One thing I found interesting in this study is the use and dosage for prednisone. It seems like dex is the steroid of choice in most current treatment regimes. Anyone who has taken dex knows the difficult side effects of the drug. When we thought I may be relapsing I convinced my doctor to prescribe prednisone instead of dex. I took 25 mg every other day. There were virtually no side effects.
In the study the dosages were either 25 mg every other day or 1.5 mg for 4 days of each cycle. Relatively low doses. I wish I knew if it is equally effective as dex, but it sure is worth a try.
Forums
Re: Revlimid 3-drug regimens no better than Revlimid-dex
Hello Andrew:
I was on Cytoxan and prednisone 32 years ago. First on oral, and second time after five years on ten days IV, afterwards oral. I remember getting ulcers as side effect of prednisone. They gave me Tagamet to control it.
Now I am on my eleventh cycle of Revlimid, normal dose of 25 mg, plus dex, reduced dose of 16 mg.
I was on Cytoxan and prednisone 32 years ago. First on oral, and second time after five years on ten days IV, afterwards oral. I remember getting ulcers as side effect of prednisone. They gave me Tagamet to control it.
Now I am on my eleventh cycle of Revlimid, normal dose of 25 mg, plus dex, reduced dose of 16 mg.
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MMFeb16,15 - Who do you know with myeloma?: Self
- When were you/they diagnosed?: February 16, 2015
- Age at diagnosis: 66
Re: Revlimid 3-drug regimens no better than Revlimid-dex
Thanks, everyone, for the additional comments in this thread. It's been an interesting discussion.
As far as the points several people made about prednisone being used in some of the regimens tested in the study, I agree that it confuses the issue a bit. My impression is that prednisone may not be as effective in combination with Revlimid (and perhaps thalidomide) as it is in combination with, say, Velcade. The same also may be true of melphalan and cyclophosphamide - they may combine better with Velcade than with Revlimid.
As far as the point JPC makes, where he writes:
I think there are some cases where this is widely believed to be true, and others where many researchers have questions.
Let's take the simple, "everyone would agree" case first.
Say you give some myeloma patients drug X, and you give other myeloma patients a placebo. Say the patients that get drug X have noticeably longer progression-free survival. Well, even if you don't have proof that X improves overall survival, we can all probably conclude that it will improve the overall survival of myeloma patients. So, assuming it is otherwise safe, it should be approved to treat myeloma.
This is the logic the FDA uses many times when it approves cancer drugs based on smaller Phase 2 studies, rather than the usual Phase 3 studies.
Now, let's turn to the more difficult case.
Let's say you give some patients drug X and dex for 6 months, and then you stop. In a second group of patients, you give them drug X and dex continuously until their disease progresses.
As long as drug X has some anti-myeloma activity, I can almost guarantee you that giving X + dex until progression will result in longer progression-free survival. But there is no guarantee, even under controlled circumstances, that the strategy will improve overall survival.
In cases where you extend treatment with a drug, or where you intensify treatment by adding more drugs to a treatment regimen, you will almost automatically get longer progression-free survival. But that is no guarantee that the strategy improves either overall survival or total quality of life.
It is debates on those issues that are important right now when it comes to treating multiple myeloma patients, and it is precisely why making the assumption that higher progression-free survival is always better is NOT correct.
As far as the points several people made about prednisone being used in some of the regimens tested in the study, I agree that it confuses the issue a bit. My impression is that prednisone may not be as effective in combination with Revlimid (and perhaps thalidomide) as it is in combination with, say, Velcade. The same also may be true of melphalan and cyclophosphamide - they may combine better with Velcade than with Revlimid.
As far as the point JPC makes, where he writes:
There are other studies, that show for the most part, that better PFS [progression-free survival] does lead to better OS [overall survival]. So if there are two treatments being compared, and the PFS data is clear, but the OS is not, most doctors will go by the PFS results, and take that to be the better approach.
I think there are some cases where this is widely believed to be true, and others where many researchers have questions.
Let's take the simple, "everyone would agree" case first.
Say you give some myeloma patients drug X, and you give other myeloma patients a placebo. Say the patients that get drug X have noticeably longer progression-free survival. Well, even if you don't have proof that X improves overall survival, we can all probably conclude that it will improve the overall survival of myeloma patients. So, assuming it is otherwise safe, it should be approved to treat myeloma.
This is the logic the FDA uses many times when it approves cancer drugs based on smaller Phase 2 studies, rather than the usual Phase 3 studies.
Now, let's turn to the more difficult case.
Let's say you give some patients drug X and dex for 6 months, and then you stop. In a second group of patients, you give them drug X and dex continuously until their disease progresses.
As long as drug X has some anti-myeloma activity, I can almost guarantee you that giving X + dex until progression will result in longer progression-free survival. But there is no guarantee, even under controlled circumstances, that the strategy will improve overall survival.
In cases where you extend treatment with a drug, or where you intensify treatment by adding more drugs to a treatment regimen, you will almost automatically get longer progression-free survival. But that is no guarantee that the strategy improves either overall survival or total quality of life.
It is debates on those issues that are important right now when it comes to treating multiple myeloma patients, and it is precisely why making the assumption that higher progression-free survival is always better is NOT correct.
Re: Revlimid 3-drug regimens no better than Revlimid-dex
I wanted to make a comment back to you Terry. Your post is well reasoned and well written, but I disagree, however, the most of my disagreement is with one word.
The word being ASSUMPTION, with respect to 3-drug regimens (and let's narrow it down to newly diagnosed multiple myeloma - NDMM). I don't think the word assumption is fair in this case. The use of 3-drug regimens for transplant eligible NDMM patients who are fit enough to take them is not an "assumption", rather it is the consensus opinion of the IMWG; as well as Msmart guidelines for NDMM. An interested reader can reference those guidelines, and there is also supporting documents explaining their opinion. I am sure that many of the frequent forum readers are very aware of those references.
On the "less is more" side, there are some very successful doctors with that opinion (Dr. Berenson and Dr. Nievitzsky), and there are other doctors on the aggressive side (UAMS). All those doctors and others who follow their respective perspectives have valid opinions. And these doctors who deviate from the consensus opinions are in some cases very knowledgeable and very successful, I would say due to their experience and their skill at practicing the art of medicine.
The mainstream approach, however, is not simply an assumption. It is based on collective hundreds of years of clinical experience, and data driven, based on the total result of all of the clinical trial up to this point. It is the consensus judgement of the doctors that 3 drug initial inductions lead to better outcomes, not only better response and better PFS, but also ultimately OS.
Here is the question when I bring it back to the case of my wife, and I think is also relevant to others in the newly diagnosed and recently diagnosed setting. I do not want to really know what was the best treatment option 3 or 5 years ago. I want to know what is the best treatment option today. With almost 100% certainty, I can say the there is no OS data on the option that is best today. That data will not come out for at least 5 years. That is why Kyprolis is moving quickly into frontline treatment based on its limited data so far.
As I said earlier, however, I do think that there does exist very good doctors who can wisely infer, based on their experience, where a superior result for PFS can be applied where there is no clear data yet on OS (and I think it is a bit more than what we used to call in engineering a WAG).
Thanks for this interesting thread and good luck to you.
and it is precisely why making the ASSUMPTION that higher progression-free survival is always better is NOT correct
The word being ASSUMPTION, with respect to 3-drug regimens (and let's narrow it down to newly diagnosed multiple myeloma - NDMM). I don't think the word assumption is fair in this case. The use of 3-drug regimens for transplant eligible NDMM patients who are fit enough to take them is not an "assumption", rather it is the consensus opinion of the IMWG; as well as Msmart guidelines for NDMM. An interested reader can reference those guidelines, and there is also supporting documents explaining their opinion. I am sure that many of the frequent forum readers are very aware of those references.
On the "less is more" side, there are some very successful doctors with that opinion (Dr. Berenson and Dr. Nievitzsky), and there are other doctors on the aggressive side (UAMS). All those doctors and others who follow their respective perspectives have valid opinions. And these doctors who deviate from the consensus opinions are in some cases very knowledgeable and very successful, I would say due to their experience and their skill at practicing the art of medicine.
The mainstream approach, however, is not simply an assumption. It is based on collective hundreds of years of clinical experience, and data driven, based on the total result of all of the clinical trial up to this point. It is the consensus judgement of the doctors that 3 drug initial inductions lead to better outcomes, not only better response and better PFS, but also ultimately OS.
Here is the question when I bring it back to the case of my wife, and I think is also relevant to others in the newly diagnosed and recently diagnosed setting. I do not want to really know what was the best treatment option 3 or 5 years ago. I want to know what is the best treatment option today. With almost 100% certainty, I can say the there is no OS data on the option that is best today. That data will not come out for at least 5 years. That is why Kyprolis is moving quickly into frontline treatment based on its limited data so far.
As I said earlier, however, I do think that there does exist very good doctors who can wisely infer, based on their experience, where a superior result for PFS can be applied where there is no clear data yet on OS (and I think it is a bit more than what we used to call in engineering a WAG).
Thanks for this interesting thread and good luck to you.
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JPC - Name: JPC
Re: Revlimid 3-drug regimens no better than Revlimid-dex
JPC,
I just want to comment on a few things you said about Kyprolis...
Despite what you've suggested, data about Kyprolis in the treatment of newly diagnosed myeloma patients have been out there for many years. Dr. Jakubowiak, for example, published results of a trial testing Kyprolis, Revlimid, and dex in newly diagnosed patients in 2012, even before Kyprolis was approved by the FDA. He and others were presenting similar data at conferences a year or two prior to the publication of those results.
Also, I don't think there is much evidence of any rush to use Kyprolis in newly diagnosed patients.
For example, even though Pomalyst has not been tested as a treatment for newly diagnosed myeloma patients, and even though Pomalyst was approved in the U.S. after Kyprolis was approved, U.S. sales of Pomalyst in the last quarter of 2015 were higher than U.S. sales of Kyprolis:
U.S. sales, fourth quarter 2015
Pomalyst: $170 million
Kyprolis: $134 million
Also, U.S. sales of Pomalyst increased more from the third to fourth quarter of last year ($20 million) than Kyprolis sales increased ($10 million).
I believe your wife is mainly under the care of myeloma specialists at Sloan-Kettering, and I know Dr. Landgren -- a major proponent of Kyprolis -- is at Sloan-Kettering. So perhaps your views on the drug and its use are colored by his perspective.
I just want to comment on a few things you said about Kyprolis...
Despite what you've suggested, data about Kyprolis in the treatment of newly diagnosed myeloma patients have been out there for many years. Dr. Jakubowiak, for example, published results of a trial testing Kyprolis, Revlimid, and dex in newly diagnosed patients in 2012, even before Kyprolis was approved by the FDA. He and others were presenting similar data at conferences a year or two prior to the publication of those results.
Also, I don't think there is much evidence of any rush to use Kyprolis in newly diagnosed patients.
For example, even though Pomalyst has not been tested as a treatment for newly diagnosed myeloma patients, and even though Pomalyst was approved in the U.S. after Kyprolis was approved, U.S. sales of Pomalyst in the last quarter of 2015 were higher than U.S. sales of Kyprolis:
U.S. sales, fourth quarter 2015
Pomalyst: $170 million
Kyprolis: $134 million
Also, U.S. sales of Pomalyst increased more from the third to fourth quarter of last year ($20 million) than Kyprolis sales increased ($10 million).
I believe your wife is mainly under the care of myeloma specialists at Sloan-Kettering, and I know Dr. Landgren -- a major proponent of Kyprolis -- is at Sloan-Kettering. So perhaps your views on the drug and its use are colored by his perspective.
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Jonah
Re: Revlimid 3-drug regimens no better than Revlimid-dex
Great post, Jonah.
Just an observation with regard to using Kyprolis for newly diagnosed patients. I am sure there are / will be some examples of some long remissions using Kyprolis upfront. I would point out that we had 3 regular contributors here in the forum that used Kyprolis as part of their upfront therapy. One of them, TerryL, posted he was MRD negative after his induction and had no cytogenetic abnormalities. He sadly passed away 4 years after diagnosis. He did not come close to the 10-year median overall survival for standard risk transplant eligible patients. The other 2 both relapsed in roughly the same time frame I would expect patients to relapse using standard therapies
My point is any proteasome inhibitor combined with Revlimid and dex can look good with short follow up. The difference is that Velcade has long-term follow up and Phase 3 data that shows it increases overall survival. Newer is not always better.
Just an observation with regard to using Kyprolis for newly diagnosed patients. I am sure there are / will be some examples of some long remissions using Kyprolis upfront. I would point out that we had 3 regular contributors here in the forum that used Kyprolis as part of their upfront therapy. One of them, TerryL, posted he was MRD negative after his induction and had no cytogenetic abnormalities. He sadly passed away 4 years after diagnosis. He did not come close to the 10-year median overall survival for standard risk transplant eligible patients. The other 2 both relapsed in roughly the same time frame I would expect patients to relapse using standard therapies
My point is any proteasome inhibitor combined with Revlimid and dex can look good with short follow up. The difference is that Velcade has long-term follow up and Phase 3 data that shows it increases overall survival. Newer is not always better.
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Mark11
Re: Revlimid 3-drug regimens no better than Revlimid-dex
Good evening Johah:
Couple of quick points back to you, just to clarify. Kyprolis was not my main point of my post, but it is an example of a new drug. There was a follow-up study to Dr. Jakubowiak's earlier study that was published in 2012 in Blood. At the 2015 ASCO, he presented the results of the following regimen: Kyprolis, Revlimid, dexamethasone (KRD) induction; followed by autologous stem cell transplantation (ASCT); followed by KRD consolidation; and KRD maintenance. Here is the link:
http://meetinglibrary.asco.org/content/150628-156
If you could tolerate the regimen, it had a complete response (CR) rate of 86%. Some of the articles that I have read stated that CR rate achieved by that regimen far exceeded anything to date. Off the top of my head, I recall that Revlimid, Velcade, and dexamethasone (RVD) and cyclophosphamide, Velcade, and dex (CyBorD) had a CR rate of a little less than 50% after ASCT. I also can tell you that my earlier research did lead me to carfilzomib, but in the second half of 2014, it was not available at any of the major centers in NY off clinical trial, so the initial induction for my wife when the multiple myeloma turned from smoldering to active was RVD. There actually was one or two clinical trials we could potentially go on, but it was not a perfect match for us, so we took the RVD. Actually, I understood that a doctor could prescribe Kyprolis off label, but none of the insurance companies would pay for it at that time.
As far as KRD use front line, I have heard Dr. Jakubowiak reporting that his center, University of Chicago, was getting Kyprolis approved front line, off clinical trial, since 2014. I also have seen reported that the Mayo clinic will use Kyprolis front line for high risk patients since last year. As we are at MSKCC, I did learn that Kyprolis has been used in front line treatment since about mid last year (too late for us). I have also heard that the other major centers in NY have either done the same or will do so shortly. If I recall correctly, Dr. Berenson also stated that he uses it in front line treatment.
For front line, Kyprolis still would be "off-label", so its mainly an issue of coverage of insurance, and at this point, I understand it is still hit or miss, not all insurance companies will cover it, however, once a few dominoes fall, the others tend to eventually fall as well. So I would just speculate that based on the study results so far, and the recent trend, that KRD will become more widely used over time for initial induction (say over the next two years, perhaps). So I have been interested in it for a while and try to keep up with the news, but I assure you I am not a salesman for it.
Also keep in mind that the FDA only approved RVD for front line in early 2015. RVD had been widely used since about 2010, however, up until 2015, it had all been done off label. In the study referenced above, the link quotes a study size of 53 patients at the end of 2014, but I believe Dr. Jakubowiak later reports a larger number (over 100?) in the study. The average follow up was less than a year. One patient (out of 53) had progression. OS was 100%. If we assume that the overall survival will be similar to the recent IFM study with RVD, ASCT, and maintenance, then it will take at least five years for early signs of that data to come in. This was actually the main point I was trying to make.
Eventually that data will come in. I would be shocked if the Kyprolis-containing regimen turned out to be worse that RVD. I guess that it could be close, but based on the better response, I would speculate (and yes it's no more than a speculation at this point) that OS will turn out to be better, and by the way, there are also the monoclonal antibodies that can be used at first and second relapse. If it turned out that Kyprolis was better in terms of OS, then it would be simply following the same trend as was the case for thalidomide, Revlimid, and Velcade, as they were first approved for relapsed / refractory multiple myeloma (RRMM), but eventually moved into the front line over time. By the way, I hope it does not come across that I am thinking this up myself. I am just regurgitating the developmental trends that I have read a number of doctors explain, for example, I think most of what I mentioned above came from Dr. Kenneth Anderson.
Lastly, to take the idea one step further, there are a number of studies out there where elotuzumab and daratumumab are being used in initial induction, and in some cases, they are being added to the 3-drug regimen, making it four drugs. I do not think that those studies have real good data yet even on response, but over the next one to two years, that data will be coming out. Of interest, Dr. Usmani reported that when adding elotuzumab to the 3-drug regimen, the overall side effect profile for the 4 drugs was no worse than the 3 drugs. I think these issues become more in focus if you have high risk cytogenetics. Although the data is early, Dr. Jakubowiak reported that he did not yet see any worse outcomes in his high-risk portion of the study. Also, Dr. Richardson of Dana Farber reports that the monoclonal antibodies seem to be also be good for high risk cases. I will certainly agree that you raise another really good question. Why are they not moving Pomalyst into the front line faster? I would be interested to learn more about that question. Good luck and Best Regards
Couple of quick points back to you, just to clarify. Kyprolis was not my main point of my post, but it is an example of a new drug. There was a follow-up study to Dr. Jakubowiak's earlier study that was published in 2012 in Blood. At the 2015 ASCO, he presented the results of the following regimen: Kyprolis, Revlimid, dexamethasone (KRD) induction; followed by autologous stem cell transplantation (ASCT); followed by KRD consolidation; and KRD maintenance. Here is the link:
http://meetinglibrary.asco.org/content/150628-156
If you could tolerate the regimen, it had a complete response (CR) rate of 86%. Some of the articles that I have read stated that CR rate achieved by that regimen far exceeded anything to date. Off the top of my head, I recall that Revlimid, Velcade, and dexamethasone (RVD) and cyclophosphamide, Velcade, and dex (CyBorD) had a CR rate of a little less than 50% after ASCT. I also can tell you that my earlier research did lead me to carfilzomib, but in the second half of 2014, it was not available at any of the major centers in NY off clinical trial, so the initial induction for my wife when the multiple myeloma turned from smoldering to active was RVD. There actually was one or two clinical trials we could potentially go on, but it was not a perfect match for us, so we took the RVD. Actually, I understood that a doctor could prescribe Kyprolis off label, but none of the insurance companies would pay for it at that time.
As far as KRD use front line, I have heard Dr. Jakubowiak reporting that his center, University of Chicago, was getting Kyprolis approved front line, off clinical trial, since 2014. I also have seen reported that the Mayo clinic will use Kyprolis front line for high risk patients since last year. As we are at MSKCC, I did learn that Kyprolis has been used in front line treatment since about mid last year (too late for us). I have also heard that the other major centers in NY have either done the same or will do so shortly. If I recall correctly, Dr. Berenson also stated that he uses it in front line treatment.
For front line, Kyprolis still would be "off-label", so its mainly an issue of coverage of insurance, and at this point, I understand it is still hit or miss, not all insurance companies will cover it, however, once a few dominoes fall, the others tend to eventually fall as well. So I would just speculate that based on the study results so far, and the recent trend, that KRD will become more widely used over time for initial induction (say over the next two years, perhaps). So I have been interested in it for a while and try to keep up with the news, but I assure you I am not a salesman for it.
Also keep in mind that the FDA only approved RVD for front line in early 2015. RVD had been widely used since about 2010, however, up until 2015, it had all been done off label. In the study referenced above, the link quotes a study size of 53 patients at the end of 2014, but I believe Dr. Jakubowiak later reports a larger number (over 100?) in the study. The average follow up was less than a year. One patient (out of 53) had progression. OS was 100%. If we assume that the overall survival will be similar to the recent IFM study with RVD, ASCT, and maintenance, then it will take at least five years for early signs of that data to come in. This was actually the main point I was trying to make.
Eventually that data will come in. I would be shocked if the Kyprolis-containing regimen turned out to be worse that RVD. I guess that it could be close, but based on the better response, I would speculate (and yes it's no more than a speculation at this point) that OS will turn out to be better, and by the way, there are also the monoclonal antibodies that can be used at first and second relapse. If it turned out that Kyprolis was better in terms of OS, then it would be simply following the same trend as was the case for thalidomide, Revlimid, and Velcade, as they were first approved for relapsed / refractory multiple myeloma (RRMM), but eventually moved into the front line over time. By the way, I hope it does not come across that I am thinking this up myself. I am just regurgitating the developmental trends that I have read a number of doctors explain, for example, I think most of what I mentioned above came from Dr. Kenneth Anderson.
Lastly, to take the idea one step further, there are a number of studies out there where elotuzumab and daratumumab are being used in initial induction, and in some cases, they are being added to the 3-drug regimen, making it four drugs. I do not think that those studies have real good data yet even on response, but over the next one to two years, that data will be coming out. Of interest, Dr. Usmani reported that when adding elotuzumab to the 3-drug regimen, the overall side effect profile for the 4 drugs was no worse than the 3 drugs. I think these issues become more in focus if you have high risk cytogenetics. Although the data is early, Dr. Jakubowiak reported that he did not yet see any worse outcomes in his high-risk portion of the study. Also, Dr. Richardson of Dana Farber reports that the monoclonal antibodies seem to be also be good for high risk cases. I will certainly agree that you raise another really good question. Why are they not moving Pomalyst into the front line faster? I would be interested to learn more about that question. Good luck and Best Regards
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JPC - Name: JPC
17 posts
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