I recognize this may not be of interest to many but
This paper was excellent in its connecting of the dots of how thalidomide caused limb defects.
I am certain many could be going well, what the heck does that have to do with multiple myeloma?
Well, the mechanism is still at play when you take it for multiple myeloma...and it provides more insight into the pathway of SPM (secondary primary mechanisms) due to destablization of DNA.
I am so happy we have researchers/scientists like Dr Trent Stephens, with such passion that they are willing to pick up the trail two decades later, when more is known and share the how and why of what happened then. Quite fascinating what he discovered to link all the molecular events together. Awesome work on his part as well. Bright minds are priceless.
It was most intriguing because we have read/heard numerous times how these IMIDs have multiple pathways and little specificity on just precisely which path could be impacting multiple myeloma or is it an interplay of the many routes?
In addition, Dr. Stephens shares there could be major species difference in terms of what is seen in the lab when it comes to DNA in rats vs rabbits, apes and humans as they have different concentrations of DNA the drug may act on. IOW's the lab may show minor impact in one species but major AE in humans simply due to variance in concentration of the gene between species.
"Rats and mice may not have as many genes in this pathway that have GC promoters, and therefore are less sensitive to thalidomide than are rabbits, humans, and other primates."
I found this statement impactful:
" Each step in this chain of events is potentially sensitive to thalidomide intercalation. The probability of linking eight steps in one chain of events all of which belong to this rare class of gene promoters is 4 x 10-9. Furthermore, with such a linked pathway, thalidomide does not have to affect any one part of the pathway to any great extent to have profound effects on the overall outcome. For example, if thalidomide decreased the efficiency of each step in the pathway by only 10 % the entire pathway efficiency would be reduced by more than 50 %. A 20 % reduction at each step would reduce the whole system by 80 %."
Wow. FOUR times TEN to the negative NINTH power!!! ...wow. nevertheless Stephens linked them....just wow....and that is followed by the holy moly bejesus...EIGHTY percent.... whoosh!!!
It is not an easy read, but here is the link:
http://www.thalidomide.ca/thalidomide-mechanism/
Forums
8 posts
• Page 1 of 1
Re: Elucidating Mechanism of Thalidomide
Hi Suzierose, thanks for the link regarding Dr. Stephen's work on uncovering the mechanism of thalidomide on growing limbs. This is really in the realm of embryology, isn't it? It is not a difficult read for anyone who has studied cell biology...and nowadays, in grade 12 biology, that sort of study of DNA and mitosis is on the curriculum Back in the '70s, when I was a Microbiology student, we were learning about this sort of thing also, although it seems that the mechanism was not ready to be discovered.
OK, here is another question for you or other researchers who are kind enough to share their highly specialized knowledge of these topics.....I understand that thalidomide is now used to treat people who suffer from leprosy....how does that work?
One thing that you can say in favour of thalidomide, is that it is cheap to obtain in markets such as Mexico and India. Probably that is why it is still widely used in myeloma, even though it causes more neuropathy than the newer drugs.
Take good care of yourself, and I hope that the protocols that you are taking for the multiple myeloma are working out really well for you!
More reading could include "Dr. Folkman's War, Angiogenesis and the Struggle to Defeat Cancer', by Robert Cooke ..published by Ramdom House, NY., 2001
OK, here is another question for you or other researchers who are kind enough to share their highly specialized knowledge of these topics.....I understand that thalidomide is now used to treat people who suffer from leprosy....how does that work?
One thing that you can say in favour of thalidomide, is that it is cheap to obtain in markets such as Mexico and India. Probably that is why it is still widely used in myeloma, even though it causes more neuropathy than the newer drugs.
Take good care of yourself, and I hope that the protocols that you are taking for the multiple myeloma are working out really well for you!
More reading could include "Dr. Folkman's War, Angiogenesis and the Struggle to Defeat Cancer', by Robert Cooke ..published by Ramdom House, NY., 2001
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Nancy Shamanna - Name: Nancy Shamanna
- Who do you know with myeloma?: Self and others too
- When were you/they diagnosed?: July 2009
Re: Elucidating Mechanism of Thalidomide
According to the World Health Organization (WHO) website, thalidomide is no longer encouraged to be used in the treatment of leprosy. For one thing, a better drug combination has been found, and for another, it is very difficult to control the use of thalidomide so that the teratogenic effects do not occur. Even now, some babies are born every year with birth defects linked to the use of thalidomide.
Should have checked my facts first....sorry about that!
Speaking of teratogenic effects, when I took Revlimid, there were very tight controls on the drug and I had to return all of the packaging every cycle, and had to answer questionnaires regarding getting pregnant etc., leaving the drugs available to others, and such. Wasn't a problem for me at my age, but they tried to be very careful about it. That is probably part of the cost of the drug too, since each patient is individually monitored , by the drug company and the hospital pharmacy.
Should have checked my facts first....sorry about that!
Speaking of teratogenic effects, when I took Revlimid, there were very tight controls on the drug and I had to return all of the packaging every cycle, and had to answer questionnaires regarding getting pregnant etc., leaving the drugs available to others, and such. Wasn't a problem for me at my age, but they tried to be very careful about it. That is probably part of the cost of the drug too, since each patient is individually monitored , by the drug company and the hospital pharmacy.
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Nancy Shamanna - Name: Nancy Shamanna
- Who do you know with myeloma?: Self and others too
- When were you/they diagnosed?: July 2009
Re: Elucidating Mechanism of Thalidomide
Hi Nancy,
Not sure if this was in realm of embryology so much as it was about angiogenesis and the inhibition of blood vessel formation, VEGF (vascular endothelial growth factor) which is needed for growth of limbs in the wombs just as it is needed for tumor growth for metasisis. Which is a long way of saying that cancer in adults needs this factor as well.
One thing that has often been postulated for anti-cancer agents is to prevent blood vessel formation and it can be contained. Unfortunately, the agents that were looked at in clinical trials were non-specific for cancer tumors, and numerous patients bled to death last I heard...haven't done a recent search lately.
I agree that Stephens article perhaps is not difficult for those with strong science bkgrds, but we have such a cross-spectrum here at the forum and it is overwhelming for many of us, to just keep the acronyms straight for our labs, let alone additional terms that don't always connect the dots back to multiple myeloma.
No problem about WHO, it was used awhile back, just not presently...our recall with this chemo not to mention sterioids...can get fuzzy..lol anywhooo
I looked up thalidomide and leprosy ( wasn't even aware of that use) but it seems it is used more for the adverse events of the disease vs. treatment of the bacteria which is responsible for the pathogenesis:
"literature concerning the use and possible mode of action of thalidomide in reactional lepromatous leprosy and in various other conditions .... Although it has no action against the leprosy bacillus, its value in the treatment of the adverse reactions in this type of leprosy is well established, many leprologists considering it to be superior to any other drug for this purpose."
Which is kinda how they give multiple myeloma patients bisphosphonates which is not efficacious for multiple myeloma but it does prevent the B in CRAB end organ damage that can ensue due to the disease.
Yeah, there are some stringent controls on access to lenalidomide/thalidomide...we were really fortunate in the USA despite those 100K dead babies in the womb, only 17 were born with limb defects in the USA because the FDA was far more stringent about safety data back in the 60s, despite it having been on the market in Europe since '57. The single female employee who refused to approve it was concerned about safety, absorption data and peripheral neuropathy moreso than teratogenic effects. Kelsey wrote:
" In particular, although this drug appeared to be remarkably nontoxic in animals and human beings, little or no information was available concerning its absorption, distribution in the body, or its excretion. Since the possibility existed that the low toxicity of the drug in certain species might be related to poor absorption in those species, and that under certain conditions the absorption in other species might be increased, further work was requested relative to the metabolism of the drug."
http://en.wikipedia.org/wiki/Frances_Oldham_Kelsey
Now back then they did not even require drugs to be tested in pregnant animals so had they had the safety data, we likely would have been as badly impacted as the UK & Germany were. Mine you though the USA had had a major recall of sulfianilmide(over 100 deaths mostly children) because it contained propylene glycol (antifreeze) in early 30s that resulted in more rigorous safety reviews and Kelsey was likely heeding the outcome of that disaster. Yet even so, she was the sole employee who did. Thank God for female tenacity.
....here is a write up on that heartwrenching recall:
http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SulfanilamideDisaster/default.htm
Sorry, this is so long...thought you might find it interesting background as to why drugs USE to take longer to make it through the FDA...AIDS was responsible for altering the length and demand for bigger trials along with safety data...they insisted it was better to try the drugs in the dying than to sign death warrants by witholding possible cures.
...ahhh...history....
Not sure if this was in realm of embryology so much as it was about angiogenesis and the inhibition of blood vessel formation, VEGF (vascular endothelial growth factor) which is needed for growth of limbs in the wombs just as it is needed for tumor growth for metasisis. Which is a long way of saying that cancer in adults needs this factor as well.
One thing that has often been postulated for anti-cancer agents is to prevent blood vessel formation and it can be contained. Unfortunately, the agents that were looked at in clinical trials were non-specific for cancer tumors, and numerous patients bled to death last I heard...haven't done a recent search lately.
I agree that Stephens article perhaps is not difficult for those with strong science bkgrds, but we have such a cross-spectrum here at the forum and it is overwhelming for many of us, to just keep the acronyms straight for our labs, let alone additional terms that don't always connect the dots back to multiple myeloma.
No problem about WHO, it was used awhile back, just not presently...our recall with this chemo not to mention sterioids...can get fuzzy..lol anywhooo
I looked up thalidomide and leprosy ( wasn't even aware of that use) but it seems it is used more for the adverse events of the disease vs. treatment of the bacteria which is responsible for the pathogenesis:
"literature concerning the use and possible mode of action of thalidomide in reactional lepromatous leprosy and in various other conditions .... Although it has no action against the leprosy bacillus, its value in the treatment of the adverse reactions in this type of leprosy is well established, many leprologists considering it to be superior to any other drug for this purpose."
Which is kinda how they give multiple myeloma patients bisphosphonates which is not efficacious for multiple myeloma but it does prevent the B in CRAB end organ damage that can ensue due to the disease.
Yeah, there are some stringent controls on access to lenalidomide/thalidomide...we were really fortunate in the USA despite those 100K dead babies in the womb, only 17 were born with limb defects in the USA because the FDA was far more stringent about safety data back in the 60s, despite it having been on the market in Europe since '57. The single female employee who refused to approve it was concerned about safety, absorption data and peripheral neuropathy moreso than teratogenic effects. Kelsey wrote:
" In particular, although this drug appeared to be remarkably nontoxic in animals and human beings, little or no information was available concerning its absorption, distribution in the body, or its excretion. Since the possibility existed that the low toxicity of the drug in certain species might be related to poor absorption in those species, and that under certain conditions the absorption in other species might be increased, further work was requested relative to the metabolism of the drug."
http://en.wikipedia.org/wiki/Frances_Oldham_Kelsey
Now back then they did not even require drugs to be tested in pregnant animals so had they had the safety data, we likely would have been as badly impacted as the UK & Germany were. Mine you though the USA had had a major recall of sulfianilmide(over 100 deaths mostly children) because it contained propylene glycol (antifreeze) in early 30s that resulted in more rigorous safety reviews and Kelsey was likely heeding the outcome of that disaster. Yet even so, she was the sole employee who did. Thank God for female tenacity.
....here is a write up on that heartwrenching recall:http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SulfanilamideDisaster/default.htm
Sorry, this is so long...thought you might find it interesting background as to why drugs USE to take longer to make it through the FDA...AIDS was responsible for altering the length and demand for bigger trials along with safety data...they insisted it was better to try the drugs in the dying than to sign death warrants by witholding possible cures.
...ahhh...history....
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Elucidating Mechanism of Thalidomide
hI again Suzierose! Your energy is really amazing! THanks for responding to my post about thalidomide. Since this is a myeloma forum, I won't go into details, but suffice it to say that the whole story of the birth defects back from 1957-1962 is written up in Wikipedia. It wasn't approved by the USDA at that time (although it was given out as sample drugs), but it was approved in Europe and Canada. So lots of terrible tragedy ensued. That is why we must be so very careful with it and any related drugs nowadays to make sure they are not used inappropriately. Even men are warned about the possible side effects, since it hasn't been shown that men would NOT be able to pass along the possibility of birth defects!
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Nancy Shamanna - Name: Nancy Shamanna
- Who do you know with myeloma?: Self and others too
- When were you/they diagnosed?: July 2009
Re: Elucidating Mechanism of Thalidomide
Hi Nancy!
Happy Sunday!!
I wasn't thinking we were off thread topic, since thalidomide is used to treat multiple myeloma. and the thread subject is the mechanism of thalidomide. Besides, intellectual curiosity allows us to put multiple myeloma on hold for a moment I also wanted to focus on the FDA approval of new agents as it stands today and how politicized it has become. The background on thalidomide was an excellent example to do so and show how stringent the FDA was about drug safety last century.
One of the front page news articles is about SPM and focused on lenalidomide which is far more potent than thalidomide, yet we did not have a label change for thalidomide despite the MOA being the same?....hmmmm
The history of how the FDA functions highlights some of the whys and wherefors as well as illustrating that my concerns are grounded in the history of the agency about the delay of new protesome inhibitors for multiple myeloma when Celgene was allowed to fast tract a drug like lenalidomide, even use thalidomide with its terrible AE history, all of which shows how politicized the process is today for approval.
I used thalidomide because I am also upset that they are not pushing carfilzomib through when it has far less AE's than pomalidomide and we already have lenalidomide and thalidomide approved. Definititely being oral is a big deal, however, a second proteasome inhibitor on the market would be far more beneficial for all those patients who have relapsed on bortezomib.
Instead, Celgene is designing trials with alternating weeks of lenalidomide and thalidomide and the FDA is going to approved pomalidomide before carfizilzomib???? Despite showing increased risk of SPM with lenalidomide which is 50,000 as potent as thalidimide and pomalidomide is 5x more potent than lenalidomide???!!! GMAB
pomalidomide also has the same mechanism as thalidomide as well so we get more drugs in a class of agents that are showing increase in SPM but not approval for a new agent that has far less
AE's??????
http://www.nature.com/leu/journal/v24/n1/fig_tab/leu2009236t1.html
Which is a really long way of saying that's why I initially started this thread.
multiple myeloma patients need carfilzomib approved much moreso than another more potent IMID with the likely risks of SPM as well as more severe myelosuppression and already demonstrating in trials that patients are getting more infections due to the later AE's.
Hrrrrrmph....politics!!!.
Happy Sunday!!
I wasn't thinking we were off thread topic, since thalidomide is used to treat multiple myeloma. and the thread subject is the mechanism of thalidomide. Besides, intellectual curiosity allows us to put multiple myeloma on hold for a moment
I also wanted to focus on the FDA approval of new agents as it stands today and how politicized it has become. The background on thalidomide was an excellent example to do so and show how stringent the FDA was about drug safety last century.One of the front page news articles is about SPM and focused on lenalidomide which is far more potent than thalidomide, yet we did not have a label change for thalidomide despite the MOA being the same?....hmmmm
The history of how the FDA functions highlights some of the whys and wherefors as well as illustrating that my concerns are grounded in the history of the agency about the delay of new protesome inhibitors for multiple myeloma when Celgene was allowed to fast tract a drug like lenalidomide, even use thalidomide with its terrible AE history, all of which shows how politicized the process is today for approval.
I used thalidomide because I am also upset that they are not pushing carfilzomib through when it has far less AE's than pomalidomide and we already have lenalidomide and thalidomide approved. Definititely being oral is a big deal, however, a second proteasome inhibitor on the market would be far more beneficial for all those patients who have relapsed on bortezomib.
Instead, Celgene is designing trials with alternating weeks of lenalidomide and thalidomide and the FDA is going to approved pomalidomide before carfizilzomib???? Despite showing increased risk of SPM with lenalidomide which is 50,000 as potent as thalidimide and pomalidomide is 5x more potent than lenalidomide???!!! GMAB
pomalidomide also has the same mechanism as thalidomide as well so we get more drugs in a class of agents that are showing increase in SPM but not approval for a new agent that has far less
AE's??????
http://www.nature.com/leu/journal/v24/n1/fig_tab/leu2009236t1.html
Which is a really long way of saying that's why I initially started this thread.
multiple myeloma patients need carfilzomib approved much moreso than another more potent IMID with the likely risks of SPM as well as more severe myelosuppression and already demonstrating in trials that patients are getting more infections due to the later AE's.
Hrrrrrmph....politics!!!.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: Elucidating Mechanism of Thalidomide
Thanks for your thoughts on these matters, Suzierose. I don't know enough about the drug approval processes to be able to make an intelligent comment, but it does seem to me that the more anti-myeloma drugs that there are to choose from, the better it will be for the patient population. I just wanted to comment yesterday about the need to safely control the use of drugs that may be implicated in teratology. Probably all of the new drugs will be approved before too long, and then the oncologists can review their efficacy and other features, and prescribe what works for each patient. Since many patients are in a position of relapse, they may need to try a variety of drugs over the years. We really don't know what the future holds for us!
I enjoy reading your posts since you are so knowledgeable! Keep up the good work but take good care of yourself also, OK?
I enjoy reading your posts since you are so knowledgeable! Keep up the good work but take good care of yourself also, OK?
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Nancy Shamanna - Name: Nancy Shamanna
- Who do you know with myeloma?: Self and others too
- When were you/they diagnosed?: July 2009
Re: Elucidating Mechanism of Thalidomide
Hey Nancy,
You are right the more drugs available are best for all.
However, have you seen the numbers for pomalidomide/dex in refractory patients? Less than a third of patients had a minor response i.e. 50% drop in M spike. The majority of patients that responded was only 23%. Now, given that this is a refractory population to both bortzomib and lenalidamide that is better than zip.
OTOH, carfilzomib, unlike bortezomib is an irreversible protesome inhibitor that is effective in the bortezomib resistant population:
"When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response."
http://www.ncbi.nlm.nih.gov/pubmed/22216088
"Importantly, carfilzomib showed increased efficacy compared with bortezomib and was active against bortezomib-resistant multiple myeloma cell lines and samples from patients with clinical bortezomib resistance. Carfilzomib also overcame resistance to other conventional agents and acted synergistically with dexamethasone to enhance cell death."
http://www.ncbi.nlm.nih.gov/pubmed/17591945
and the numbers for carfilzomib as a single agent in refractory patients:
"A total of 24 percent of patients achieved a partial response or better. Dr. Siegel added that 10 percent of patients achieved a minimal response.
“The reason I point out the 10 percent of minimal responders,” explained Dr. Siegel, “is that the duration of response was 8.3 months, and this 8.3 months was maintained in both the partial response or better population and the minimal response or better population.”
https://myelomabeacon.org/news/2010/12/20/carfilzomib-shows-promise-in-both-newly-diagnosed-and-relapsed-refractory-multiple-myeloma-patients-ash-2010/
So carfilzomib as a SINGLE agent is as good as pomalidomide with dex in refractory patients, who only got one month PFS, btw...and who wants to take a steroid if they don't have to?..hehehehe
Millenium and Celegene will see revenues drop drastically instantly, after all the largest multiple myeloma patient population are the refractory/relapsed patients, not the newly diagnosed.
Delay, delay, delay FDA is the tune their singing allllll the way to the bank.
ok ok..it's Sunday...stepping down off soapbox
And thanks for the compliment and especially well wishes, I need them. First it was my allergies that were going crazy, now the post nasal drip from that has gone pulmonary and I am starting to cough off yellow tinged phelgm..ooooh nooooo!! Don't need that while on steroids.
Sending you blessings Nancy...and good health wishes as well.
You are right the more drugs available are best for all.
However, have you seen the numbers for pomalidomide/dex in refractory patients? Less than a third of patients had a minor response i.e. 50% drop in M spike. The majority of patients that responded was only 23%. Now, given that this is a refractory population to both bortzomib and lenalidamide that is better than zip.
OTOH, carfilzomib, unlike bortezomib is an irreversible protesome inhibitor that is effective in the bortezomib resistant population:
"When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response."
http://www.ncbi.nlm.nih.gov/pubmed/22216088
"Importantly, carfilzomib showed increased efficacy compared with bortezomib and was active against bortezomib-resistant multiple myeloma cell lines and samples from patients with clinical bortezomib resistance. Carfilzomib also overcame resistance to other conventional agents and acted synergistically with dexamethasone to enhance cell death."
http://www.ncbi.nlm.nih.gov/pubmed/17591945
and the numbers for carfilzomib as a single agent in refractory patients:
"A total of 24 percent of patients achieved a partial response or better. Dr. Siegel added that 10 percent of patients achieved a minimal response.
“The reason I point out the 10 percent of minimal responders,” explained Dr. Siegel, “is that the duration of response was 8.3 months, and this 8.3 months was maintained in both the partial response or better population and the minimal response or better population.”
https://myelomabeacon.org/news/2010/12/20/carfilzomib-shows-promise-in-both-newly-diagnosed-and-relapsed-refractory-multiple-myeloma-patients-ash-2010/
So carfilzomib as a SINGLE agent is as good as pomalidomide with dex in refractory patients, who only got one month PFS, btw...and who wants to take a steroid if they don't have to?..hehehehe
Millenium and Celegene will see revenues drop drastically instantly, after all the largest multiple myeloma patient population are the refractory/relapsed patients, not the newly diagnosed.
Delay, delay, delay FDA is the tune their singing allllll the way to the bank.
ok ok..it's Sunday...stepping down off soapbox
And thanks for the compliment and especially well wishes, I need them. First it was my allergies that were going crazy, now the post nasal drip from that has gone pulmonary and I am starting to cough off yellow tinged phelgm..ooooh nooooo!! Don't need that while on steroids.
Sending you blessings Nancy...and good health wishes as well.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
8 posts
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