Hello,
There have been several threads recently that deal with the general question of when to begin treatment (or intensify treatment if the patient has been on maintenance therapy) when there are signs of disease progression.
I had an interesting conversation with my myeloma specialist on this topic when I saw him yesterday for my monthly visit. One of the things he told me is that there may soon be clinical trials started to look at the effectiveness of beginning treatment when patients move from minimal residual disease (MRD) negative status to MRD positive.
This would be done independent of the status of any other disease markers like M-spike or the free light chain ratio. He said several drugs are under consideration for the treatment regimen, but didn't give any more details.
Because there is work in progress to develop MRD tests that use blood rather than bone marrow, we can look forward to a time when MRD testing is done much more easily and frequently for patients in CR than it is now.
In a way, the idea to treat when a patient moves from MRD negative to positive seems similar to me to the trials looking at treating smoldering myeloma before it progresses to active multiple myeloma. Hit the disease as early as possible.
It will be interesting to see how these trials go.
Mike
Forums
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mikeb - Name: mikeb
- Who do you know with myeloma?: self
- When were you/they diagnosed?: 2009 (MGUS at that time)
- Age at diagnosis: 55
Re: When to treat with disease progression?
Hi Mike,
I think this is a great question. Not just the minimal residual disease (MRD) results, but I think there are many opinions as to when to start treatment based only on serologic relapse without any CRAB features.
Coach Hoke
I think this is a great question. Not just the minimal residual disease (MRD) results, but I think there are many opinions as to when to start treatment based only on serologic relapse without any CRAB features.
Coach Hoke
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coachhoke - Name: coachhoke
- When were you/they diagnosed?: Apri 2012
- Age at diagnosis: 71
Re: When to treat with disease progression?
Thanks for the information, Mike. I always enjoy your posts.
I guess the question such a trial would address is interesting from a scientific perspective. However, I think most of the people here familiar with myeloma research carried out over the last 25 years would say that there isn't much evidence suggesting treatment at the earliest signs of relapse will lead to an overall survival advantage.
To me, business – not science – is the real motivation for such a trial.
Imagine you're a pharmaceutical company. You've managed to convince a lot of myeloma specialists that they should treat patients until their disease progresses, rather than for a fixed period of time. Of course, the evidence in favor of doing this is sketchy, at best. But it lengthens how long patients are being treated, which dramatically expands sales of your drug and just about every myeloma therapy.
So now you're asking yourself: How can I increase even more the length of time that patients are on our drugs?
And you come up with the answer: Have patients start taking the drug at the earliest possible sign of relapse!
We're talking REALLY early -- like when there is just a tiny, tiny sign that the myeloma is starting to progress.
What amazes me is that so few people see through ruses like this.
If a trial like the one that Mike described is launched, everyone should look closely at the design. Where will the study be carried out? Will the study include control arms and, if so, what treatment will the patients in the control arm get? How will the results of the trial be reported? Under what conditions will the trial be halted.
I can almost guarantee everyone that the design of the trial will be stacked in favor of "proving" early treatment is better – just as so many recent trials have been stacked in favor of "proving" longer, or earlier, treatment is better.
I guess the question such a trial would address is interesting from a scientific perspective. However, I think most of the people here familiar with myeloma research carried out over the last 25 years would say that there isn't much evidence suggesting treatment at the earliest signs of relapse will lead to an overall survival advantage.
To me, business – not science – is the real motivation for such a trial.
Imagine you're a pharmaceutical company. You've managed to convince a lot of myeloma specialists that they should treat patients until their disease progresses, rather than for a fixed period of time. Of course, the evidence in favor of doing this is sketchy, at best. But it lengthens how long patients are being treated, which dramatically expands sales of your drug and just about every myeloma therapy.
So now you're asking yourself: How can I increase even more the length of time that patients are on our drugs?
And you come up with the answer: Have patients start taking the drug at the earliest possible sign of relapse!
We're talking REALLY early -- like when there is just a tiny, tiny sign that the myeloma is starting to progress.
What amazes me is that so few people see through ruses like this.
If a trial like the one that Mike described is launched, everyone should look closely at the design. Where will the study be carried out? Will the study include control arms and, if so, what treatment will the patients in the control arm get? How will the results of the trial be reported? Under what conditions will the trial be halted.
I can almost guarantee everyone that the design of the trial will be stacked in favor of "proving" early treatment is better – just as so many recent trials have been stacked in favor of "proving" longer, or earlier, treatment is better.
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JimNY
Re: When to treat with disease progression?
Hi Jim -
Can you point to a study that was intentionally designed to show that earlier or longer treatment is superior to not treating or treating at some later point? - Thanks.
I find the "treat at MRD positive" idea interesting. My doctors aren't interested in even knowing whether I'm MRD negative or not as, in their view, it won't change anything regarding treatment. I'll move on to some new treatment once I hit whatever serologic or CRAB markers require it but in the meantime the MRD status is just an interesting detail. (They also aren't all that impressed with the accuracy of bone marrow assays in general, so that also plays into the situation.) I'm sure that would change if there were a proven benefit to using that status to determine timing of treatment.
Can you point to a study that was intentionally designed to show that earlier or longer treatment is superior to not treating or treating at some later point? - Thanks.
I find the "treat at MRD positive" idea interesting. My doctors aren't interested in even knowing whether I'm MRD negative or not as, in their view, it won't change anything regarding treatment. I'll move on to some new treatment once I hit whatever serologic or CRAB markers require it but in the meantime the MRD status is just an interesting detail. (They also aren't all that impressed with the accuracy of bone marrow assays in general, so that also plays into the situation.) I'm sure that would change if there were a proven benefit to using that status to determine timing of treatment.
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Mike F - Name: Mike F
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: May 18, 2012
- Age at diagnosis: 53
Re: When to treat with disease progression?
Hi Mike F,
You asked:
I can't prove intention, but I can point to design features that fostered the result that longer or earlier therapy would be the "proven" outcomes.
In many of the cases I'll discuss below, the key piece of information to keep in mind is that, if a patient is treated with Drug X for a fixed period of time, the patient's overall survival is likely to be longer if an attempt is made to retreat the patient with Drug X at relapse before moving on to other treatments.
Patients very often respond to drugs they have been treated with in the past – particularly drugs they have responded well to. It is commonly noted, for example, that patients who respond well to stem cell transplants are prime candidates for a second transplant.
It's also important for overall survival, of course, that patients have access to the most number of therapies possible. Patients who don't have access to Darzalex, for example, are not likely to have overall survival as long as those who do.
With that in mind, let's look at three groups of studies that, in my mind, were designed from the start to generate results favoring extended treatment, or early treatment.
1. Maintenance therapy until disease progression
As most people here know, there have been three phase 3 studies focused on "testing" Revlimid maintenance versus no maintenance. Based on what I wrote above, these studies ideally would have been designed as follows:
Arm A: Gets Revlimid maintenance until disease progression, then gets something else.
Arm B: Gets placebo, then gets Revlimid treatment at relapse, then gets something else.
In none of the three maintenance trials, however, were the participants in Arm B (the control arm) guaranteed to be treated with Revlimid at relapse. Instead, they could be treated with anything. In particular, their doctors could choose NOT to use Revlimid at all after relapse, causing those patients to lose out on a treatment that could make a difference in their overall survival.
(This is just one issue with the maintenance studies. Another key issue is that, in the only study of the three that, on its own, showed an overall survival benefit, the induction therapy prior to maintenance was not controlled, and the study was halted early and crossover was forced.)
2. Early treatment for high-risk smoldering myeloma
Historically, trials testing early treatment of smoldering myeloma have been designed like this:
Arm A: Gets early treatment with drug "X"
Arm B: Gets placebo until diagnosis with symptomatic disease, then gets drug "X"
The Spanish study that recently tested early treatment with Revlimid for high-risk smoldering myeloma was not designed this way. The patients in the equivalent of "Arm B" in that trial were not guaranteed to get Revlimid when their disease progressed to the symptomatic stage.
In fact, because the study was done in Spain, most of the patients probably did NOT get Revlimid. Instead, the patients in Arm B instead got mostly a melphalan-based regimen, which is more likely to cause serious side effects.
3. Continuous initial therapy for newly diagnosed myeloma
The "FIRST" trial supposedly proves that continuous induction therapy with Revlimid-dexamethasone leads to higher overall survival than fixed length induction therapy with either Revlimid-dexamethasone or melphalan, prednisone, and thalidomide (MPT).
As with the previous examples, the FIRST trial did not control what patients got as treatment at relapse. So patients who got fixed-length treatment with Revlimid and dex, for example, were not guaranteed to have retreatment with Revlimid and dex once they relapsed.
There also was no guarantee that patients who got MPT as induction therapy would ever be treated with Revlimid.
If you think concerns about post relapse access to Revlimid treatment weren't relevant to the results of the study, you may want to take into account where the study was carried out. The trial was conducted almost entirely outside the United States, where the ability to retreat patients with Revlimid – and access to Revlimid in general – is severely limited. Of the more than 1600 patients who took part in the FIRST trial, only 60 (yes, sixty) were in the U.S.
I could go on. Hopefully this gives enough of a taste, though, of why I am suspicious about the motivation for the sort of trial MikeB described.
You asked:
Can you point to a study that was intentionally designed to show that earlier or longer treatment is superior to not treating or treating at some later point?
I can't prove intention, but I can point to design features that fostered the result that longer or earlier therapy would be the "proven" outcomes.
In many of the cases I'll discuss below, the key piece of information to keep in mind is that, if a patient is treated with Drug X for a fixed period of time, the patient's overall survival is likely to be longer if an attempt is made to retreat the patient with Drug X at relapse before moving on to other treatments.
Patients very often respond to drugs they have been treated with in the past – particularly drugs they have responded well to. It is commonly noted, for example, that patients who respond well to stem cell transplants are prime candidates for a second transplant.
It's also important for overall survival, of course, that patients have access to the most number of therapies possible. Patients who don't have access to Darzalex, for example, are not likely to have overall survival as long as those who do.
With that in mind, let's look at three groups of studies that, in my mind, were designed from the start to generate results favoring extended treatment, or early treatment.
1. Maintenance therapy until disease progression
As most people here know, there have been three phase 3 studies focused on "testing" Revlimid maintenance versus no maintenance. Based on what I wrote above, these studies ideally would have been designed as follows:
Arm A: Gets Revlimid maintenance until disease progression, then gets something else.
Arm B: Gets placebo, then gets Revlimid treatment at relapse, then gets something else.
In none of the three maintenance trials, however, were the participants in Arm B (the control arm) guaranteed to be treated with Revlimid at relapse. Instead, they could be treated with anything. In particular, their doctors could choose NOT to use Revlimid at all after relapse, causing those patients to lose out on a treatment that could make a difference in their overall survival.
(This is just one issue with the maintenance studies. Another key issue is that, in the only study of the three that, on its own, showed an overall survival benefit, the induction therapy prior to maintenance was not controlled, and the study was halted early and crossover was forced.)
2. Early treatment for high-risk smoldering myeloma
Historically, trials testing early treatment of smoldering myeloma have been designed like this:
Arm A: Gets early treatment with drug "X"
Arm B: Gets placebo until diagnosis with symptomatic disease, then gets drug "X"
The Spanish study that recently tested early treatment with Revlimid for high-risk smoldering myeloma was not designed this way. The patients in the equivalent of "Arm B" in that trial were not guaranteed to get Revlimid when their disease progressed to the symptomatic stage.
In fact, because the study was done in Spain, most of the patients probably did NOT get Revlimid. Instead, the patients in Arm B instead got mostly a melphalan-based regimen, which is more likely to cause serious side effects.
3. Continuous initial therapy for newly diagnosed myeloma
The "FIRST" trial supposedly proves that continuous induction therapy with Revlimid-dexamethasone leads to higher overall survival than fixed length induction therapy with either Revlimid-dexamethasone or melphalan, prednisone, and thalidomide (MPT).
As with the previous examples, the FIRST trial did not control what patients got as treatment at relapse. So patients who got fixed-length treatment with Revlimid and dex, for example, were not guaranteed to have retreatment with Revlimid and dex once they relapsed.
There also was no guarantee that patients who got MPT as induction therapy would ever be treated with Revlimid.
If you think concerns about post relapse access to Revlimid treatment weren't relevant to the results of the study, you may want to take into account where the study was carried out. The trial was conducted almost entirely outside the United States, where the ability to retreat patients with Revlimid – and access to Revlimid in general – is severely limited. Of the more than 1600 patients who took part in the FIRST trial, only 60 (yes, sixty) were in the U.S.
I could go on. Hopefully this gives enough of a taste, though, of why I am suspicious about the motivation for the sort of trial MikeB described.
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JimNY
Re: When to treat with disease progression?
Are there any estimates as to when MRD tests going to be readily available and routine? I don't think these tests are done at very many places yet.
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DallasGG - Name: Kent
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: 6/20/2013
- Age at diagnosis: 56
Re: When to treat with disease progression?
Very interesting topic. The type of thing I am interested in. Thanks for starting this thread, Mike. A lot of interesting points already. I wanted to touch on one aspect brought up by JimNY.
I think its valid to say that all of multiple myeloma research, and expanding, all of cancer research, all research, and all medical practice is in someway touched by money. I think that it is a given. For the good, the bad, and the ugly of it. You could argue that the profit motive hurts patients, and certainly it has, but the profit motive also drives new drugs. Money is what makes the world go round. (Give unto Ceasar, etc., etc.)
That being said, I will slightly disagree with JimNY (despite all the good points he always makes) in that I think that generally, several posters have been quick to dismiss valid issues as being done only for "money". Yes, it is a dimension of the issue. But raising it detracts from the valid discussion as to whether its good medicine or not. It sometimes is interpreted as a means to head off the issue at the pass, without giving it a good look on its merits.
So setting aside that someone is earning a living or making a profit or trying to make a career of this (which is certainly true), is this an issue that can help improve the lives of patients in the future?? I think very probably yes, and I will briefly add a point or two to support that.
Other cancers are best dealt with by finding and treating early. multiple myeloma is unique in the concept of "wait as long as you can". When multiple myeloma is advancing, at some point it morphs into being something more aggressive and difficult to treat. If there is a way to keep it suppressed for the long term, nipping it in the bud, so to speak, that MAY turn out to be a valid treatment paradigm. So, I am suggesting that this approach needs to be investigated, and I am sure that based on the rules of the game of clinical trials, it will take a good many years to figure this out, and it may turn out not to work, or other approaches may overtake it. But I do think its a valid issue to study. Good luck to all.
I think its valid to say that all of multiple myeloma research, and expanding, all of cancer research, all research, and all medical practice is in someway touched by money. I think that it is a given. For the good, the bad, and the ugly of it. You could argue that the profit motive hurts patients, and certainly it has, but the profit motive also drives new drugs. Money is what makes the world go round. (Give unto Ceasar, etc., etc.)
That being said, I will slightly disagree with JimNY (despite all the good points he always makes) in that I think that generally, several posters have been quick to dismiss valid issues as being done only for "money". Yes, it is a dimension of the issue. But raising it detracts from the valid discussion as to whether its good medicine or not. It sometimes is interpreted as a means to head off the issue at the pass, without giving it a good look on its merits.
So setting aside that someone is earning a living or making a profit or trying to make a career of this (which is certainly true), is this an issue that can help improve the lives of patients in the future?? I think very probably yes, and I will briefly add a point or two to support that.
Other cancers are best dealt with by finding and treating early. multiple myeloma is unique in the concept of "wait as long as you can". When multiple myeloma is advancing, at some point it morphs into being something more aggressive and difficult to treat. If there is a way to keep it suppressed for the long term, nipping it in the bud, so to speak, that MAY turn out to be a valid treatment paradigm. So, I am suggesting that this approach needs to be investigated, and I am sure that based on the rules of the game of clinical trials, it will take a good many years to figure this out, and it may turn out not to work, or other approaches may overtake it. But I do think its a valid issue to study. Good luck to all.
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JPC - Name: JPC
Re: When to treat with disease progression?
I have been posting about this lately. My status is in the blurry area of asymptomatic relapse versus symptomatic relapse. As of late, my M-spike continues to go up, but only vague symptoms (stomach issues, fatigue, and mouth sores, which for me are a low immunity issue). Latest bone survey showed increased subtle bone involvement. Will find out next month if it is enough to warrant treating the relapse or to continue in the watch-and-wait status (which should really be called stress-and-wait).
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lys2012 - Name: Alyssa
- When were you/they diagnosed?: 2010, Toronto, Canada
- Age at diagnosis: 32
Re: When to treat with disease progression?
Thanks for the interesting comments to my original post on this thread. When I wrote that post, I was wondering what kind of reaction it would get. Looks like it stirred up the pot a little bit, which I think is good.
Because I wrote the original post, I feel like I should loop back and comment on some of the comments, for what it's worth.
Coach Hoke - Good point that there's still a difference of opinion about when to re-start/change treatment when traditional measures of relapse are used. MRD testing adds another log to that fire.
JimNY - I had not thought of the financial motivation with regard to this type of trial. I have thought about it a lot with regard to maintenance therapy. Your point about the similarities is a valid one, I think. I would hope, though, that the money motivation and the science (or improved treatment) motivation are not mutually exclusive. I think that's another way of stating the main point that JPC made in his post.
Also, JimNY, you made a good point about the lack of experimental rigor in some of the studies you cited. As you mentioned, the McCarthy, et al (2012) (link) (related Beacon article) paper purporting to show improved overall survival for continuous Revlimid therapy is hard to interpret because of the fact that some patients crossed over from the non-maintenance to the maintenance arm part-way through the study.
Wearing my scientist hat, these kinds of studies are frustrating to me because in other scientific disciplines, if you designed an experiment like this, it would never get published. However, with my patient hat on, I can understand why they offered patients the opportunity to cross over between arms. Clinical trials are dealing with real people whose lives are at stake, not mice or rats. So the data that we need to use to make decisions is not as clean as we would like. Sometimes it is hard to know what is a real effect.
(As a clinical trial patient, perhaps another thread sometime would deal with the tradeoffs I've seen in my own treatment between science versus what is considered best for this patient.)
MikeF - Interesting to hear that your docs aren't impressed with the accuracy of bone marrow assays. Is that mainly because they're "drilling for oil" in one spot, when it's known that the oil is patchily distributed? Or are there other issues in addition that make your doctors concerned about bone marrow assays?
DallasGG - That's a great question about when minimal residual disease (MRD) testing will become routinely available. The short answer is that I don't know. Based on some patient conferences I've been to, it's certainly something thought leaders are trying to move toward. And even in the past couple of years I think we see it being used as a measure of treatment response (along with more traditional things like progression-free survival and overall survival) in many more clinical trials. Research is also underway to find a way to measure MRD through a simple blood test instead of a bone marrow biopsy. I think if / when that test is proven and standardized, we'll really see MRD testing move into the mainstream.
JPC - Thanks for your comments. My own thinking is pretty close to what you've expressed.
Alyssa - I'm sorry to hear that you're in that blurry area. But I hope you can stay on the "good" side of the symptomatic line quite awhile longer. I hope you get good news next month.
Mike
Because I wrote the original post, I feel like I should loop back and comment on some of the comments, for what it's worth.
Coach Hoke - Good point that there's still a difference of opinion about when to re-start/change treatment when traditional measures of relapse are used. MRD testing adds another log to that fire.
JimNY - I had not thought of the financial motivation with regard to this type of trial. I have thought about it a lot with regard to maintenance therapy. Your point about the similarities is a valid one, I think. I would hope, though, that the money motivation and the science (or improved treatment) motivation are not mutually exclusive. I think that's another way of stating the main point that JPC made in his post.
Also, JimNY, you made a good point about the lack of experimental rigor in some of the studies you cited. As you mentioned, the McCarthy, et al (2012) (link) (related Beacon article) paper purporting to show improved overall survival for continuous Revlimid therapy is hard to interpret because of the fact that some patients crossed over from the non-maintenance to the maintenance arm part-way through the study.
Wearing my scientist hat, these kinds of studies are frustrating to me because in other scientific disciplines, if you designed an experiment like this, it would never get published. However, with my patient hat on, I can understand why they offered patients the opportunity to cross over between arms. Clinical trials are dealing with real people whose lives are at stake, not mice or rats. So the data that we need to use to make decisions is not as clean as we would like. Sometimes it is hard to know what is a real effect.
(As a clinical trial patient, perhaps another thread sometime would deal with the tradeoffs I've seen in my own treatment between science versus what is considered best for this patient.)
MikeF - Interesting to hear that your docs aren't impressed with the accuracy of bone marrow assays. Is that mainly because they're "drilling for oil" in one spot, when it's known that the oil is patchily distributed? Or are there other issues in addition that make your doctors concerned about bone marrow assays?
DallasGG - That's a great question about when minimal residual disease (MRD) testing will become routinely available. The short answer is that I don't know. Based on some patient conferences I've been to, it's certainly something thought leaders are trying to move toward. And even in the past couple of years I think we see it being used as a measure of treatment response (along with more traditional things like progression-free survival and overall survival) in many more clinical trials. Research is also underway to find a way to measure MRD through a simple blood test instead of a bone marrow biopsy. I think if / when that test is proven and standardized, we'll really see MRD testing move into the mainstream.
JPC - Thanks for your comments. My own thinking is pretty close to what you've expressed.
Alyssa - I'm sorry to hear that you're in that blurry area. But I hope you can stay on the "good" side of the symptomatic line quite awhile longer. I hope you get good news next month.
Mike
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mikeb - Name: mikeb
- Who do you know with myeloma?: self
- When were you/they diagnosed?: 2009 (MGUS at that time)
- Age at diagnosis: 55
Re: When to treat with disease progression?
Further on the topic of the philosophy of when and how early to treat, I found this trial on Revlimid, Velcade, and dexamethasone (RVD) plus Darzalex that opened up earlier this month:
"Study Comparing Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) Versus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Subjects With Newly Diagnosed Multiple Myeloma" (information at clinicaltrials.gov)
Understanding that the original question related to treatment at disease progression, I did want to point out the following. RVD has a rate of getting a CR response at about 35%, based on recent studies. Until the recent past, minimal residual disease (MRD) evaluation was not routinely done, but very roughly, half the people who made complete response (CR) had residual disease (this comes from some of the MRD research), so the MRD-negative rate for RVD induction was in the range of 20%. Actually getting to MRD negative has to date proven to result in long remissions for most patients, and some doctors speculate it does not matter how you get there, as long as you do.
It will be very interesting what CR rate and MRD negative rate will come from adding Darzalex to the mix. If this can get the MRD negative rate to over 50%, that will be good for the patients, but also will result in impact to treatment approaches. It might actually drive down the rate of autologous stem cell transplant at initial diagnosis, based on having met the best measurable response. As a caveat, I have heard leading doctors point out that MRD negative does not yet guarantee that no more treatment is needed, but if the test gains in sensitivity, it might at one point get there.
For those who did not reach MRD negative on initial induction, a transplant might then be considered (depending on other factors). The patients would be going into a transplant, potentially with lower markers (based on better average response), which of course would improve the overall result of transplantation. After transplantation, there would still be a percentage of patients not at CR, relatively smaller than today, but they would be eligible for consolidation / maintenance, etc. So the goal would be for the majority of patients to get to MRD negative with this standard treatment (when it reaches that point). (I did assume transplant eligible patients in this scenario.)
Getting back to Mike's original question relating to relapse, the thought process to treatment at first relapse is very similar to treatment of newly diagnosed multiple myeloma. If you are presently in first remission, very likely you did not receive Darzalex. However, if it would be approved for first relapse (I actually think it probably is in the U.S.), then Darzalex could be used in a "quadlet", which would at least in some cases, I am sure, result in a deeper response than initial induction. I think, as relates to timing of treatment, if the goal is to get to MRD negative (I am speculating it will get there at some point in the future), then I think the tendency would be start to treat earlier, to have a better chance of achieving that level.
My hope would be that more patients would realistically get both a good long first remission, AND the same for the second remission, at least. One final thought. Doing the research on the basis of depth of response is MUCH better for research and drug development. The various national approval agencies as a rule up to now, like to see hard data on overall survival. That data, of course I think is important, but takes much longer and is much more costly to get.
Good luck to all.
"Study Comparing Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) Versus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Subjects With Newly Diagnosed Multiple Myeloma" (information at clinicaltrials.gov)
Understanding that the original question related to treatment at disease progression, I did want to point out the following. RVD has a rate of getting a CR response at about 35%, based on recent studies. Until the recent past, minimal residual disease (MRD) evaluation was not routinely done, but very roughly, half the people who made complete response (CR) had residual disease (this comes from some of the MRD research), so the MRD-negative rate for RVD induction was in the range of 20%. Actually getting to MRD negative has to date proven to result in long remissions for most patients, and some doctors speculate it does not matter how you get there, as long as you do.
It will be very interesting what CR rate and MRD negative rate will come from adding Darzalex to the mix. If this can get the MRD negative rate to over 50%, that will be good for the patients, but also will result in impact to treatment approaches. It might actually drive down the rate of autologous stem cell transplant at initial diagnosis, based on having met the best measurable response. As a caveat, I have heard leading doctors point out that MRD negative does not yet guarantee that no more treatment is needed, but if the test gains in sensitivity, it might at one point get there.
For those who did not reach MRD negative on initial induction, a transplant might then be considered (depending on other factors). The patients would be going into a transplant, potentially with lower markers (based on better average response), which of course would improve the overall result of transplantation. After transplantation, there would still be a percentage of patients not at CR, relatively smaller than today, but they would be eligible for consolidation / maintenance, etc. So the goal would be for the majority of patients to get to MRD negative with this standard treatment (when it reaches that point). (I did assume transplant eligible patients in this scenario.)
Getting back to Mike's original question relating to relapse, the thought process to treatment at first relapse is very similar to treatment of newly diagnosed multiple myeloma. If you are presently in first remission, very likely you did not receive Darzalex. However, if it would be approved for first relapse (I actually think it probably is in the U.S.), then Darzalex could be used in a "quadlet", which would at least in some cases, I am sure, result in a deeper response than initial induction. I think, as relates to timing of treatment, if the goal is to get to MRD negative (I am speculating it will get there at some point in the future), then I think the tendency would be start to treat earlier, to have a better chance of achieving that level.
My hope would be that more patients would realistically get both a good long first remission, AND the same for the second remission, at least. One final thought. Doing the research on the basis of depth of response is MUCH better for research and drug development. The various national approval agencies as a rule up to now, like to see hard data on overall survival. That data, of course I think is important, but takes much longer and is much more costly to get.
Good luck to all.
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JPC - Name: JPC
11 posts
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