Looking through different studies, it seems like there are good indications that consolidation therapy after ASCT is beneficial. See, for example, this paper by Moreau, Facon, and Attal in Blood: "Frontline therapy of multiple myeloma" (Blood, May 2015).
Yet, when I look at the actual practice today, it seems to be large differences between different doctors, such as Jakubowiak, Landgren, McCarthy, etc.:
http://www.researchtopractice.com/COCMM14/1/Commentary5
From a patient's perspective, I would like to achieve minimal residual disease (MRD) negativity, and consolidation therapy looks like one additional way of reaching that goal and hence prolong the time before relapsing.
Does anyone have suggestions to why consolidation therapy is not established, or if it will be established in the not-too-distant future?
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JohnC - Name: JohnC
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: April 2014
- Age at diagnosis: 47
Re: Consolidation therapy after ASCT
Hello John:
This is a question that I have looked at too, and I will give you my thoughts. Without going into proven benefit of consolidation and whether or not its a positive thing to do, in my research, it appeared that it came out as a strong recommendation only recently, about the time of ASH 2014 (about 15, 16 months ago). If you go back and look at 2013 and earlier studies and myeloma news, it is not mentioned too much. But I think many leading doctors came out in 2014 and stated that is was useful/productive. I think that there are a relatively few number of studies that they refer to, but not many.
The issue with consolidation after ASCT is whether or not you tolerated the initial induction well. If your initial side effect profile was severe, a doctor might forgo it and go straight to maintenance (if you could tolerate that). If you were healthy, and had minimal or manageable side effects, then the new recent thinking is to add some consolidation. The number I have seen repeatedly is a total of 8 rounds between initial induction and consolidation (if you did 4 rounds of initial induction, then perhaps four more post ASCT).
Myeloma specialists have different philosophies, however. In addition to the toxicity issues, there are some doctors that have other reasons not to consolidate, that they are not yet convinced yet, or that they don't think maintenance/consolidation is good in the long run. The argument for consolidation ( as well as maintenance, too) is that it will prolong the time of first remission to first relapse. Many doctors think that is a critical metric in this day and age. Specifically, if you can push that out a period of time, there may be better meds/treatments available at that time.
This is a question that I have looked at too, and I will give you my thoughts. Without going into proven benefit of consolidation and whether or not its a positive thing to do, in my research, it appeared that it came out as a strong recommendation only recently, about the time of ASH 2014 (about 15, 16 months ago). If you go back and look at 2013 and earlier studies and myeloma news, it is not mentioned too much. But I think many leading doctors came out in 2014 and stated that is was useful/productive. I think that there are a relatively few number of studies that they refer to, but not many.
The issue with consolidation after ASCT is whether or not you tolerated the initial induction well. If your initial side effect profile was severe, a doctor might forgo it and go straight to maintenance (if you could tolerate that). If you were healthy, and had minimal or manageable side effects, then the new recent thinking is to add some consolidation. The number I have seen repeatedly is a total of 8 rounds between initial induction and consolidation (if you did 4 rounds of initial induction, then perhaps four more post ASCT).
Myeloma specialists have different philosophies, however. In addition to the toxicity issues, there are some doctors that have other reasons not to consolidate, that they are not yet convinced yet, or that they don't think maintenance/consolidation is good in the long run. The argument for consolidation ( as well as maintenance, too) is that it will prolong the time of first remission to first relapse. Many doctors think that is a critical metric in this day and age. Specifically, if you can push that out a period of time, there may be better meds/treatments available at that time.
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JPC - Name: JPC
Re: Consolidation therapy after ASCT
Hi JPC,
You might be right that it is still quite a new thing.
Below is a French phase II study that seemingly gives a clear indication of the contribition of consolidation as well as the importance of MRD negativity.
M Roussel et al, "Front-Line Transplantation Program With Lenalidomide, Bortezomib, and Dexamethasone Combination As Induction and Consolidation Followed by Lenalidomide Maintenance in Patients With Multiple Myeloma: A Phase II Study by the Intergroupe Francophone du Myélome," Journal of Clinical Oncology, July 14, 2014 (abstract)
"Overall, 68% of patients achieved MRD negativity; none of these patients relapsed. "
John
You might be right that it is still quite a new thing.
Below is a French phase II study that seemingly gives a clear indication of the contribition of consolidation as well as the importance of MRD negativity.
M Roussel et al, "Front-Line Transplantation Program With Lenalidomide, Bortezomib, and Dexamethasone Combination As Induction and Consolidation Followed by Lenalidomide Maintenance in Patients With Multiple Myeloma: A Phase II Study by the Intergroupe Francophone du Myélome," Journal of Clinical Oncology, July 14, 2014 (abstract)
"Overall, 68% of patients achieved MRD negativity; none of these patients relapsed. "
John
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JohnC - Name: JohnC
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: April 2014
- Age at diagnosis: 47
Re: Consolidation therapy after ASCT
Hi JohnC,
You have to remember only about 25% of myeloma patients do autos. Only a small percentage of myeloma patients are in clinical trials as part of upfront therapy, so data on this topic of consolidation is likely to be minimal. You have to remember that as a 47 year old patient you are not a typical patient. I did not care what the "standard of care" was when making my therapy decision as a younger patient since the average myeloma patient is 70 years old.
Mark
You have to remember only about 25% of myeloma patients do autos. Only a small percentage of myeloma patients are in clinical trials as part of upfront therapy, so data on this topic of consolidation is likely to be minimal. You have to remember that as a 47 year old patient you are not a typical patient. I did not care what the "standard of care" was when making my therapy decision as a younger patient since the average myeloma patient is 70 years old.
Mark
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Mark11
Re: Consolidation therapy after ASCT
Does anyone know if the French study mentioned above included patients with high risk cytogenetics? Has there been any followup since last July? .
Re: Consolidation therapy after ASCT
The French study is summarised in this article,
"Treatment Regimen Featuring Revlimid-Velcade-Dexamethasone Therapy And Stem Cell Transplantation Yields Deep Responses In Newly Diagnosed Multiple Myeloma," The Myeloma Beacon, July 16, 2014
John - As usual, both JPC and Mark have provided some valuable perspectives. I might quibble a bit with Mark's 25% statistic. I think the statistic is for the States, and the equivalent number is probably higher for other countries. However, his advice to take into account your age, and think beyond standard approaches to treatment, is well worth considering.
I'd quibble a bit more earnestly with JPC's statement,
He is absolutely right that the arguments made in favor of consolidation are the same as those made in favor of maintenance therapy. But the notion that prolonging remission will improve a patient's access to new, not-yet-approved, treatments, doesn't seem to me to make any sense.
If neither consolidation nor maintenance has any effect on OVERALL survival, which is really the key question, then how will a patient's access to future, not-yet-available treatments be improved by consolidation or maintenance therapy?
In fact, I could argue exactly the opposite. If long-term therapy leads to bone marrow suppression, as often is the case with long-term continuous treatment, a patient may find herself / himself unable to participate in many clinical trials testing new, not-yet-approved therapies. Such trials often have minimum blood count requirements, which a marrow-suppressed patient may not be able to fulfill.
"Treatment Regimen Featuring Revlimid-Velcade-Dexamethasone Therapy And Stem Cell Transplantation Yields Deep Responses In Newly Diagnosed Multiple Myeloma," The Myeloma Beacon, July 16, 2014
John - As usual, both JPC and Mark have provided some valuable perspectives. I might quibble a bit with Mark's 25% statistic. I think the statistic is for the States, and the equivalent number is probably higher for other countries. However, his advice to take into account your age, and think beyond standard approaches to treatment, is well worth considering.
I'd quibble a bit more earnestly with JPC's statement,
The argument for consolidation (as well as maintenance, too) is that it will prolong the time of first remission to first relapse. Many doctors think that is a critical metric in this day and age. Specifically, if you can push that out a period of time, there may be better meds/treatments available at that time."
He is absolutely right that the arguments made in favor of consolidation are the same as those made in favor of maintenance therapy. But the notion that prolonging remission will improve a patient's access to new, not-yet-approved, treatments, doesn't seem to me to make any sense.
If neither consolidation nor maintenance has any effect on OVERALL survival, which is really the key question, then how will a patient's access to future, not-yet-available treatments be improved by consolidation or maintenance therapy?
In fact, I could argue exactly the opposite. If long-term therapy leads to bone marrow suppression, as often is the case with long-term continuous treatment, a patient may find herself / himself unable to participate in many clinical trials testing new, not-yet-approved therapies. Such trials often have minimum blood count requirements, which a marrow-suppressed patient may not be able to fulfill.
Re: Consolidation therapy after ASCT
Ian is correct that the 25% statistic is based on US patients. Here is a link to the Beacon article discussing use of autologous transplant.
https://myelomabeacon.org/news/2013/05/30/trends-stem-cell-transplantation-multiple-myeloma/
I 100% agree with Ian's point:
"In fact, I could argue exactly the opposite. If long-term therapy leads to bone marrow suppression, as often is the case with long-term continuous treatment, a patient may find herself / himself unable to participate in many clinical trials testing new, not-yet-approved therapies. Such trials often have minimum blood count requirements, which a marrow-suppressed patient may not be able to fulfill."
Every long term survivor (20 plus years) that I have ever read about has two things in common - they take therapy breaks and they have used alkylators.
To the OP's original question, I believe the largest study with respect to consolidation therapy after autos is this study which used two cycles of VTD-PACE for consolidation after tandem autos. Looks like about a 30% chance for 10 years PFS with about 6 or so years of them drug free.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231416/
Mark
https://myelomabeacon.org/news/2013/05/30/trends-stem-cell-transplantation-multiple-myeloma/
I 100% agree with Ian's point:
"In fact, I could argue exactly the opposite. If long-term therapy leads to bone marrow suppression, as often is the case with long-term continuous treatment, a patient may find herself / himself unable to participate in many clinical trials testing new, not-yet-approved therapies. Such trials often have minimum blood count requirements, which a marrow-suppressed patient may not be able to fulfill."
Every long term survivor (20 plus years) that I have ever read about has two things in common - they take therapy breaks and they have used alkylators.
To the OP's original question, I believe the largest study with respect to consolidation therapy after autos is this study which used two cycles of VTD-PACE for consolidation after tandem autos. Looks like about a 30% chance for 10 years PFS with about 6 or so years of them drug free.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231416/
Mark
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Mark11
Re: Consolidation therapy after ASCT
Hello Ian:
Thank you for your points. I gather that you (and Mark) have strong OPINIONS regarding the topics of maintenance and consolidation, specifically that they are not beneficial in the long run. I was trying to give some perspective to John on his original question as to where and why consolidation stands today (and not I did not offer a specific suggestion in his case). Getting into that debate, which I have seen frequently before is not exactly what I had intended to do, but I will offer the following.
First, the opinion that you advocate, although not universally accepted, is also held be some very top doctors, much more educated, successful, and knowledgeable than myself, and I certainly respect the line of thought, and I realize that top doctors committed to that approach have great success like other top doctors do, however, I do think from my recent readings its the minority opinion, and moving more so in that direction.
[quote="Ian"]If neither consolidation nor maintenance has any effect on OVERALL survival,[/quote]
I gather you wrote the above as established fact. Perhaps you meant to state that as your opinion, but it read as a declarative statement. I do not think its an accurate statement. Studies on this question to my knowledge are old, obsolete, and do not incorporate the latest novel agents. RVD consolidation for the most part is something that was not largely talked about before 2014. It is not a fact (with respect to the latest novel agents). It is an open hypothesis, not proven either way. However, it is a correct observation that if you review the latest literature, that the OPINIONS of some of the leading doctors in the field advocate consolidation in some, but perhaps not all cases. A very short list of some of the doctors that I believe I recall having said this are: Dr. Ken Anderson, Dr. Lonial, Dr. Durie, and Dr. Langren., there are many others as well.
The question of consolidation with the latest novel agents (for example RVD) to my knowledge does not even have a study started. If there was a study in the works to make a large randomized multi-arm study to evaluate Overall Survival with consolidation, it would take twelve months to write and get approved, eighteen months to recruit participants, and maybe five or six more years to get useful preliminary data. It would have to be multi-arm, random, with a large population. If might never get done. Further, there would not be (nor should there be in any way) any study control at point of first relapse, when all the patients need to try and get the best available treatment at that time, and this complicates studies where the try and measure OS.
if your orientation is that you would not be convinced until you saw the study results, and you feel strongly regarding that point, that is fine by me, however, many doctors and patients will feel that they need to make a decision on the best thing to do based on the best information available to them at the time they need to make the decision.
Even though there are no studies on OS for RVD consolidation (and lets add Kyprolis, Pom, Farydak, Elo, Dara, CAR-T, etc.) judgments are in fact made that they might be best for OS. Very simply, the thinking behind it might be as follows.
1. A treatment has a deeper response (studies can measure that in a much shorter time frame).
2. A treatment has longer time to first relapse.
3. Other studies have shown that very generally deeper responses lead to better OS.
4. Still other studies have shown that longer period to first relapse has longer OS.
Again, not so much to change the mind of anyone who feels strongly on the point, but I would disagree with the statement Ian made above. In my opinion the recent data appears to be moving in the other direction, though it will be a long time until a hard answer is achieved.
Good luck to John in his decision and good luck to all. Rgds,
Thank you for your points. I gather that you (and Mark) have strong OPINIONS regarding the topics of maintenance and consolidation, specifically that they are not beneficial in the long run. I was trying to give some perspective to John on his original question as to where and why consolidation stands today (and not I did not offer a specific suggestion in his case). Getting into that debate, which I have seen frequently before is not exactly what I had intended to do, but I will offer the following.
First, the opinion that you advocate, although not universally accepted, is also held be some very top doctors, much more educated, successful, and knowledgeable than myself, and I certainly respect the line of thought, and I realize that top doctors committed to that approach have great success like other top doctors do, however, I do think from my recent readings its the minority opinion, and moving more so in that direction.
[quote="Ian"]If neither consolidation nor maintenance has any effect on OVERALL survival,[/quote]
I gather you wrote the above as established fact. Perhaps you meant to state that as your opinion, but it read as a declarative statement. I do not think its an accurate statement. Studies on this question to my knowledge are old, obsolete, and do not incorporate the latest novel agents. RVD consolidation for the most part is something that was not largely talked about before 2014. It is not a fact (with respect to the latest novel agents). It is an open hypothesis, not proven either way. However, it is a correct observation that if you review the latest literature, that the OPINIONS of some of the leading doctors in the field advocate consolidation in some, but perhaps not all cases. A very short list of some of the doctors that I believe I recall having said this are: Dr. Ken Anderson, Dr. Lonial, Dr. Durie, and Dr. Langren., there are many others as well.
The question of consolidation with the latest novel agents (for example RVD) to my knowledge does not even have a study started. If there was a study in the works to make a large randomized multi-arm study to evaluate Overall Survival with consolidation, it would take twelve months to write and get approved, eighteen months to recruit participants, and maybe five or six more years to get useful preliminary data. It would have to be multi-arm, random, with a large population. If might never get done. Further, there would not be (nor should there be in any way) any study control at point of first relapse, when all the patients need to try and get the best available treatment at that time, and this complicates studies where the try and measure OS.
if your orientation is that you would not be convinced until you saw the study results, and you feel strongly regarding that point, that is fine by me, however, many doctors and patients will feel that they need to make a decision on the best thing to do based on the best information available to them at the time they need to make the decision.
Even though there are no studies on OS for RVD consolidation (and lets add Kyprolis, Pom, Farydak, Elo, Dara, CAR-T, etc.) judgments are in fact made that they might be best for OS. Very simply, the thinking behind it might be as follows.
1. A treatment has a deeper response (studies can measure that in a much shorter time frame).
2. A treatment has longer time to first relapse.
3. Other studies have shown that very generally deeper responses lead to better OS.
4. Still other studies have shown that longer period to first relapse has longer OS.
Again, not so much to change the mind of anyone who feels strongly on the point, but I would disagree with the statement Ian made above. In my opinion the recent data appears to be moving in the other direction, though it will be a long time until a hard answer is achieved.
Good luck to John in his decision and good luck to all. Rgds,
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JPC - Name: JPC
Re: Consolidation therapy after ASCT
Good morning, Mark:
A comment on your post. The Blood article on the Total Therapy approach of UAMS was very interesting, and I will have to go through it again in more detail. Your main point of your post was (in support of Ian), that consolidation and too much treatment is BAD. The Total Therapy approach, however, is the poster child for aggressive treatment. The TT approach is typically not considered as plain vanilla consolidation, because it is detailed, and customizes treatment based on GEP. But I think you are right, that TT2 and TT3 uses VDT-PACE, which is a type of consolidation. The point of the article, however, contradicts the main point of your post, because the article's main thrust is that the more aggressive treatment leads to superior outcomes, and is GOOD. Thus, its contradictory to your article. If I am missing something, pls clarify for me. Rgds,
A comment on your post. The Blood article on the Total Therapy approach of UAMS was very interesting, and I will have to go through it again in more detail. Your main point of your post was (in support of Ian), that consolidation and too much treatment is BAD. The Total Therapy approach, however, is the poster child for aggressive treatment. The TT approach is typically not considered as plain vanilla consolidation, because it is detailed, and customizes treatment based on GEP. But I think you are right, that TT2 and TT3 uses VDT-PACE, which is a type of consolidation. The point of the article, however, contradicts the main point of your post, because the article's main thrust is that the more aggressive treatment leads to superior outcomes, and is GOOD. Thus, its contradictory to your article. If I am missing something, pls clarify for me. Rgds,
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JPC - Name: JPC
Re: Consolidation therapy after ASCT
Hi JPC,
I think my thoughts on my consolidation and maintenance therapy for younger myeloma patients are as clear as could be. I think most people that frequent this site are aware that my consolidation and maintenance therapy was a full allogeneic transplant. Given my status as being in CR at the time of transplant, female donor to male recipient, and sustained molecular response since transplant, it is very likely that I will never relapse due to my choice of consolidation and maintenance. I have also mentioned on multiple occasions that I am not aware of any therapy-related side effects from my transplant / therapy. How could you think that someone who thinks his consolidation and maintenance cured them of cancer and has provided them with an excellent quality of life not have a positive view of the consolidation and maintenance therapy they used?!
That is an all time first. Most patients think I favor very aggressive therapy and was overly aggressive with my therapy choices. You do not think an allogeneic transplant with myeloablative conditioning in first complete response is aggressive therapy!? I think you are the only person on this site who thinks that.
If you read my posts it should be very clear that I feel very strongly that immunotherapy is the best consolidation and maintenance therapy available. That is why I chose to use the most successful form of immunotherapy – allogeneic transplant – in first complete response. Total Therapy does not include any immunotherapy and the patients need to stay on DRUGS for maintenance for three years as opposed to relying on a healthy functioning donor immune system, so I would not want to do it.
However, in my opinion, after allogeneic transplant in first complete response, it appears patients who did Total Therapy have the best chance of having long term DRUG FREE remissions. From the peer-reviewed papers I read, it does not appear that many of Dr. Anderson, Durie, Lonial, or Landgen's patients get to enjoy the DRUG FREE remission period that I am currently enjoying, and some of the patients that did Total Therapy get to enjoy. They all advocate never ending cycles of drugs, so apparently their patients do not get very deep of responses using all of the new drugs you listed above for prolonged periods of time.
I put the link up regarding Total Therapy because to my knowledge that is the largest study that incorporates consolidation therapy after an auto(s). I got the impression that is something the OP was looking for and I put up the link so he could read it and make up his own mind about the study. Total Therapy is not for me, but I try to put out links to journal articles that help others make their own therapy decisions. If he would have asked about allogeneic transplant as consolidation and maintenance of first CR, I would have been very happy to have discussed my very positive experience with it!
Mark
I think my thoughts on my consolidation and maintenance therapy for younger myeloma patients are as clear as could be. I think most people that frequent this site are aware that my consolidation and maintenance therapy was a full allogeneic transplant. Given my status as being in CR at the time of transplant, female donor to male recipient, and sustained molecular response since transplant, it is very likely that I will never relapse due to my choice of consolidation and maintenance. I have also mentioned on multiple occasions that I am not aware of any therapy-related side effects from my transplant / therapy. How could you think that someone who thinks his consolidation and maintenance cured them of cancer and has provided them with an excellent quality of life not have a positive view of the consolidation and maintenance therapy they used?!
Your main point of your post was (in support of Ian), that consolidation and too much treatment is BAD.
That is an all time first. Most patients think I favor very aggressive therapy and was overly aggressive with my therapy choices. You do not think an allogeneic transplant with myeloablative conditioning in first complete response is aggressive therapy!? I think you are the only person on this site who thinks that.
If you read my posts it should be very clear that I feel very strongly that immunotherapy is the best consolidation and maintenance therapy available. That is why I chose to use the most successful form of immunotherapy – allogeneic transplant – in first complete response. Total Therapy does not include any immunotherapy and the patients need to stay on DRUGS for maintenance for three years as opposed to relying on a healthy functioning donor immune system, so I would not want to do it.
However, in my opinion, after allogeneic transplant in first complete response, it appears patients who did Total Therapy have the best chance of having long term DRUG FREE remissions. From the peer-reviewed papers I read, it does not appear that many of Dr. Anderson, Durie, Lonial, or Landgen's patients get to enjoy the DRUG FREE remission period that I am currently enjoying, and some of the patients that did Total Therapy get to enjoy. They all advocate never ending cycles of drugs, so apparently their patients do not get very deep of responses using all of the new drugs you listed above for prolonged periods of time.
I put the link up regarding Total Therapy because to my knowledge that is the largest study that incorporates consolidation therapy after an auto(s). I got the impression that is something the OP was looking for and I put up the link so he could read it and make up his own mind about the study. Total Therapy is not for me, but I try to put out links to journal articles that help others make their own therapy decisions. If he would have asked about allogeneic transplant as consolidation and maintenance of first CR, I would have been very happy to have discussed my very positive experience with it!
Mark
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Mark11
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