Mike F:
Thanks very much for posting both articles. Very interesting. The first study, however, is subject to the potential fallacy Dr. Rajkumar noted in the contribution I referenced – that it is invalid to conclude that because a patient cohort undergoing a given treatment regimen achieves better overall survival (OS) if they obtain a deeper response – specifically, a complete response (CR) – it nonetheless does not follow that intensifying treatment in order to achieve a CR will result in better OS.
The second paper is fraught with too many contradictions and caveats to draw any conclusions from, or so it seems to me.
blueblood:
The idea that cancer cells are in fact constantly being produced in the bodies of healthy people but are held in check by their immune systems is an old one -- at least forty years old, I believe. But I don't know what its current status is among clinicians and researchers in oncology.
I do think that, as Multibilly notes, the possibilities raised by Kevin J have adherents today, and they do have some explanatory power in resolving some puzzling issues around the value/lack of value in striving for deep responses to treatment.
Mark11:
What makes me say that there is a push for achieving deeper responses in multiple myeloma treatments are principally my own experiences seeking second and third opinions at well-known multiple myeloma centers on or near the West Coast. I have heard this from several multiple myeloma experts with world class reputations. As for identifying scientific papers that back this claim, I have no specific references to point to, and I doubt that it is well-founded in that sense.
However, the criteria I am using for what are characterized as "deep responses" are the results of tests – whether tests like the serum tests used to detect, quantify, and track heavy chain M-spikes, or tests like the urine tests and serum free light chain assays used to track free light chain M-spikes. In contrast, you appear to be using real world evidence of a lack of progression as a measure of response depth.
I recall the surprising paucity of autologous transplants among initial treatments in newly diagnosed patients, and your discussion of why that persists. I don't know why the frequency is so low for the autologous case. In the case of allo transplants, their reputation for having much higher morbidity rates I suspect has a lot to do with it. I do recall your raising some good points establishing that this "higher morbidity" may have been exaggerated.
Forums
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MrPotatohead - Name: MrPotatohead
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: March, 2015
- Age at diagnosis: 65
Re: Does a deeper response mean longer overall survival?
Hi Mr. Potatohead,
I think what Dr. Rajkumar is cautioning against in his Beacon article is treating in a manner like I was treated. As I am far from a "routine" myeloma patient given my age and high risk status, treating in the manner I did can make sense in a small number of cases like mine.
Let me show you what my treatment plan turned out to be – see this figure – so you see what using MRD testing to help make therapy decisions looks like, as opposed to just using MRD status as a prognostic marker.
Note that, in the flow chart, therapy decisions are made based on the patient's response to therapy. When you hit MRD negative status, the patient stops treating. The "myeloma thought leaders" do not treat anything like that. You typically hear them say things like "maintenance increases PFS" and "patients who are MRD negative have longer PFS than patients who are MRD positive". You can put any therapy you want into any individual box in that treatment plan, but you rarely see doctors using MRD testing to make therapy decisions as was done in my case. Running an MRD test is one thing, using it to make therapy decisions is another. As an example, I have seen multiple doctors state that they keep their MRD negative patients on never ending cycles of drugs just like they keep their MRD positive patients.
Also, note this post by JimNY. It seems to me the "myeloma thought leaders" are using MRD testing as a reason to use more drugs for longer periods of time, as opposed to the way I used it - to get a long term drug free remission / cure. Note the link Multibilly posted. The conclusion is just what I would expect from doctors that receive "consulting fees" from drug companies - stay on never ending cycles of drugs because it may help you get to MRD negative status. If you really want to have a deep, durable response you treat with aggressive therapy early in disease course. Dr. Emil Frei is credited with proving that for blood cancers all the way back in the 1960's - hardly an unproven concept.
You wrote:
I just had to comment on that point. You cannot just look at overall survival stats to make therapy decisions. You also have to look at long term quality of life. When I was making my therapy decision, this quality of life study was very influential in my decision.
"Most survivors beyond 5 years had an excellent performance status with no difference in physical and mental health and higher HRQL scores (P = .02) compared with population norms. Although physical and psychologic symptom distress was low, those with higher symptom distress experienced inferior HRQL. These results show that 5 or more years after T cell-depleted HSCT for hematologic malignancy most individuals survive disease free with an excellent performance status, preserved physical and psychological health, and excellent HRQL."
Source: Le, RQ, et al, "Favorable outcomes in patients surviving 5 or more years after allogeneic hematopoietic stem cell transplantation for hematologic malignancies," Biology of Blood and Marrow Transplantation, August 2010 (full text of article)
Based on papers I have read, patients on long term myelo- / immunosuppressive therapy do not have QOL on par with the general population, and certainly no one with relapsed myeloma has QOL on par with the general population. Long-term QOL is one of the major benefits of using the treatment plan I posted above.
This is a great thread. Thanks again for posting that article.
Mark
I think what Dr. Rajkumar is cautioning against in his Beacon article is treating in a manner like I was treated. As I am far from a "routine" myeloma patient given my age and high risk status, treating in the manner I did can make sense in a small number of cases like mine.
Let me show you what my treatment plan turned out to be – see this figure – so you see what using MRD testing to help make therapy decisions looks like, as opposed to just using MRD status as a prognostic marker.
Note that, in the flow chart, therapy decisions are made based on the patient's response to therapy. When you hit MRD negative status, the patient stops treating. The "myeloma thought leaders" do not treat anything like that. You typically hear them say things like "maintenance increases PFS" and "patients who are MRD negative have longer PFS than patients who are MRD positive". You can put any therapy you want into any individual box in that treatment plan, but you rarely see doctors using MRD testing to make therapy decisions as was done in my case. Running an MRD test is one thing, using it to make therapy decisions is another. As an example, I have seen multiple doctors state that they keep their MRD negative patients on never ending cycles of drugs just like they keep their MRD positive patients.
Also, note this post by JimNY. It seems to me the "myeloma thought leaders" are using MRD testing as a reason to use more drugs for longer periods of time, as opposed to the way I used it - to get a long term drug free remission / cure. Note the link Multibilly posted. The conclusion is just what I would expect from doctors that receive "consulting fees" from drug companies - stay on never ending cycles of drugs because it may help you get to MRD negative status. If you really want to have a deep, durable response you treat with aggressive therapy early in disease course. Dr. Emil Frei is credited with proving that for blood cancers all the way back in the 1960's - hardly an unproven concept.
You wrote:
"I do think that, as Multibilly notes, the possibilities raised by Kevin J have adherents today, and they do have some explanatory power in resolving some puzzling issues around the value/lack of value in striving for deep responses to treatment.
I just had to comment on that point. You cannot just look at overall survival stats to make therapy decisions. You also have to look at long term quality of life. When I was making my therapy decision, this quality of life study was very influential in my decision.
"Most survivors beyond 5 years had an excellent performance status with no difference in physical and mental health and higher HRQL scores (P = .02) compared with population norms. Although physical and psychologic symptom distress was low, those with higher symptom distress experienced inferior HRQL. These results show that 5 or more years after T cell-depleted HSCT for hematologic malignancy most individuals survive disease free with an excellent performance status, preserved physical and psychological health, and excellent HRQL."
Source: Le, RQ, et al, "Favorable outcomes in patients surviving 5 or more years after allogeneic hematopoietic stem cell transplantation for hematologic malignancies," Biology of Blood and Marrow Transplantation, August 2010 (full text of article)
Based on papers I have read, patients on long term myelo- / immunosuppressive therapy do not have QOL on par with the general population, and certainly no one with relapsed myeloma has QOL on par with the general population. Long-term QOL is one of the major benefits of using the treatment plan I posted above.
This is a great thread. Thanks again for posting that article.
Mark
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Mark11
Re: Does a deeper response mean longer overall survival?
Mark:
I clicked on your link/figure.
I have done a bunch of multiple myeloma research and have never seen this before. What disease is the flow chart for?
I clicked on your link/figure.
I have done a bunch of multiple myeloma research and have never seen this before. What disease is the flow chart for?
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JPC - Name: JPC
Re: Does a deeper response mean longer overall survival?
Hi Mark11,
Thanks for the detail about your therapy. I understand your points a lot better now. And I can't help but agree with them. First, the protocol you followed obviously worked, and worked very well. Second, it went against the growing trend to keep myeloma patients on a never-ending "maintenance" regimen, which, as contrasted with a drug-free remisssion, is likely to undercut one's quality of life due to side effects. Third, it utilized an allo transplant to achieve what may well be a cure, despite the fact that most practitioners seem to eschew allo transplants.
What I am still confused about is why some people never achieve a complete response (never mind achieving a negative result for MRD), and yet have long overall survival. That was the point Dr. Rajkumar made that I was most interested in, and Kevin J postulates a mechanism that might explain it --- the idea of there being multiple myeloma strains in a given patient, with some more virulent than others. And it may be that wiping out a more benign strain that is dominant over a more virulent one will cause the more virulent strain to hold sway, leading to poorer survival.
If such is indeed an explanation for why "stable disease" may be a better goal than a complete response in some cases, one is only left with explaining how the weaker strain dominates the more virulent one. But I am sure that multiple myeloma is complex enough to admit of a plausible theory for such an effect.
Thanks for the detail about your therapy. I understand your points a lot better now. And I can't help but agree with them. First, the protocol you followed obviously worked, and worked very well. Second, it went against the growing trend to keep myeloma patients on a never-ending "maintenance" regimen, which, as contrasted with a drug-free remisssion, is likely to undercut one's quality of life due to side effects. Third, it utilized an allo transplant to achieve what may well be a cure, despite the fact that most practitioners seem to eschew allo transplants.
What I am still confused about is why some people never achieve a complete response (never mind achieving a negative result for MRD), and yet have long overall survival. That was the point Dr. Rajkumar made that I was most interested in, and Kevin J postulates a mechanism that might explain it --- the idea of there being multiple myeloma strains in a given patient, with some more virulent than others. And it may be that wiping out a more benign strain that is dominant over a more virulent one will cause the more virulent strain to hold sway, leading to poorer survival.
If such is indeed an explanation for why "stable disease" may be a better goal than a complete response in some cases, one is only left with explaining how the weaker strain dominates the more virulent one. But I am sure that multiple myeloma is complex enough to admit of a plausible theory for such an effect.
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MrPotatohead - Name: MrPotatohead
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: March, 2015
- Age at diagnosis: 65
Re: Does a deeper response mean longer overall survival?
Hi all.
There's a recent JAMA article that many of you may be interested in:
Munshi, NC, et al, "Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis," JAMA Oncology, Sep 15, 2016 (full text of article)
The conclusion:
"The results of this large analysis showed that MRD negativity, as determined by various high-sensitivity methods, predicted better PFS and OS in patients with multiple myeloma, including those who had achieved CR. Minimal residual disease status is a marker of long-term outcomes in patients with multiple myeloma. It should therefore be considered a new end point in clinical trials and clearly has a role as a surrogate marker of OS."
This paper does NOT address using MRD to change therapeutic decisions and in fact few clinicians appear to be changing course to target MRD status at this time (except where the counts are dramatically increasing). Likewise, using MRD to avoid transplantation or discontinue or avoid maintenance are not recommended yet. Our doctors discussed that several of their MRD patients elected to avoid maintenance in the past and had recurrences in as few as 6 months while others remained MRD negative.
We had a post autologous stem cell transplant / Kyprolis-Revlimid-dexamethasone (KRD) maintenance followup appointment yesterday where we discussed these issues with our multiple myeloma team and for the most part it all remains to be researched. But those lucky enough to achieve MRD negative clearly seem to have both a deeper response and an overall survival advantage.
There's a recent JAMA article that many of you may be interested in:
Munshi, NC, et al, "Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis," JAMA Oncology, Sep 15, 2016 (full text of article)
The conclusion:
"The results of this large analysis showed that MRD negativity, as determined by various high-sensitivity methods, predicted better PFS and OS in patients with multiple myeloma, including those who had achieved CR. Minimal residual disease status is a marker of long-term outcomes in patients with multiple myeloma. It should therefore be considered a new end point in clinical trials and clearly has a role as a surrogate marker of OS."
This paper does NOT address using MRD to change therapeutic decisions and in fact few clinicians appear to be changing course to target MRD status at this time (except where the counts are dramatically increasing). Likewise, using MRD to avoid transplantation or discontinue or avoid maintenance are not recommended yet. Our doctors discussed that several of their MRD patients elected to avoid maintenance in the past and had recurrences in as few as 6 months while others remained MRD negative.
We had a post autologous stem cell transplant / Kyprolis-Revlimid-dexamethasone (KRD) maintenance followup appointment yesterday where we discussed these issues with our multiple myeloma team and for the most part it all remains to be researched. But those lucky enough to achieve MRD negative clearly seem to have both a deeper response and an overall survival advantage.
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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: Does a deeper response mean longer overall survival?
Hi Rick
Thank you for posting this very interesting study, Bringing some of the points raised in this thread together, I wonder if one can draw the following conclusions:
1. Most myeloma patients harbor multiple clones / subclones of myeloma that may be variable in their markers and aggressiveness (Kevin J and also Dr. Gareth Morgan);
2. Using just one or two measures for CR may therefore be inadequate to track eradication of myeloma;
3. More sensitive measures, specifically, those targeted at identifying MRD, that may be able to track myeloma despite clonal heterogeneity, may be necessary (Rick's reference);
4. Basing treatment decisions on MRD measures may be the most effective strategy for achieving a durable remission and even cure (Mark11).
In summary, it may be that the tendency for relapse, as well as the tendency to develop more refractory and aggressive disease, are all related through the aforementioned mechanisms / parameters, and that treatment must be therefore be based on more sensitive MRD measures to make real progress toward long-standing remission and cure.
Thank you for posting this very interesting study, Bringing some of the points raised in this thread together, I wonder if one can draw the following conclusions:
1. Most myeloma patients harbor multiple clones / subclones of myeloma that may be variable in their markers and aggressiveness (Kevin J and also Dr. Gareth Morgan);
2. Using just one or two measures for CR may therefore be inadequate to track eradication of myeloma;
3. More sensitive measures, specifically, those targeted at identifying MRD, that may be able to track myeloma despite clonal heterogeneity, may be necessary (Rick's reference);
4. Basing treatment decisions on MRD measures may be the most effective strategy for achieving a durable remission and even cure (Mark11).
In summary, it may be that the tendency for relapse, as well as the tendency to develop more refractory and aggressive disease, are all related through the aforementioned mechanisms / parameters, and that treatment must be therefore be based on more sensitive MRD measures to make real progress toward long-standing remission and cure.
Last edited by MrPotatohead on Thu Sep 22, 2016 9:58 am, edited 1 time in total.
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MrPotatohead - Name: MrPotatohead
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: March, 2015
- Age at diagnosis: 65
Re: Does a deeper response mean longer overall survival?
I wanted to chime in on the narrow issue of depth of response to overall survival. Maintenance, doctor's philosophies, alternate treatment approaches are all very valid issues, but they tend to confuse what is a very simple issue. I assume that maintenance is something that could be addressed after first line of treatment. I do not think that newly diagnosed multiple myeloma, when dealing with their first line of treatment, are even thinking about maintenance.
I found an article in Blood discussing the displacement of the pre-novel agent regimen, vincristine, doxorubicin, and dexamethasone (VAD) with thalidomide dex. Here is the link:
Rajkumar, SV, "Multiple myeloma: the death of VAD as initial therapy," Blood, 2005 (full text of article)
Interestingly, they had been using this approach for something like 10 years, but at that time they found that VAD worked, but was very close to dex alone, and perhaps almost all of the effectiveness of VAD came from dex.
From the various studies on the novel agents since early the 2000's, it is quite clear that better agents that get a better depth of response (significant statistically) that always the result is better PFS. Note that I did not say ALMOST. I am fairly sure that is the case, maybe there is an outlier, but review of many studies will prove that out.
For overall survival, however, it is more difficult to measure. After relapse, study "control" is lost. That is not bad, as doctors should do the best available option for their patients, however, it is generally true that OS is NEVER measured under a controlled study. It is harder for that reason to translate PFS to OS, however, if the difference is big enough in PFS between two groups, the one with the better head start will win.
So where the difference is big enough, say RVD (Revlimid, Velcade, and dexamethasone) vs. VAD, it is quite clear that when comparing across studies that depth of response translates to better overall survival. There are studies where both are done without maintenance, and there is several years difference. However, for regimens with small differences, this will not be readily evident.
Depth of response does correlate with overall survival, however, as pointed out, it is not perfect. Some VGPR patients will do better than some CR patients. It is a decent correlation, but not a perfect one. If you add in, however, a second factor, the known cytogenetic abnormalities, then the correlation does become really strong. For instance, within the del 17 P patients, there will be a very strong correlation between depth of response and OS. Getting a CR is important. Same for the standard risk. A lot of the "contradictions" go away when considering risk factor. As a reference, you could stratify by the Mayo Clinic's mSmart, in that regard.
The latest data, which is still early, is important, I think. Jumping the hurdle to minimal residual disease (MRD) negative (by the most stringent available test) is significant for ALL categories, and also simplifies some of the apparent contradictions. It appears that ALL patients do well with that depth of response.
As it turns out, the studies on Kyprolis, Revlimid, and dexamethasone (KRD) for newly diagnosed patients by Dr. Jakubowiak of the University of Chicago, are tracking MRD status, even though that was not the point of the study, and there are other studies out there on this issue. His first study – no autologous stem cell transplant (ASCT) – achieved about 70% after 4 years without progression, which will trend in the range to about 5.5 to 6 years progression-free survival, which is longer than the overall survival for some of the earlier studies. His second study, with ASCT and KRD consolidation, is newer, but will probably have better PFS numbers. The reason is likely the high rate of MRD negative status. If you could get there with Darzalex (daratumumab), instead, or one of the other new immunotherapies, it would probably be just as good. Good luck to all.
I found an article in Blood discussing the displacement of the pre-novel agent regimen, vincristine, doxorubicin, and dexamethasone (VAD) with thalidomide dex. Here is the link:
Rajkumar, SV, "Multiple myeloma: the death of VAD as initial therapy," Blood, 2005 (full text of article)
Interestingly, they had been using this approach for something like 10 years, but at that time they found that VAD worked, but was very close to dex alone, and perhaps almost all of the effectiveness of VAD came from dex.
From the various studies on the novel agents since early the 2000's, it is quite clear that better agents that get a better depth of response (significant statistically) that always the result is better PFS. Note that I did not say ALMOST. I am fairly sure that is the case, maybe there is an outlier, but review of many studies will prove that out.
For overall survival, however, it is more difficult to measure. After relapse, study "control" is lost. That is not bad, as doctors should do the best available option for their patients, however, it is generally true that OS is NEVER measured under a controlled study. It is harder for that reason to translate PFS to OS, however, if the difference is big enough in PFS between two groups, the one with the better head start will win.
So where the difference is big enough, say RVD (Revlimid, Velcade, and dexamethasone) vs. VAD, it is quite clear that when comparing across studies that depth of response translates to better overall survival. There are studies where both are done without maintenance, and there is several years difference. However, for regimens with small differences, this will not be readily evident.
Depth of response does correlate with overall survival, however, as pointed out, it is not perfect. Some VGPR patients will do better than some CR patients. It is a decent correlation, but not a perfect one. If you add in, however, a second factor, the known cytogenetic abnormalities, then the correlation does become really strong. For instance, within the del 17 P patients, there will be a very strong correlation between depth of response and OS. Getting a CR is important. Same for the standard risk. A lot of the "contradictions" go away when considering risk factor. As a reference, you could stratify by the Mayo Clinic's mSmart, in that regard.
The latest data, which is still early, is important, I think. Jumping the hurdle to minimal residual disease (MRD) negative (by the most stringent available test) is significant for ALL categories, and also simplifies some of the apparent contradictions. It appears that ALL patients do well with that depth of response.
As it turns out, the studies on Kyprolis, Revlimid, and dexamethasone (KRD) for newly diagnosed patients by Dr. Jakubowiak of the University of Chicago, are tracking MRD status, even though that was not the point of the study, and there are other studies out there on this issue. His first study – no autologous stem cell transplant (ASCT) – achieved about 70% after 4 years without progression, which will trend in the range to about 5.5 to 6 years progression-free survival, which is longer than the overall survival for some of the earlier studies. His second study, with ASCT and KRD consolidation, is newer, but will probably have better PFS numbers. The reason is likely the high rate of MRD negative status. If you could get there with Darzalex (daratumumab), instead, or one of the other new immunotherapies, it would probably be just as good. Good luck to all.
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JPC - Name: JPC
Re: Does a deeper response mean longer overall survival?
From JPC "If you could get there with Darzalex (daratumumab), instead, or one of the other new immunotherapies, it would probably be just as good."
That leads to a question of how we should approach first relapse. Should we aim for the deepest response possible either through induction followed by an autologous stem cell transplant or through using the new Darzalex, Revlimid, dex triplet? Or should be try to milk out everything we can from using older novel agents and hold Darzalex and the other new immunotherapies in reserve? An interesting conundrum.
That leads to a question of how we should approach first relapse. Should we aim for the deepest response possible either through induction followed by an autologous stem cell transplant or through using the new Darzalex, Revlimid, dex triplet? Or should be try to milk out everything we can from using older novel agents and hold Darzalex and the other new immunotherapies in reserve? An interesting conundrum.
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Ron Harvot - Name: Ron Harvot
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: Feb 2009
- Age at diagnosis: 56
Re: Does a deeper response mean longer overall survival?
Hi Ron,
I agree that is the whole point of the "thought experiment". What do you decide to do at the time you need to decide. Obviously, the study needed to answer that question is not yet complete (and may not have yet started).
However, my gut gives me the impression to try and get to minimal residual disease (MRD) negative at initial induction. Hope and pray at that point that you are average to better than average in terms of the response "sticking". Then, after a hopefully long remission, try and get to MRD negative again. How that would be done for each individual patient is another question, and maybe the topic of some interesting threads in the future.
Good luck to you and regards,
I agree that is the whole point of the "thought experiment". What do you decide to do at the time you need to decide. Obviously, the study needed to answer that question is not yet complete (and may not have yet started).
However, my gut gives me the impression to try and get to minimal residual disease (MRD) negative at initial induction. Hope and pray at that point that you are average to better than average in terms of the response "sticking". Then, after a hopefully long remission, try and get to MRD negative again. How that would be done for each individual patient is another question, and maybe the topic of some interesting threads in the future.
Good luck to you and regards,
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JPC - Name: JPC
Re: Does a deeper response mean longer overall survival?
Contrary to what's been written elsewhere in this thread, just about every multiple myeloma trial does, in fact, report overall survival results. As has been noted many times in news articles and forum postings at this site, most studies show that, over time, there is little or no difference in overall survival between patients who received more drugs, for a longer period of time, upfront versus patients who did not.
There are some important exceptions. The SWOG S0777 study compared Revlimid, Velcade, and dexamethasone (RVD) versus Revlimid and dexamethasone (RD) in newly diagnosed patients, and found longer overall survival in the patients who received RVD (related ASH 2015 abstract).
The detailed results of the SWOG study, however, have yet to be published. More importantly, it's not clear whether the study proves more intensive therapy upfront is better, or if it just proves that there is synergy between Revlimid and Velcade that makes it better to use them together than to use them separately. There are preclinical results suggesting such synergy, and synergy is known to exist, for example, between Empliciti and Revlimid: Empliciti by itself has little anti-myeloma activity.
Otherwise, studies repeatedly show that patients who get more drugs at a time, or more drugs closer together in time (such as maintenance) do not actually get longer overall survival.
The response of the "more is better" proponents to this consistent result over time is to say "Well, it's just statistically hard to control for things when people leave a clinical trial."
That's true. However, when study after study comes up with the same result, the repeating pattern means something. That pattern is that it makes no difference whether you use lots of therapies together, for as long as possible -- perhaps even continuously -- to get as deep a response as possible, or you spread out the use of the drugs over time, using them in a more sequential manner.
Separately, there is both solid evidence and sound theoretical arguments behind what KevinJ wrote earlier in this thread. In particular, intensive therapy that wipes out a lot of a disease, but doesn't wipe it out completely, can actually make things worse for the patient, decreasing overall survival.
This is explained in the "How does clonal evolution contribute to resistance to therapy?" section of this paper:
Landau, DA, et al, "Clonal evolution in hematological malignancies and therapeutic implications," Leukemia, Oct 2013 (full text of article)
Treatment can promote the growth of highly resistant clones of a disease through at least three mechanisms (See Figure 2 in the paper):
There are some important exceptions. The SWOG S0777 study compared Revlimid, Velcade, and dexamethasone (RVD) versus Revlimid and dexamethasone (RD) in newly diagnosed patients, and found longer overall survival in the patients who received RVD (related ASH 2015 abstract).
The detailed results of the SWOG study, however, have yet to be published. More importantly, it's not clear whether the study proves more intensive therapy upfront is better, or if it just proves that there is synergy between Revlimid and Velcade that makes it better to use them together than to use them separately. There are preclinical results suggesting such synergy, and synergy is known to exist, for example, between Empliciti and Revlimid: Empliciti by itself has little anti-myeloma activity.
Otherwise, studies repeatedly show that patients who get more drugs at a time, or more drugs closer together in time (such as maintenance) do not actually get longer overall survival.
The response of the "more is better" proponents to this consistent result over time is to say "Well, it's just statistically hard to control for things when people leave a clinical trial."
That's true. However, when study after study comes up with the same result, the repeating pattern means something. That pattern is that it makes no difference whether you use lots of therapies together, for as long as possible -- perhaps even continuously -- to get as deep a response as possible, or you spread out the use of the drugs over time, using them in a more sequential manner.
Separately, there is both solid evidence and sound theoretical arguments behind what KevinJ wrote earlier in this thread. In particular, intensive therapy that wipes out a lot of a disease, but doesn't wipe it out completely, can actually make things worse for the patient, decreasing overall survival.
This is explained in the "How does clonal evolution contribute to resistance to therapy?" section of this paper:
Landau, DA, et al, "Clonal evolution in hematological malignancies and therapeutic implications," Leukemia, Oct 2013 (full text of article)
Treatment can promote the growth of highly resistant clones of a disease through at least three mechanisms (See Figure 2 in the paper):
- The treatment can cause mutations in the disease, making it more difficult to treat
- The treatment can wipe out less resistant clones of the disease, giving the resistant clones easier access to the resources (nourishment, etc.) that enable the clones to survive and grow
- The treatment can affect equally all the clones of the disease; however, the increased resources available to the surviving disease cells allows the more aggressive clones to grow faster than if no treatment had been done.
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