I thought I would quickly chime in here on the subject of maintenance. I was surprised by the absence of comment so far on the forum from news coming out of the latest meeting earlier this month from the meeting of the American Society of Clinical Oncology. Debbie discussed her particular case in this thread (I hope the good news keeps coming, Debbie!), and Cheryl commented on the subject as well in that thread.
There was a presentation about two weeks ago on the latest data on maintenance at the ASCO annual meeting. It was presented by Dr. McCarthy of Roswell Park. It was advanced statistics (a meta-analysis) on three different Revlimid maintenance studies. Here is the presentation, copied from the Beacon section on the ASCO meeting:
https://myelomabeacon.org/docs/asco2016/8001.pdf
I am not the authority on advanced statistics, however, I do have from my work a sort of basic grasp of some of the concepts. When you combine studies, if you do it the right way, there is a larger overall population, and the results become more "statistically significant".
When you go through the results of the study, it reports that median overall survival (OS) improved by about 33% from in the range of 7 to 7.5 years, to the range of 9.5 to 10 years, by the application of Revlimid maintenance to progression of first relapse. As these studies are ongoing, subsequent analyses will refine the results, and they could improve or get worse slightly. If they change a lot, then that would be a signal that the meta-analysis would have an as yet unidentified fatal flaw (however, at this stage, I hope the researchers did their job well).
I try to keep up on my reading, and I have to tell you that many doctors have come out with statements to the effect that this is a very significant result, and will likely impact their decisions in the clinic, going forward.
Regarding individual decisions, the biggest caveat in the reporting of this has been that toxicities could be any issue which would impact the degree of Revlimid maintenance, and there are several other issues, as well. So certainly it's true that Revlimid maintenance would not be appropriate in ALL cases. However, I do think that doctors are reporting that this data would suggest that Revlimid maintenance would certainly be considered and would become a type of "default" for an average or standard case, without complications.
And this is not the final answer, in that there are people who may need more or stronger maintenance, and others who may need less or no maintenance, but the state of the art cannot identify those people reliably yet. Future studies I am sure will illuminate those questions (however, they may take a long time to get useful results).
Respectfully to Cheryl, you may not agree that this is correct, and I am sure that there are top doctors (at this point I am pretty sure a minority) that would share your concerns. That is fine and I would not want to try and convince you otherwise. However, I do not think that it is right to suggest that all who disagree with you on this point are "brainwashed".
As for Debbie: I would just urge you do read that study, discuss it with your doctor, and make the decision that you are comfortable with you, and my best wishes that it all works for the best.
Good luck to all.
Forums
Re: Meta-analysis of Revlimid maintenance post-transplant
Hi JPC,
When did you change your opinion on meta analysis of data? Back on November 21, 2015 you wrote:
Does your view change based on if you agree with the data?
Mark
When did you change your opinion on meta analysis of data? Back on November 21, 2015 you wrote:
To make my main point clearly, let me state that a meta-analysis or retrospective study is not a REAL study. It is a rehash of older studies that are combined together. It has no original data. In the hierarchy of studies, in is at the low end of rigor. It is like a back of the envelope estimation compared to the more rigorous studies.
There were several new drugs approved this year. Regulatory agencies would never approve a new drug or a new procedure based on a retrospective study or meta analysis. Approvals would need to be based on the results of large multi-arm, multi-center randomized phase 3 studies, which are the most rigorous type of study. One such study on maintenance, in fact, was the recent update to the CALGB study that disagreed with the results of this retrospective meta-analysis, with respect to overall survival on maintenance.
So you could look at this newly published study, and say, well, this balances out the CALGB study, and we are back to square 1 at maintenance. So in that regard, I think the original post in this thread could be misinterpreted. When you read an abstract for a meta-analysis, it has confidence intervals and statistics that look like other studies, so if you read it quickly, you could leap to the conclusion that a meta-analysis is equal to a rigorous phase 3 study that has been recently published, but it is not.
I will take back my original comment at the start of this post that a meta-analysis is not a REAL study. I was just making a point Properly interpreted and explained, it is valid and has its place, and I am sure has proved very useful in some settings. However, very likely, that data is very old. By the very nature of studies, and the fast advance of the new treatment options coming out, the newest of studies are somewhat obsolete on the day that they were just published. For a meta-analysis of older studies, with no control between studies and inherent biases that are unavoidable, the data is in all likelihood very obsolete, and not applicable (or at best loosely applicable) to today's standard of care.
Does your view change based on if you agree with the data?
Mark
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Mark11
Re: Meta-analysis of Revlimid maintenance post-transplant
Thank you for starting this thread, JPC.
This topic is of the utmost interest to me as I am currently struggling with my decision on the maintenance issue.
I was diagnosed with stage 3 myeloma in November 2015. I have no adverse risk cytogenetics and underwent induction therapy (4 cycles of cyclophosphamide, Velcade, and dexamethasone – CyBorD) from November 2015 – February 2016. My ASCT took place in April 2016, and I have now achieved a complete response (CR).
My doctors feel that, for me, the overall survival benefit of Revlimid maintenance does not outweigh the risk of developing a secondary cancer (in my case a tertiary cancer, as I have already survived breast cancer).
It’s just 2 months since my autologous stem cell transplant, but I’ve tentatively decided to forego Revlimid maintenance therapy. I will, of course, be monitored very closely for signs of relapse. My quality of life has always been quite negatively impacted while on chemotherapeutics (doxorubicin + cyclophosphamide + paclitaxel for breast cancer, and CyBorD for myeloma), and I imagine that Revlimid would be no different. I am finally starting to feel good again, but I do worry somewhat about my decision to forego maintenance therapy, and am interested in hearing all thoughts on this matter.
This topic is of the utmost interest to me as I am currently struggling with my decision on the maintenance issue.
I was diagnosed with stage 3 myeloma in November 2015. I have no adverse risk cytogenetics and underwent induction therapy (4 cycles of cyclophosphamide, Velcade, and dexamethasone – CyBorD) from November 2015 – February 2016. My ASCT took place in April 2016, and I have now achieved a complete response (CR).
My doctors feel that, for me, the overall survival benefit of Revlimid maintenance does not outweigh the risk of developing a secondary cancer (in my case a tertiary cancer, as I have already survived breast cancer).
It’s just 2 months since my autologous stem cell transplant, but I’ve tentatively decided to forego Revlimid maintenance therapy. I will, of course, be monitored very closely for signs of relapse. My quality of life has always been quite negatively impacted while on chemotherapeutics (doxorubicin + cyclophosphamide + paclitaxel for breast cancer, and CyBorD for myeloma), and I imagine that Revlimid would be no different. I am finally starting to feel good again, but I do worry somewhat about my decision to forego maintenance therapy, and am interested in hearing all thoughts on this matter.
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KarenaD - Name: Karen
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: November 4, 2015
- Age at diagnosis: 54
Re: Meta-analysis of Revlimid maintenance post-transplant
Hi Karena D:
I have read several of your recent posts, and I know what you are going through, its about 1 year after my wife. I am glad to hear that you are in CR. Your condition, having already had breast cancer, is a wild card that I am almost 1,000% sure that there is no study out there to tell you what to do. And I can not tell you definitely either (as I have said many times, I am not a doctor). However, I can give you a quick thought to research. If you are looking into maintenance options, there is possibly Velcade or Ixazomib. It turns out that for the t 4,14 translocation (which you do not have) that Velcade is the recommended maintenance option.
Now, these are new, and it is not known for sure whether they have the secondary cancer risk or not. This is just a thought. The other thought would be for you to look at possible clinical trials. I have not checked lately, but there were some trials out there possibly looking at some of the Mab's in the maintenance setting. Good luck to you. Regards,
I have read several of your recent posts, and I know what you are going through, its about 1 year after my wife. I am glad to hear that you are in CR. Your condition, having already had breast cancer, is a wild card that I am almost 1,000% sure that there is no study out there to tell you what to do. And I can not tell you definitely either (as I have said many times, I am not a doctor). However, I can give you a quick thought to research. If you are looking into maintenance options, there is possibly Velcade or Ixazomib. It turns out that for the t 4,14 translocation (which you do not have) that Velcade is the recommended maintenance option.
Now, these are new, and it is not known for sure whether they have the secondary cancer risk or not. This is just a thought. The other thought would be for you to look at possible clinical trials. I have not checked lately, but there were some trials out there possibly looking at some of the Mab's in the maintenance setting. Good luck to you. Regards,
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JPC - Name: JPC
Re: Meta-analysis of Revlimid maintenance post-transplant
Hi all.
I'm wondering how your thoughts on maintenance therapy might be effected by next gen MRD testing?
My husband just finished the daily care part of is autologous stem cell transplant (ASCT). We're at Day #14. 4:14 + to start, 4 cycles Kyprolis, Revlimid, and dexamethasone (KRD) and now ASCT.
During the ASCT, the pre-transplant minimal residual disease (MRD) results came back and he was unexpectedly MRD "-" going into the transplant. We will be repeating the MRD test at Day 100 but currently are really pleased and also scheduled for consolidation with 4 more cycles of KRD in the fall, and then the issue of maintenance and with what surfaces.
Karena d, I'm not sure if Health Canada covers MRD testing in myeloma (I googled it and couldn't find an answer, but it is covered for pediatric leukemias), but you are coming up on the 100 day point and this testing might help you make or confirm your decision. I'd imagine if you are MRD negative, you might be more comfortable and relaxed forgoing maintenance.
We're too close to the ASCT to focus on this yet, but I'd like to know what those of you who have grappled with maintenance, and which maintenance, think.
I'm wondering how your thoughts on maintenance therapy might be effected by next gen MRD testing?
My husband just finished the daily care part of is autologous stem cell transplant (ASCT). We're at Day #14. 4:14 + to start, 4 cycles Kyprolis, Revlimid, and dexamethasone (KRD) and now ASCT.
During the ASCT, the pre-transplant minimal residual disease (MRD) results came back and he was unexpectedly MRD "-" going into the transplant. We will be repeating the MRD test at Day 100 but currently are really pleased and also scheduled for consolidation with 4 more cycles of KRD in the fall, and then the issue of maintenance and with what surfaces.
Karena d, I'm not sure if Health Canada covers MRD testing in myeloma (I googled it and couldn't find an answer, but it is covered for pediatric leukemias), but you are coming up on the 100 day point and this testing might help you make or confirm your decision. I'd imagine if you are MRD negative, you might be more comfortable and relaxed forgoing maintenance.
We're too close to the ASCT to focus on this yet, but I'd like to know what those of you who have grappled with maintenance, and which maintenance, think.
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rick - Name: rick
- Who do you know with myeloma?: husband
- When were you/they diagnosed?: nov 2015
- Age at diagnosis: 50
Re: Meta-analysis of Revlimid maintenance post-transplant
The Beacon's ASCO articles have coverage of the meta-analysis JPC mentioned, and I think it is very useful for understanding what implications, if any, should be drawn from the results of the "study". This is the article with coverage of the Revlimid meta-analysis presentation, and here is the text in the article about the presentation:
The second oral presentation on Friday was by Dr. Philip McCarthy of the Roswell Park Cancer Institute in Buffalo, New York. Dr. McCarthy reported on results of a combined (meta) analysis of results from three clinical trials that have investigated the impact of Revlimid maintenance therapy on survival outcomes (abstract, presentation slides [PDF] courtesy of Dr. McCarthy).
Researchers from the Mayo Clinic have previously presented a meta analysis of Revlimid maintenance therapy trial results at a meeting of the American Society of Hematology (abstract, presentation slides [PDF]). The Mayo Clinic analysis found that Revlimid maintenance consistently improved progression-free survival across the four trials included in the study. However, the impact on overall survival was less clear, but perhaps slightly positive.
A broader meta analysis of maintenance therapy studies involving Revlimid and thalidomide, which is in the same class of drugs as Revlimid, also found that maintenance therapy with the drugs improves progression-free survival, but does not improve overall survival (abstract).
Studies that investigated maintenance therapy prior to the use of thalidomide and Revlimid to treat multiple myeloma found that maintenance with chemotherapy drugs, interferon, or steroids consistently improved progression-free survival, but had an inconsistent effect on overall survival (see, for example, the first part of the “Results and Discussion” section of this International Myeloma Working Group statement on maintenance therapy).
The study that Dr. McCarthy discussed during Friday's session takes a focused approach to investigating the impact of Revlimid maintenance therapy on survival. The study includes only trials that investigated Revlimid maintenance when it is administered following an upfront stem cell transplant. Thus, the study includes data from just three Revlimid maintenance therapy trials: the U.S. CALGB trial (460 patients), the French IFM 2005-02 trial (614 patients), and the Italian GIMEMA-RVMM-PI-209 trial (135 patients in the transplant arms of the trial).
The new meta analysis also focuses solely on the impact of Revlimid maintenance on overall survival.
Of the three trials included in the McCarthy analysis, only one – the CALGB trial – has results showing that Revlimid maintenance therapy has a statistically significant positive impact on overall survival.
However, when data from the three trials are combined, the overall dataset indicates that Revlimid maintenance has a statistically significant positive impact on overall survival (see the overall survival curves in Figure 2 below).
With a median follow up of 80 months, the median overall survival is 86 months for patients in the three studies who did not have Revlimid maintenance after their initial transplant.
Median survival has not yet been reached for the patients who did have Revlimid maintenance after their initial transplant. However, Dr. McCarthy and his co-authors estimate the median could be as much as 2.5 years more than the 86 months observed for the non-maintenance patients.
The second oral presentation on Friday was by Dr. Philip McCarthy of the Roswell Park Cancer Institute in Buffalo, New York. Dr. McCarthy reported on results of a combined (meta) analysis of results from three clinical trials that have investigated the impact of Revlimid maintenance therapy on survival outcomes (abstract, presentation slides [PDF] courtesy of Dr. McCarthy).
Researchers from the Mayo Clinic have previously presented a meta analysis of Revlimid maintenance therapy trial results at a meeting of the American Society of Hematology (abstract, presentation slides [PDF]). The Mayo Clinic analysis found that Revlimid maintenance consistently improved progression-free survival across the four trials included in the study. However, the impact on overall survival was less clear, but perhaps slightly positive.
A broader meta analysis of maintenance therapy studies involving Revlimid and thalidomide, which is in the same class of drugs as Revlimid, also found that maintenance therapy with the drugs improves progression-free survival, but does not improve overall survival (abstract).
Studies that investigated maintenance therapy prior to the use of thalidomide and Revlimid to treat multiple myeloma found that maintenance with chemotherapy drugs, interferon, or steroids consistently improved progression-free survival, but had an inconsistent effect on overall survival (see, for example, the first part of the “Results and Discussion” section of this International Myeloma Working Group statement on maintenance therapy).
The study that Dr. McCarthy discussed during Friday's session takes a focused approach to investigating the impact of Revlimid maintenance therapy on survival. The study includes only trials that investigated Revlimid maintenance when it is administered following an upfront stem cell transplant. Thus, the study includes data from just three Revlimid maintenance therapy trials: the U.S. CALGB trial (460 patients), the French IFM 2005-02 trial (614 patients), and the Italian GIMEMA-RVMM-PI-209 trial (135 patients in the transplant arms of the trial).
The new meta analysis also focuses solely on the impact of Revlimid maintenance on overall survival.
Of the three trials included in the McCarthy analysis, only one – the CALGB trial – has results showing that Revlimid maintenance therapy has a statistically significant positive impact on overall survival.
However, when data from the three trials are combined, the overall dataset indicates that Revlimid maintenance has a statistically significant positive impact on overall survival (see the overall survival curves in Figure 2 below).
With a median follow up of 80 months, the median overall survival is 86 months for patients in the three studies who did not have Revlimid maintenance after their initial transplant.
Median survival has not yet been reached for the patients who did have Revlimid maintenance after their initial transplant. However, Dr. McCarthy and his co-authors estimate the median could be as much as 2.5 years more than the 86 months observed for the non-maintenance patients.
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Jonah
Re: Meta-analysis of Revlimid maintenance post-transplant
Thanks for your thoughts, JPC. Lots to think about, but I’d be hesitant to try any maintenance therapies that are not proven – especially as they relate to secondary cancers.
The issue of my myeloma also possibly becoming resistant to Revlimid was one of the factors that I’ve been considering as I ponder maintenance. Yes, I could relapse earlier without Revlimid maintenance, but at relapse, Revlimid would be a drug in my arsenal that my myeloma has not yet had a chance to become resistant to.
Rick: Great news that your husband is MRD negative! I hadn’t considered MRD testing; nor had any of my doctors mentioned it. You are right that if I was MRD negative, I would be a lot more comfortable with my decision to forego Revlimid maintenance. I’m not sure if this testing is covered in Ontario, but I will raise the subject at my next appointment with my hematologist-oncologist. Thank you.
The issue of my myeloma also possibly becoming resistant to Revlimid was one of the factors that I’ve been considering as I ponder maintenance. Yes, I could relapse earlier without Revlimid maintenance, but at relapse, Revlimid would be a drug in my arsenal that my myeloma has not yet had a chance to become resistant to.
Rick: Great news that your husband is MRD negative! I hadn’t considered MRD testing; nor had any of my doctors mentioned it. You are right that if I was MRD negative, I would be a lot more comfortable with my decision to forego Revlimid maintenance. I’m not sure if this testing is covered in Ontario, but I will raise the subject at my next appointment with my hematologist-oncologist. Thank you.
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KarenaD - Name: Karen
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: November 4, 2015
- Age at diagnosis: 54
Re: Meta-analysis of Revlimid maintenance post-transplant
Hi Karena:
Couple of quick thoughts back to you. I totally understand your feeling regarding untried approaches, very understandable, and reasonable. The maintenance approach most studied has been Revlimid. There was a study, I believe at last year's European meeting on Velcade maintenance. Much less studied than Revlimid, however, there was a progress-free survival (PFS) advantage. Even though it has not been studied an approved "targeted" study, it has been used widely in the case of t(4;14), and there are more studies going on now. So Velcade is an option that is less studied than Revlimid, but probably better than "untried".
My only other comment with respect new meds in maintenance is that Darzalex (daratumumab) I think would be called untried with respect to the maintenance, but it as proven so well so far, that if there was a clinical trial with Darzalex for maintenance that we could potentially participate in, I would take a good look at it.
Couple of quick thoughts back to you. I totally understand your feeling regarding untried approaches, very understandable, and reasonable. The maintenance approach most studied has been Revlimid. There was a study, I believe at last year's European meeting on Velcade maintenance. Much less studied than Revlimid, however, there was a progress-free survival (PFS) advantage. Even though it has not been studied an approved "targeted" study, it has been used widely in the case of t(4;14), and there are more studies going on now. So Velcade is an option that is less studied than Revlimid, but probably better than "untried".
My only other comment with respect new meds in maintenance is that Darzalex (daratumumab) I think would be called untried with respect to the maintenance, but it as proven so well so far, that if there was a clinical trial with Darzalex for maintenance that we could potentially participate in, I would take a good look at it.
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JPC - Name: JPC
Re: Meta-analysis of Revlimid maintenance post-transplant
Hello Jonah:
I think everything you wrote was very factual, relevant, and very well written, and logically organized. Nothing I would say to suggest it's bad information in any way. However, it may not be the most current, in all respects, and Dr. McCarthy's study (and the other authors) may represent more current information.
Since my initial post on this, I learned something very interesting from Dr. Mateos, a member of the IMWG, from Spain. I was not aware that Revlimid maintenance is not approved and not normally given in Europe. Dr. Mateos had a statement that based on Dr. McCarthy's study, that she would be involved with a group that would submit Revlimid maintenance for approval in Europe, and based on anticipated approval, she thought that it would be a good thing to have the option for this approach in Europe.
Good luck to you all. Rgds
I think everything you wrote was very factual, relevant, and very well written, and logically organized. Nothing I would say to suggest it's bad information in any way. However, it may not be the most current, in all respects, and Dr. McCarthy's study (and the other authors) may represent more current information.
Since my initial post on this, I learned something very interesting from Dr. Mateos, a member of the IMWG, from Spain. I was not aware that Revlimid maintenance is not approved and not normally given in Europe. Dr. Mateos had a statement that based on Dr. McCarthy's study, that she would be involved with a group that would submit Revlimid maintenance for approval in Europe, and based on anticipated approval, she thought that it would be a good thing to have the option for this approach in Europe.
Good luck to you all. Rgds
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JPC - Name: JPC
Re: Meta-analysis of Revlimid maintenance post-transplant
Hello Rick:
I am very glad to hear about your husband's MRD- status. It sounds like you are hooked up with some of the latest available treatments. My wife, also has the t(4;14) translocation, and I am researching the best thing to do. Based on early data so far, Kyprolis is working quite well for t(4;14).
I have read articles that reaching MRD- is potentially an argument to dial back maintenance. This of course is counter-balanced by having an adverse cytogenetic abnormality. As my doctor would say, I do not think that there are any clinical trials out there to guide you. I would just very generally say that early signals from the monoclonal antibodies suggest that they also do well for t(4;14). Are you familiar with Dr. Jakubowiak's study at the University of Chicago on Kyprolis, Revlimid, and dexamethasone (KRD), autologous stem cell transplantation (ASCT), KRD consolidation, and KRD maintenance? I have heard that the KRD maintenance schedule is something like a lower dose of KRD for about a year, and then moving to Revlimid maintenance. Regards,
I am very glad to hear about your husband's MRD- status. It sounds like you are hooked up with some of the latest available treatments. My wife, also has the t(4;14) translocation, and I am researching the best thing to do. Based on early data so far, Kyprolis is working quite well for t(4;14).
I have read articles that reaching MRD- is potentially an argument to dial back maintenance. This of course is counter-balanced by having an adverse cytogenetic abnormality. As my doctor would say, I do not think that there are any clinical trials out there to guide you. I would just very generally say that early signals from the monoclonal antibodies suggest that they also do well for t(4;14). Are you familiar with Dr. Jakubowiak's study at the University of Chicago on Kyprolis, Revlimid, and dexamethasone (KRD), autologous stem cell transplantation (ASCT), KRD consolidation, and KRD maintenance? I have heard that the KRD maintenance schedule is something like a lower dose of KRD for about a year, and then moving to Revlimid maintenance. Regards,
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JPC - Name: JPC
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