Hi Bond!
Congrats to you Bond on your 20 years of successful management of this disease!! I too an ineligible for BSCT and had come to the pretty much the same decision you have executed which is to simply hope to maintain low grade disease until the new therapeutic agents are available.I pray for 20 year of such sustained disease management. Your story is uplifting, especially given you did all this without FISH, FLC's and GEP.
I would like to learn more about rituxin being used to purge stem cells and/or it's use as the hi-dose chem to hit the stems in the BM. Would you happen to have a link to any data on rituxin's present use in stem cell harvesting?.
I wholeheartedly concur with you about the need to alter the stem cells in order to approach a 'cure' for multiple myeloma. I wonder though if stem cells are akin to fiddling with an individual's DNA.
Forums
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Suzie Rose. I do not have specific links for rituxin but searching the web I have found a couple of articles , but my present hematologist/oncologist heads the stem cell laboratory and bone marrow transplant program at the university centre that I attend and provides any answers I need on the subject. In 1991 when I presented as a stage 3 with multiple fractures my sister was fortunately not a match as it turned for an allo SCT .. Rituxin provides great results in the treatment of non-Hodgkin's lymphoma but has shown not to have a role in myeloma treatment. The myeloma stem cells that remain in the bone marrow are certainly a formidable challenge if they survive the induction and mega dose of melphalan used in the SCT process.
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bond007
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Bond007, Suzierose,
The closest thing there is to an Auto transplant with a clean graft are syngeneic (exact twin) transplants. They are briefly discussed in this paper - Here is some brief discussion on this topic and the link if anyone is interested in checking into the links that are applicable:
"The outcomes of
syngeneic transplant recipients were superior in terms of lower incidence
of relapse/progression, PFS and, for the EMBT patients, longer
OS compared to Auto-SCT. A possible explanation for this observation
would be the presence of a syngeneic GVM (as demonstrated in
animal models, but has not been successfully reproduced in humans)
91,92 or due to absence of contaminating myeloma cells in the
donor graft. This latter explanation is not supported by purging results
of Auto-SCT.93-96"
http://myeloma.org/pdfs/IMWG_JCO_allo_2010.pdf
No links related to Rituxin purging that I have ever seen. I think a clinical trail /study using rituxin would be interesting.
Mark
The closest thing there is to an Auto transplant with a clean graft are syngeneic (exact twin) transplants. They are briefly discussed in this paper - Here is some brief discussion on this topic and the link if anyone is interested in checking into the links that are applicable:
"The outcomes of
syngeneic transplant recipients were superior in terms of lower incidence
of relapse/progression, PFS and, for the EMBT patients, longer
OS compared to Auto-SCT. A possible explanation for this observation
would be the presence of a syngeneic GVM (as demonstrated in
animal models, but has not been successfully reproduced in humans)
91,92 or due to absence of contaminating myeloma cells in the
donor graft. This latter explanation is not supported by purging results
of Auto-SCT.93-96"
http://myeloma.org/pdfs/IMWG_JCO_allo_2010.pdf
No links related to Rituxin purging that I have ever seen. I think a clinical trail /study using rituxin would be interesting.
Mark
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Mark
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Bond007,
Thanks for the informative posts. 20 years plus and going strong - that is awesome. I agree with most of your points but I would like to point out a study that was presented with 10 year followup regarding Auto and Allo transplants. The Allo group is younger and more and to have higher stage disease than the patients than the Auto group. Here are the results.
"In the entire group, overall survival was 47.1% at five years and 33.4% at 10 years. Overall survival in the allogeneic group was 48.1% at five years and 39.9% at 10 years, compared with 46.2% and 30.8% in the autologous group.
Event-free survival for the entire group was 33.1% at five years and 22.9% at 10 years. The allogeneic group had a 33.3% event-free survival at five years and a 31.4% event-free survival at 10 years, compared with 32.9% and 15.2% in the autologous group."
The stat that jumps out at me is that the relapses are few between 5 and 10 years in the Allo group while the Auto group continues to fall. It is encouraging that the Auto group still has 15% PFS at 10 years. The patients in the study do not have the benefit of novel agents, so that would improve outcomes for both Auto and Allo group. I think this data supports the thought that current drugs/Autos do not target the Cancer Stem cell and that the Donor Immune system can be part of a cure. I have not seen a 20 year long term followup study, but the chance of relapse appears low to the Allo patients after 5 years.
Also, Dr. Rajkumar wrote this in the Blood article regarding Cure/Control:
"Third, in most cases, it is probably impossible (with the possible exception of allogeneic transplantation where true complete eradication is possible for a minority of patients), unnecessary, and prohibitively toxic to attempt to eradicate all clonal plasma cells."
http://bloodjournal.hematologylibrary.org/content/118/12/3205.full
Great discussion.
Mark
Thanks for the informative posts. 20 years plus and going strong - that is awesome. I agree with most of your points but I would like to point out a study that was presented with 10 year followup regarding Auto and Allo transplants. The Allo group is younger and more and to have higher stage disease than the patients than the Auto group. Here are the results.
"In the entire group, overall survival was 47.1% at five years and 33.4% at 10 years. Overall survival in the allogeneic group was 48.1% at five years and 39.9% at 10 years, compared with 46.2% and 30.8% in the autologous group.
Event-free survival for the entire group was 33.1% at five years and 22.9% at 10 years. The allogeneic group had a 33.3% event-free survival at five years and a 31.4% event-free survival at 10 years, compared with 32.9% and 15.2% in the autologous group."
The stat that jumps out at me is that the relapses are few between 5 and 10 years in the Allo group while the Auto group continues to fall. It is encouraging that the Auto group still has 15% PFS at 10 years. The patients in the study do not have the benefit of novel agents, so that would improve outcomes for both Auto and Allo group. I think this data supports the thought that current drugs/Autos do not target the Cancer Stem cell and that the Donor Immune system can be part of a cure. I have not seen a 20 year long term followup study, but the chance of relapse appears low to the Allo patients after 5 years.
Also, Dr. Rajkumar wrote this in the Blood article regarding Cure/Control:
"Third, in most cases, it is probably impossible (with the possible exception of allogeneic transplantation where true complete eradication is possible for a minority of patients), unnecessary, and prohibitively toxic to attempt to eradicate all clonal plasma cells."
http://bloodjournal.hematologylibrary.org/content/118/12/3205.full
Great discussion.
Mark
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Mark
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Mark, I agree that at present the only theoretical cure is with an allogeneic transplant, but at the present time myeloma specialists don't know yet who is best to receive it and where it fits in the scheme of things. The procedural mortality is too high at 15% for it to be routine versus 2% or less for autologous SCT. Hopefully they can improve on that figure as they have since the 30-40% figure from the early 1990's .
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bond007
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Mark,Bond007
I am loving this discourse!!
Thanks for the follow up links, Mark
Bond007, I do tend to agree with you about the outcome stats on allos. There needs to be significant improvement prior to it becoming a standard of therapeutic practice. Those odds are frightening at present.
However, what do you guys think about new drugs being used for hi-dose chemo prior to stem cell transplant. Even Barlogie admits in the debate, that it is clear that the higher the dose of melphan the better the results, of course the lungs and GI falling out were dosing limiting toxicities for him.
OTOH, carfilzomib seems to not have such dose limitations and in fact it seems based on the feedback from ASH2011, they may not have submitted high enough doses for FDA approval.
http://ash.confex.com/ash/2011/webprogram/Paper38282.html
I think it would be great if instead of melphan or other toxic alkylating agents, if hi-dose protesome inhibitors were used in hi-risk multiple myeloma patients. Particularly, as they have shown that those patients actually do significantly worse on following alklyators. Based on the medicinal chemistry, it seems that their efficacy is due to genetic disruption and hi risk multiple myeloma patients already have genetic instability based on their GEP so the added effect of the agent is deleterious.
I would like to see clinical trials set up where hi-risk MMpatients receive protesome inhibitors high dose vs conventional multiple myeloma patients receiving the traditional standard alklylators and compare the outcomes.
Your thoughts?
I am loving this discourse!!
Thanks for the follow up links, Mark
Bond007, I do tend to agree with you about the outcome stats on allos. There needs to be significant improvement prior to it becoming a standard of therapeutic practice. Those odds are frightening at present.
However, what do you guys think about new drugs being used for hi-dose chemo prior to stem cell transplant. Even Barlogie admits in the debate, that it is clear that the higher the dose of melphan the better the results, of course the lungs and GI falling out were dosing limiting toxicities for him.
OTOH, carfilzomib seems to not have such dose limitations and in fact it seems based on the feedback from ASH2011, they may not have submitted high enough doses for FDA approval.
http://ash.confex.com/ash/2011/webprogram/Paper38282.html
I think it would be great if instead of melphan or other toxic alkylating agents, if hi-dose protesome inhibitors were used in hi-risk multiple myeloma patients. Particularly, as they have shown that those patients actually do significantly worse on following alklyators. Based on the medicinal chemistry, it seems that their efficacy is due to genetic disruption and hi risk multiple myeloma patients already have genetic instability based on their GEP so the added effect of the agent is deleterious.
I would like to see clinical trials set up where hi-risk MMpatients receive protesome inhibitors high dose vs conventional multiple myeloma patients receiving the traditional standard alklylators and compare the outcomes.
Your thoughts?
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Hi, Bond007 and suzierose:
This is excellent discussion and I learned a lot from your comments and posted links. In your knowledge what therapies, novel drugs included, have been proven to have none or little effects on multiple myeloma stem cells even though they are effective on multiple myeloma plasma cells? suzierose mentioned the UAMS experience that higher dosage of Melphan yields better results. Could it be possible that Melphan or some of the large number of agents used by UAMS have actually been effective on multiple myeloma stem cells in addition to plasma cells? Love to hear your views and thanks!
Ben
This is excellent discussion and I learned a lot from your comments and posted links. In your knowledge what therapies, novel drugs included, have been proven to have none or little effects on multiple myeloma stem cells even though they are effective on multiple myeloma plasma cells? suzierose mentioned the UAMS experience that higher dosage of Melphan yields better results. Could it be possible that Melphan or some of the large number of agents used by UAMS have actually been effective on multiple myeloma stem cells in addition to plasma cells? Love to hear your views and thanks!
Ben
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Ben S.
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Joe,
Sorry I did not respond to your earlier post with regard to Allogeneic transplants earlier. Since an Allo is a "real" transplant many factors can influence the outcome. An Auto is correctly called a transplant but the therapy is only a High Dose of Chemo. For instance, using Marrow as opposed to Peripheral blood stem cells and sex of donor can impact outcomes.
I obviously am not qualified to comment out how the trial you are considering may turn out. I have never used Revlimid or Sirolimus. I used Tacrolimus and did not have any problem with GVHD. I had only a mild acute skin rash that lasted about 2.5 weeks and than resolved. It is common to gradually taper off the Tacrolimus and finish using it in the Day +180 range. I am about 8 monts out, off the Tacrolimus and have a very slight Chronic GVHD skin rash. The type of GVHD I have had is considered a good thing since it does not impact quality of life.
One thing not mentioned in the study is if you are using ATG (antithymocyte globulin). ATG is typically used Days -3 through -1 and has been shown to reduce the incidence and severity of Chronic GVHD. That is extremely important for QOL. Doctors at Mayo found using ATG with Mismatched Allos a safe procedure at this years ASH. Hopefully you have a matched donor. ATG is a form of In-Vivo T Cell depletion.
http://ash.confex.com/ash/2011/webprogram/Paper38494.html
I made an attempt to discuss what DLI's were in this thread. Hopefully this helps.
https://myelomabeacon.org/forum/post3203.html#p3203
Mark
Sorry I did not respond to your earlier post with regard to Allogeneic transplants earlier. Since an Allo is a "real" transplant many factors can influence the outcome. An Auto is correctly called a transplant but the therapy is only a High Dose of Chemo. For instance, using Marrow as opposed to Peripheral blood stem cells and sex of donor can impact outcomes.
I obviously am not qualified to comment out how the trial you are considering may turn out. I have never used Revlimid or Sirolimus. I used Tacrolimus and did not have any problem with GVHD. I had only a mild acute skin rash that lasted about 2.5 weeks and than resolved. It is common to gradually taper off the Tacrolimus and finish using it in the Day +180 range. I am about 8 monts out, off the Tacrolimus and have a very slight Chronic GVHD skin rash. The type of GVHD I have had is considered a good thing since it does not impact quality of life.
One thing not mentioned in the study is if you are using ATG (antithymocyte globulin). ATG is typically used Days -3 through -1 and has been shown to reduce the incidence and severity of Chronic GVHD. That is extremely important for QOL. Doctors at Mayo found using ATG with Mismatched Allos a safe procedure at this years ASH. Hopefully you have a matched donor. ATG is a form of In-Vivo T Cell depletion.
http://ash.confex.com/ash/2011/webprogram/Paper38494.html
I made an attempt to discuss what DLI's were in this thread. Hopefully this helps.
https://myelomabeacon.org/forum/post3203.html#p3203
Mark
-
Mark
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Suzierose,
I had read about some studies that included Velcade with Melphalan and it got some better results. I am guessing that some type of Mustard Gas would have to be included in the Auto. It probably would be a good idea to try Carfilzomib in a higher dose with the Melphalan. Here is a link to study from ASH 2010.
http://ash.confex.com/ash/2010/webprogram/Paper34450.html
You may find this interesting. Back in 1996 an article in Blood that was co-authored by Dr. Barlogie discusses the use of DLIs after an Allo transplant. The paper describes a patient that was relapsed and drugs/Autos cannot get him back into remission. They do a T Cell depleted Allo and they cannot get him back into Remission but DLI's do. Here is a passage:
"It is a humbling experience for BMT physicians to appreciate a profound antitumor effect exerted by donor PB cells after failure of myeloablative chemoradiotherapy."
Here is the conclusion of the article:
"It is likely that future progress in cancer therapy will depend on judicious and safe manipulation of the immune system, rather than on further intensification of cytotoxic
agents."
http://bloodjournal.hematologylibrary.org/content/87/3/1196.full.pdf+html
What happend?!?!?! Afterall, we all hear about all the progress they are making at UAMS toward a cure.
Mark
I had read about some studies that included Velcade with Melphalan and it got some better results. I am guessing that some type of Mustard Gas would have to be included in the Auto. It probably would be a good idea to try Carfilzomib in a higher dose with the Melphalan. Here is a link to study from ASH 2010.
http://ash.confex.com/ash/2010/webprogram/Paper34450.html
You may find this interesting. Back in 1996 an article in Blood that was co-authored by Dr. Barlogie discusses the use of DLIs after an Allo transplant. The paper describes a patient that was relapsed and drugs/Autos cannot get him back into remission. They do a T Cell depleted Allo and they cannot get him back into Remission but DLI's do. Here is a passage:
"It is a humbling experience for BMT physicians to appreciate a profound antitumor effect exerted by donor PB cells after failure of myeloablative chemoradiotherapy."
Here is the conclusion of the article:
"It is likely that future progress in cancer therapy will depend on judicious and safe manipulation of the immune system, rather than on further intensification of cytotoxic
agents."
http://bloodjournal.hematologylibrary.org/content/87/3/1196.full.pdf+html
What happend?!?!?! Afterall, we all hear about all the progress they are making at UAMS toward a cure.
Mark
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Mark
Re: Barlogie-Rajkumar Debate - Part 1 of 5
Hi SusieRose,
I agree with you on lack of alternatives of high dose chemo prior to SCT. Since the SCT is to rescue you from the chemo killing that kills your bone marrow, you'd think they could throw the kitchen sink at you! Draino comes to mind. But I'm not an oncologist.
I agree with you on lack of alternatives of high dose chemo prior to SCT. Since the SCT is to rescue you from the chemo killing that kills your bone marrow, you'd think they could throw the kitchen sink at you! Draino comes to mind. But I'm not an oncologist.
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Stann
21 posts
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