark!
Does Barlogie even do allos?
The Beacon has kinda set this up where we are discussing/summarizing what transpires in each part of the debate, so we will have to hold off until the part 5 to declare Rajkumar the winner
I completely agree with you in terms of not including allos when cures for multiple myeloma are being discussed, but do you think that has to do with the mortality rates of allos?
Does Barlogie even do allos?
The Beacon has kinda set this up where we are discussing/summarizing what transpires in each part of the debate, so we will have to hold off until the part 5 to declare Rajkumar the winner
I completely agree with you in terms of not including allos when cures for multiple myeloma are being discussed, but do you think that has to do with the mortality rates of allos?
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Hi Bond!
I agree with you that when cure is being discussed stem cells need to be the active target of the regimen. Until then we are looking at chronic disease vs cure... at this juncture effective therapies treating multiple myeloma as a chronic disease would be a leap forward and because it would be far more lucrative for big Pharma we might not ever approach cure. Not much annual profits in cures.
So we agree again..chronic disease control is the goal.
I agree with you that when cure is being discussed stem cells need to be the active target of the regimen. Until then we are looking at chronic disease vs cure... at this juncture effective therapies treating multiple myeloma as a chronic disease would be a leap forward and because it would be far more lucrative for big Pharma we might not ever approach cure. Not much annual profits in cures.
So we agree again..chronic disease control is the goal.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Suzierose,
UAMS does not do many Allos and that is a good thing. The reason I say that is Marrow.org gives statistics for Allo transplants and their numbers are rather poor. Note that only 3 were for myeloma patients and 19 is a very low number for a transplant center.
"This analysis is based on transplants performed from Jan. 1, 2007 through Dec. 31, 2009 using unrelated donors and transplants performed from Jan. 1, 2008 through Dec. 31, 2009 using related donors. It only includes patients who underwent their first allogeneic transplant within these respective time periods and who had at least 100-day follow-up.
1.This center reported survival status data for 19 patients.
2.The actual one-year survival of these patients was 16%.
3.The predicted one-year survival was 55% (with a 95% confidence limit that the predicted survival was between 34% and 76%).
4.This center's actual results are below the predicted range for this center."
http://marrow.org/pages/TransplantCenterDirectory.aspx?ctr_id=580&p_src=state
Most centers are slightly above or below the predicted range.
I do not think Allos are discussed because many multiple myeloma patients are not eligible for them. They are typically considered as frontline therapy for patients 60 and under (Reduced Intensity and 55 and under is also a common age cutoff) and the average age for myeloma diagnosis is in the upper 60's range. Also, most statistics that patients (and likely many Myeloma Doctors)are familiar with for Allos are not for Allos done as frontline therapy and they are typically fairly old. I am sure that most statistics you read for Allos are similar to those the Swiss group reported for non-planned Allos in a relapse setting or to patients not responding to Chemo (and you are a VERY educated patient). The Allo is likely not beneficial for patients diagnosed in their 60's with low or standard risk disease with the novel agents that are available.
Allos are unlikely to show superior outcomes before 5-7 years. Dr. Rajkumar shows 80% OS at 6 years - not much chance any therapy could do better than what he is doing in terms of OS at 6 years. The advantage to the Allo is when the PFS curve goes flat and that is not typically until the year 5-7 range. Also, as Dr. Barlogie mentions at the end of the presentation that his reputation as the Doctor whose name is associated with aggressive therapy/cure keeps his referrals high. Why would he want to discuss the therapy that actually does give the longest Chemo-free PFS to younger patients when his institution does not perform them? That would not be good for business.
Mark
UAMS does not do many Allos and that is a good thing. The reason I say that is Marrow.org gives statistics for Allo transplants and their numbers are rather poor. Note that only 3 were for myeloma patients and 19 is a very low number for a transplant center.
"This analysis is based on transplants performed from Jan. 1, 2007 through Dec. 31, 2009 using unrelated donors and transplants performed from Jan. 1, 2008 through Dec. 31, 2009 using related donors. It only includes patients who underwent their first allogeneic transplant within these respective time periods and who had at least 100-day follow-up.
1.This center reported survival status data for 19 patients.
2.The actual one-year survival of these patients was 16%.
3.The predicted one-year survival was 55% (with a 95% confidence limit that the predicted survival was between 34% and 76%).
4.This center's actual results are below the predicted range for this center."
http://marrow.org/pages/TransplantCenterDirectory.aspx?ctr_id=580&p_src=state
Most centers are slightly above or below the predicted range.
I do not think Allos are discussed because many multiple myeloma patients are not eligible for them. They are typically considered as frontline therapy for patients 60 and under (Reduced Intensity and 55 and under is also a common age cutoff) and the average age for myeloma diagnosis is in the upper 60's range. Also, most statistics that patients (and likely many Myeloma Doctors)are familiar with for Allos are not for Allos done as frontline therapy and they are typically fairly old. I am sure that most statistics you read for Allos are similar to those the Swiss group reported for non-planned Allos in a relapse setting or to patients not responding to Chemo (and you are a VERY educated patient). The Allo is likely not beneficial for patients diagnosed in their 60's with low or standard risk disease with the novel agents that are available.
Allos are unlikely to show superior outcomes before 5-7 years. Dr. Rajkumar shows 80% OS at 6 years - not much chance any therapy could do better than what he is doing in terms of OS at 6 years. The advantage to the Allo is when the PFS curve goes flat and that is not typically until the year 5-7 range. Also, as Dr. Barlogie mentions at the end of the presentation that his reputation as the Doctor whose name is associated with aggressive therapy/cure keeps his referrals high. Why would he want to discuss the therapy that actually does give the longest Chemo-free PFS to younger patients when his institution does not perform them? That would not be good for business.
Mark
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Mark
Re: Barlogie-Rajkumar Debate - Part 1 of 5
I listened to the videos a month or two ago and did again just now to refresh my memory. I think the debate eludicated a subtler point that, in Dr. Rajkumar's own words, for a subset of low-risk patients, a cure "may actually be possible," though he did add that the survive curve looks flatter when you draw the curve for those very patients.
Therefore, curability is not completely against reality. When comparing the survival statistics, Dr. Rajkumar mentioned a 70-80% number around the 5th and 6th year, which are similar to the statistics derived by UAMS. However, the comparison did not go beyond the 5th-6th years. That's where UMAS' survival curves are trying to show. Granted, the curves are not going as far as we want them to because of the limited number of years passed beween the initiation of Total Therapy 3 and now. But if you believe the imposibility of Total Therapies 1 and 2, the closest we can have at the moment, considering the availability of the newer novel drugs that were unavailable to the previous two therapies, the TT3 curves are indeed very promising for low-risk patients who are after a long-term event-free survival.
I admire Dr. Rajkumar's presentation that laid out the topic in a more logical and clearer way. He earned my respect in being respectful and forceful at the same time. His works in the fields are world-renown and have great impact in shaping the treatments for this disease. But Dr. Barlogie, along with his colleagues in UAMS, deserves equal, if not more, amount of respect for his tireless pioneering work in treating and eventually curing multiple myeloma patients. Let's all remember that his clinic treats the most patients in the world and keeps the most exhausting amount of treatment and follow-up statistics, not to mention that UAMS started many treatment regimens now other multiple myeloma clinics take for granted.
Regarding the existence of myeloma stem cells that flies in the face of curability with the current treatment regimens that target myeloma cells only, my understanding is that theory is still being regarded as "controversial." At this point, I would rather invest my faith in sound statistics. On the other hand, the allo treatment remains out of mainstream because of its high mortality rate, despite articles from some clinics that say otherwise, and the difficulty for patients to find suitable stem cell donors. I believe one of the Beacon's own medical advisers stated the same status quo on this very forum.
Therefore, curability is not completely against reality. When comparing the survival statistics, Dr. Rajkumar mentioned a 70-80% number around the 5th and 6th year, which are similar to the statistics derived by UAMS. However, the comparison did not go beyond the 5th-6th years. That's where UMAS' survival curves are trying to show. Granted, the curves are not going as far as we want them to because of the limited number of years passed beween the initiation of Total Therapy 3 and now. But if you believe the imposibility of Total Therapies 1 and 2, the closest we can have at the moment, considering the availability of the newer novel drugs that were unavailable to the previous two therapies, the TT3 curves are indeed very promising for low-risk patients who are after a long-term event-free survival.
I admire Dr. Rajkumar's presentation that laid out the topic in a more logical and clearer way. He earned my respect in being respectful and forceful at the same time. His works in the fields are world-renown and have great impact in shaping the treatments for this disease. But Dr. Barlogie, along with his colleagues in UAMS, deserves equal, if not more, amount of respect for his tireless pioneering work in treating and eventually curing multiple myeloma patients. Let's all remember that his clinic treats the most patients in the world and keeps the most exhausting amount of treatment and follow-up statistics, not to mention that UAMS started many treatment regimens now other multiple myeloma clinics take for granted.
Regarding the existence of myeloma stem cells that flies in the face of curability with the current treatment regimens that target myeloma cells only, my understanding is that theory is still being regarded as "controversial." At this point, I would rather invest my faith in sound statistics. On the other hand, the allo treatment remains out of mainstream because of its high mortality rate, despite articles from some clinics that say otherwise, and the difficulty for patients to find suitable stem cell donors. I believe one of the Beacon's own medical advisers stated the same status quo on this very forum.
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Ben S.
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Mark. Appreciate your clear analysis of why the Swiss results are so superior to aggregate results for Allo and mini Allo transplants. Is it entirely a matter of the age and condition of the patients, or were there variables from how the transplant was done that help explain the results.
I am 62 (diagnosed at 57) and have been advised to consider allotransplant - sponsored in clinical trial by Celgene. It features sirolimus and tacrolimus beginning on day 3 as prophylaxis for HvHD and sirolimus and Revlimid as maintenance after Day 30. http://clinicaltrial.gov/ct2/show/NCT01303965?term=allogeneic+stem+cell+transplant+faraq&rank=3
I am wondering what "T-cell depletion" is and also what "low dose donor lymphocyte infusions" are. (From the Sloan- Kettering study). In short I think I understandhow the variables of age and what shape the patient is in and how they can dramatically affect outcomes, but I have trouble understanding the variables involved in the particular treatments.Maybe a physician or you, Mark, could provide some overview of how the transplants differ. (How the various Mini- Allo procedures differ ) Joe
I am 62 (diagnosed at 57) and have been advised to consider allotransplant - sponsored in clinical trial by Celgene. It features sirolimus and tacrolimus beginning on day 3 as prophylaxis for HvHD and sirolimus and Revlimid as maintenance after Day 30. http://clinicaltrial.gov/ct2/show/NCT01303965?term=allogeneic+stem+cell+transplant+faraq&rank=3
I am wondering what "T-cell depletion" is and also what "low dose donor lymphocyte infusions" are. (From the Sloan- Kettering study). In short I think I understandhow the variables of age and what shape the patient is in and how they can dramatically affect outcomes, but I have trouble understanding the variables involved in the particular treatments.Maybe a physician or you, Mark, could provide some overview of how the transplants differ. (How the various Mini- Allo procedures differ ) Joe
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Joe
Re: Barlogie-Rajkumar Debate - Part 1 of 5
I am surprised that the existence of myeloma stem cells and their failure to respond to present drugs are considered "controversial". As a physician and myeloma patient, I have always understood that relapse after autologous SCT after an average 2 years was due to the presence of the myeloma stem cells. When the harvested stem cells are infused back into the patient they also contain myeloma stem cells and as well, there are remaining myeloma stem cells in the bone marrow. Four years ago researchers at John Hopkins identified and isolated the myeloma stem cell. In vitro testing in the lab with several individual drugs killed the malignant plasma cells but did not touch the stem cells. Using rituxin they are now able purge the myeloma stem cells from the harvested pool.; this apparently is not done as it is felt that the relapse is due to the stem cells that remained behind in the bone marrow despite induction therapy and a mega dose of melphalan. I myself wonder why it is not done as it strikes me that reducing the total myeloma stem cell population could possibly extend the time to relapse.
In the late 1980s and early 1990s , allogeneic stem cell transplants were theoretically seen as a cure for myeloma. However, due to the 30-40% mortality from the procedure and the fact that everyone relapsed , they fell out of favour . They have been able to reduce the mortality to a still significant 15% but as far as a cure they will have to go 15-20 years without relapse to convince me and not just a flat graph at 5 years.
Dr. Barlogie in the past has stated that if a patient is relapse free for 5 years after Total Treatment they are cured. This may be true for solid tumours but not for myeloma. Ten years past between ending treatment for my second relapse and my third relapse onset; at no time did I consider myself cured. RVD has controlled things for the past 2+ years ; when it stops being of benefit I will just keep trying various combinations as each one runs its course and hopefully continue to extend my life. Cure should be the ultimate goal, but myeloma as a chronic disease is realistic at present I feel. April, 2012 will be 21 years for me and without autologous SCT as I am unable to have one due to extensive melphalan use in the 1990s. Myeloma is an extremely complex disease with many variants that require each patient to be assessed and treated individually.
In the late 1980s and early 1990s , allogeneic stem cell transplants were theoretically seen as a cure for myeloma. However, due to the 30-40% mortality from the procedure and the fact that everyone relapsed , they fell out of favour . They have been able to reduce the mortality to a still significant 15% but as far as a cure they will have to go 15-20 years without relapse to convince me and not just a flat graph at 5 years.
Dr. Barlogie in the past has stated that if a patient is relapse free for 5 years after Total Treatment they are cured. This may be true for solid tumours but not for myeloma. Ten years past between ending treatment for my second relapse and my third relapse onset; at no time did I consider myself cured. RVD has controlled things for the past 2+ years ; when it stops being of benefit I will just keep trying various combinations as each one runs its course and hopefully continue to extend my life. Cure should be the ultimate goal, but myeloma as a chronic disease is realistic at present I feel. April, 2012 will be 21 years for me and without autologous SCT as I am unable to have one due to extensive melphalan use in the 1990s. Myeloma is an extremely complex disease with many variants that require each patient to be assessed and treated individually.
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bond007
21 posts
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