- How is it determined whether one does not need further drugs until relapse or that drugs are still necessary? Is "drug free until relapse" just an older approach that is now being abandoned or is there some scientific basis for it?
- Is "maintenance" post-SCT generally characterized by a lowering in dosage of the induction drugs?
- If patients reach nCR or CR and do NOT go on to a SCT, do they continue, generally speaking, with the same regimen and at the same dosages that seemingly worked successfully during induction?
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What is "maintenance therapy" and how is it determined?
I gather that, after a successful stem cell transplant, myeloma patients proceed either drug free until relapse or are placed on "maintenance therapy."
Re: What is "maintenance therapy" and how is it determined?
Hi mrozdav,
I can't answer all of your questions right now, but I thought it might be worth pointing you to this earlier forum discussion which discusses the definitions of induction, consolidation, and maintenance therapy.
"Induction vs consolidation vs maintenance?," forum disc. started Nov 10, 2014
Most of the time, maintenance therapy is single-agent therapy, whereas induction therapy will be a two- or three-drug therapy. There is no hard and fast rule about that, however, and you'll find some myeloma patients who are on a "maintenance" regimen that is basically no different than their induction therapy. That, though, is not common, as far as I can tell.
I can't answer all of your questions right now, but I thought it might be worth pointing you to this earlier forum discussion which discusses the definitions of induction, consolidation, and maintenance therapy.
"Induction vs consolidation vs maintenance?," forum disc. started Nov 10, 2014
Most of the time, maintenance therapy is single-agent therapy, whereas induction therapy will be a two- or three-drug therapy. There is no hard and fast rule about that, however, and you'll find some myeloma patients who are on a "maintenance" regimen that is basically no different than their induction therapy. That, though, is not common, as far as I can tell.
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JimNY
Re: What is "maintenance therapy" and how is it determined?
JimNY:
Thank you so much for pointing me to the prior forum discussion. Your prior entry and Multibilly's have answered my questions quite satisfactorily.
I still wonder, however, whether the no maintenance decision is something of the past or does it depend on the special circumstances of the patient.
Thank you so much for pointing me to the prior forum discussion. Your prior entry and Multibilly's have answered my questions quite satisfactorily.
I still wonder, however, whether the no maintenance decision is something of the past or does it depend on the special circumstances of the patient.
Re: What is "maintenance therapy" and how is it determined?
Hi mrozdav,
Glad to hear the link was helpful.
My impression is that maintenance is becoming more common – particularly maintenance Revlimid. It's hard to explain why and, to be honest, I personally don't understand it. There's no question that Revlimid maintenance will lengthen the first remission in most patients, but there is only limited evidence, at best, that it provides an overall survival benefit.
As you probably know, there have been three studies that were explicitly designed to test the potential benefit of Revlimid maintenance. All three of them found a benefit in terms of progression-free survival. Only one of the studies, however, found an overall survival benefit, and there are valid concerns that the design of that one study was biased to finding an overall survival benefit. See this forum posting for more on that issue:
"Dr. Rajkumar on maintenance therapy," forum disc. started May 1, 2014
I can see doing maintenance for a while to try to further deepen someone's first response to treatment (although you can even debate that point). But maintenance for someone who already has gotten to an sCR, or is MRD negative? I'm not sure I get the motivation in that case – particularly given evidence that Revlimid can impact marrow function with long-term use. See, for example, the links in this forum discussion that Mark started:
"Revlimid (lenalidomide) maintenance," forum disc. started Nov 19, 2013
I hope this helps a bit more.
Glad to hear the link was helpful.
My impression is that maintenance is becoming more common – particularly maintenance Revlimid. It's hard to explain why and, to be honest, I personally don't understand it. There's no question that Revlimid maintenance will lengthen the first remission in most patients, but there is only limited evidence, at best, that it provides an overall survival benefit.
As you probably know, there have been three studies that were explicitly designed to test the potential benefit of Revlimid maintenance. All three of them found a benefit in terms of progression-free survival. Only one of the studies, however, found an overall survival benefit, and there are valid concerns that the design of that one study was biased to finding an overall survival benefit. See this forum posting for more on that issue:
"Dr. Rajkumar on maintenance therapy," forum disc. started May 1, 2014
I can see doing maintenance for a while to try to further deepen someone's first response to treatment (although you can even debate that point). But maintenance for someone who already has gotten to an sCR, or is MRD negative? I'm not sure I get the motivation in that case – particularly given evidence that Revlimid can impact marrow function with long-term use. See, for example, the links in this forum discussion that Mark started:
"Revlimid (lenalidomide) maintenance," forum disc. started Nov 19, 2013
I hope this helps a bit more.
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JimNY
Re: What is "maintenance therapy" and how is it determined?
I had tandem stem cell transplants July 2012 and November 2012. My doctors said that my results were so good they did not want to do any maintenance therapy.
In August 2014, we found a large mass in my right thigh. My blood work was great that week. A sore hip sent me to the doctor and MRI and light chain ratio was 177.
I went back on Revlimid and dexamethasone once a week. Free light ratio is down to 28. And I had a rod placed in leg to avoid break.
Would I have been better off taking maintenance? Not sure, but I had two years of no meds, so I think that was good.
In August 2014, we found a large mass in my right thigh. My blood work was great that week. A sore hip sent me to the doctor and MRI and light chain ratio was 177.
I went back on Revlimid and dexamethasone once a week. Free light ratio is down to 28. And I had a rod placed in leg to avoid break.
Would I have been better off taking maintenance? Not sure, but I had two years of no meds, so I think that was good.
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Music box lady - Name: Margie
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: 2012
- Age at diagnosis: 60
Re: What is "maintenance therapy" and how is it determined?
Great answer by JimNY. The other point that I think is important with respect to the studies on Revlimid maintenance is mentioned in this paper.
A major focus of research has been on the prolonged use of subtherapeutic doses of an active drug in the absence of observable benefit to the patient, called “maintenance.”
Maintenance with melphalan, cyclophosphamide, interferon-alpha, thalidomide, lenalidomide, and bortezomib have all been shown to be more toxic than placebo, to consistently prolong progression-free survival, but not in general overall survival. In most of the studies, only about one half of the placebo group received therapeutic doses of the novel drug at relapse, so that, in effect, one is comparing a group that all receive the novel drug, to one in which only half of the patients do.
Given this inherent bias, it is surprising that a more consistent survival benefit is not seen, and the absence of which suggests that continuous, chronic, subtherapeutic dosing is likely inferior to intermittent therapeutic dosing.
Recent genomic studies have identified a high degree of clonal heterogeneity in multiple myeloma that is dynamically modulated under sequential therapeutic pressure. Future therapeutic strategies will need to be designed taking this heterogeneity into account."
Source: PL Bergsagel, "Where We Were, Where We Are, Where We Are Going: Progress in Multiple Myeloma," ASCO 2014 Educational Book (link to full text of article)
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Mark11
Re: What is "maintenance therapy" and how is it determined?
Good day, all:
Dr. Antonio Palumbo is one of the leading doctors in Italy as a myeloma specialist. He has several studies on the topic of maintenance. I have heard and read several of his discussions. Here is what I took away from Dr. Palumbo's discussions.
A basic concern with maintenance compared with no continuous treatment is that many doctors acknowledged that PFS is enhanced with maintenance in a population, but when the myeloma comes back, it possibly comes back more aggressively on maintenance. Off maintenance, it comes back earlier, but first / second / third relapses were thought by some to be more treatable without maintenance. Or, to put it another way, maintenance did help PFS, but it was in debate whether or not it improved OS.
That was the issue, and most doctors agreed in the past that it was an open issue, but they did individually – for the most part – form an opinion on maintenance. We have spoken to several doctors, and my impression was that the majority of doctors felt that maintenance was better, but they did acknowledge that it was open issue.
And so Dr. Palumbo studied this in a number of clinical trials. His conclusion was a little complicated, but basically, he felt that his studies did establish that over a population, maintenance is more beneficial than no maintenance. Here is a link to an ASCO abstract on one of his trials:
"Continuous treatment (CT) versus fixed duration of therapy (FDT) in newly diagnosed myeloma patients: PFS1, PFS2, OS endpoints," ASCO 2014 annual meeting abstract abstract 8515 (link to abstract text)
I will try and explain in a little detail his point. One study arm was with maintenance, the other without. Maintenance (Revlimid or Velcade) after initial induction provided a one year advantage to first relapse. After first relapse to second relapse, the arms stayed the same. The duration after the first to second relapse between the two arms was the same. So he concluded that maintenance was superior by one year to second relapse.
After second relapse, things got more complicated. No one is going to (or should they) stick to an initial narrow treatment plan after two relapses. They will have to make the best decision on the then available treatments. Plus, with improvements in treatment, you would need to have the study go on 5+ or 7+ years today (for younger patients) to start to get some interpretable data beyond second relapse. Actually, his data and explanation suggested to me is that it will be very difficult to answer questions on clinical trials regarding the best detail approach for OS. When the results come out, they are reporting on an issue that was open 4 or 5 or 6 years earlier, which may no longer be the most current treatment option.
I am helping out with the research, supporting my wife who is doing the hard part. She has decided to go on Velcade maintenance; it has not yet started. If our initial treatment got us to MRD - [minimal residual disease negative], however, we might reconsider.
Dr. Antonio Palumbo is one of the leading doctors in Italy as a myeloma specialist. He has several studies on the topic of maintenance. I have heard and read several of his discussions. Here is what I took away from Dr. Palumbo's discussions.
A basic concern with maintenance compared with no continuous treatment is that many doctors acknowledged that PFS is enhanced with maintenance in a population, but when the myeloma comes back, it possibly comes back more aggressively on maintenance. Off maintenance, it comes back earlier, but first / second / third relapses were thought by some to be more treatable without maintenance. Or, to put it another way, maintenance did help PFS, but it was in debate whether or not it improved OS.
That was the issue, and most doctors agreed in the past that it was an open issue, but they did individually – for the most part – form an opinion on maintenance. We have spoken to several doctors, and my impression was that the majority of doctors felt that maintenance was better, but they did acknowledge that it was open issue.
And so Dr. Palumbo studied this in a number of clinical trials. His conclusion was a little complicated, but basically, he felt that his studies did establish that over a population, maintenance is more beneficial than no maintenance. Here is a link to an ASCO abstract on one of his trials:
"Continuous treatment (CT) versus fixed duration of therapy (FDT) in newly diagnosed myeloma patients: PFS1, PFS2, OS endpoints," ASCO 2014 annual meeting abstract abstract 8515 (link to abstract text)
I will try and explain in a little detail his point. One study arm was with maintenance, the other without. Maintenance (Revlimid or Velcade) after initial induction provided a one year advantage to first relapse. After first relapse to second relapse, the arms stayed the same. The duration after the first to second relapse between the two arms was the same. So he concluded that maintenance was superior by one year to second relapse.
After second relapse, things got more complicated. No one is going to (or should they) stick to an initial narrow treatment plan after two relapses. They will have to make the best decision on the then available treatments. Plus, with improvements in treatment, you would need to have the study go on 5+ or 7+ years today (for younger patients) to start to get some interpretable data beyond second relapse. Actually, his data and explanation suggested to me is that it will be very difficult to answer questions on clinical trials regarding the best detail approach for OS. When the results come out, they are reporting on an issue that was open 4 or 5 or 6 years earlier, which may no longer be the most current treatment option.
I am helping out with the research, supporting my wife who is doing the hard part. She has decided to go on Velcade maintenance; it has not yet started. If our initial treatment got us to MRD - [minimal residual disease negative], however, we might reconsider.
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JPC - Name: JPC
Re: What is "maintenance therapy" and how is it determined?
Thank you all for your contributions to this thread.
As with so many things right now, the "right" answer or path is difficult to determine at times. Having just finished my SCT (and recuperating now at home), I am facing the maintenance discussion with my regular hematologist in a few weeks. I know that the hospital where I got my SCT has the approach that maintenance is unnecessary, more toxic, and that I should enjoy my quality of life. Hopefully the SCT has given me a longer period of remission, although we will not know my exact myeloma results for another 3 months or so when I get my update procedures.
For me, personally, I think that part of the answer or the path we select (my wife and I) depends on those results. Hopefully, I will have achieved a complete response, and my type of myeloma, at least right now, appears to be one of the less aggressive types. Those results will probably factor into my decision-making. I think we do need to be acknowledging the complexity of the situations we are in and the fact that the many different forms of the disease may lead to different outcomes and possibly different treatment paths.
As a psychologist, I wish we had more clear data and results to base our decisions on, but I still think tremendous progress has been made. I'm reading MB forum discussions right now about maintenance as I think through this process.
As with so many things right now, the "right" answer or path is difficult to determine at times. Having just finished my SCT (and recuperating now at home), I am facing the maintenance discussion with my regular hematologist in a few weeks. I know that the hospital where I got my SCT has the approach that maintenance is unnecessary, more toxic, and that I should enjoy my quality of life. Hopefully the SCT has given me a longer period of remission, although we will not know my exact myeloma results for another 3 months or so when I get my update procedures.
For me, personally, I think that part of the answer or the path we select (my wife and I) depends on those results. Hopefully, I will have achieved a complete response, and my type of myeloma, at least right now, appears to be one of the less aggressive types. Those results will probably factor into my decision-making. I think we do need to be acknowledging the complexity of the situations we are in and the fact that the many different forms of the disease may lead to different outcomes and possibly different treatment paths.
As a psychologist, I wish we had more clear data and results to base our decisions on, but I still think tremendous progress has been made. I'm reading MB forum discussions right now about maintenance as I think through this process.
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dranton - Name: Anton Tolman
- Who do you know with myeloma?: Self
- When were you/they diagnosed?: August, 2014
- Age at diagnosis: 51
Re: What is "maintenance therapy" and how is it determined?
Great thread. Thoughtful contributions from everyone!
The study JPC mentions is updated in the attachment. Not all patients had access to Revlimid / novel agents at relapse. The group that got the Revlimid maintenance also were more likely to have access to Velcade compared to the other groups.
"Patients originally assigned to MPR-R were more likely to receive a bortezomib-based regimen as second-line therapy (49%) than those originally assigned to MP (21%), whereas lenalidomide-based therapy was more commonly chosen for patients originally assigned to MP (72%) or MPR (58%) than for those who received MPR-R (28%) (Table 2)."
Some patients in the melphalan - prednisone group appeared to have no access to novel agents.
Based on this study the only thing I could conclude is that patients with access to novel agents will do better than patients with no access to them. I do not agree with the authors conclusions. Of course I do not receive compensation from the drug companies like the authors of this study do.
"Acknowledgments: The authors received editorial support in the preparation of this manuscript from Adriana Stan, PhD, and Anna Georgieva, MD, PhD, from Excerpta Medica, funded by Celgene Corporation. The authors were fully responsible for all content and editorial decisions for this manuscript."
"Funding: This work was supported by Celgene Corporation."
"MAD was a consultant for, and received honoraria from, Celgene Corporation. MTP received honoraria from Celgene Corporation and Janssen-Cilag, and served on the advisory committee for Bristol-Myers Squibb. RF is an advisory board member and received honoraria from Celgene Corporation. JC was an advisory board member of and received personal fees, including service on the speakers bureau, from Celgene Corporation. MK is a member of an advisory committee for Celgene Corporation and Ortho Biotech, is on the speakers bureau of Janssen-Cilag, and received honoraria from Celgene Corporation. ET received honoraria from Celgene Corporation. JZ, LG, and CJ are Celgene Corporation employees. AP was a consultant for, and received honoraria from, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen-Cilag, Millennium, and Onyx."
Reference:
MA Dimopoulos et al, "Impact of maintenance therapy on subsequent treatment in patients with newly diagnosed multiple myeloma: use of “progression-free survival 2” as a clinical trial end-point," Haematologica, Apr 3, 2015 (link to PDF with full text of article)
The study JPC mentions is updated in the attachment. Not all patients had access to Revlimid / novel agents at relapse. The group that got the Revlimid maintenance also were more likely to have access to Velcade compared to the other groups.
"Patients originally assigned to MPR-R were more likely to receive a bortezomib-based regimen as second-line therapy (49%) than those originally assigned to MP (21%), whereas lenalidomide-based therapy was more commonly chosen for patients originally assigned to MP (72%) or MPR (58%) than for those who received MPR-R (28%) (Table 2)."
Some patients in the melphalan - prednisone group appeared to have no access to novel agents.
Based on this study the only thing I could conclude is that patients with access to novel agents will do better than patients with no access to them. I do not agree with the authors conclusions. Of course I do not receive compensation from the drug companies like the authors of this study do.
"Acknowledgments: The authors received editorial support in the preparation of this manuscript from Adriana Stan, PhD, and Anna Georgieva, MD, PhD, from Excerpta Medica, funded by Celgene Corporation. The authors were fully responsible for all content and editorial decisions for this manuscript."
"Funding: This work was supported by Celgene Corporation."
"MAD was a consultant for, and received honoraria from, Celgene Corporation. MTP received honoraria from Celgene Corporation and Janssen-Cilag, and served on the advisory committee for Bristol-Myers Squibb. RF is an advisory board member and received honoraria from Celgene Corporation. JC was an advisory board member of and received personal fees, including service on the speakers bureau, from Celgene Corporation. MK is a member of an advisory committee for Celgene Corporation and Ortho Biotech, is on the speakers bureau of Janssen-Cilag, and received honoraria from Celgene Corporation. ET received honoraria from Celgene Corporation. JZ, LG, and CJ are Celgene Corporation employees. AP was a consultant for, and received honoraria from, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen-Cilag, Millennium, and Onyx."
Reference:
MA Dimopoulos et al, "Impact of maintenance therapy on subsequent treatment in patients with newly diagnosed multiple myeloma: use of “progression-free survival 2” as a clinical trial end-point," Haematologica, Apr 3, 2015 (link to PDF with full text of article)
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Mark11
Re: What is "maintenance therapy" and how is it determined?
All,
You might find these recent counterpoint discussions from Drs. Berenson, Vesole and Siegel on the subject of maintenance therapy to be insightful:
"Counterpoints: Do Patients With Multiple Myeloma Need Maintenance Treatment?," Clinical Advances in Hematology & Oncology, March 2015 (full text via OBR Oncology)
Excerpts:
Dr. Berenson:
"It is our recommendation that all patients who do not show disease progression should receive maintenance therapy with the same agents used during their treatment. One exception is chemotherapeutic agents, which should be discontinued. Maintenance agents are typically administered at lower doses or less frequently than therapeutic doses, or in combination with corticosteroids. For instance, bortezomib is given every other week instead of 4 times monthly and IMiDs are continued along with corticosteroids if corticosteroids were part of the patient’s treatment regimen."
Drs. Vesole & Siegel:
"For better or worse, almost all US-based transplant centers have incorporated lenalidomide [Revlimid] maintenance therapy into their treatment algorithm after autologous transplantation, even though it is not approved by the US Food and Drug Administration for this indication and is not recommended by the IMWG or the UK Myeloma Forum. Although it is clear that PFS is improved, it remains to be determined whether this results in improved OS or quality of life, and whether it is indicated for high-risk patients, after consolidation, or in MRD-negative patients ...
Therefore, at this time maintenance therapy should continue to be considered only in the context of clinical trials whose goal is to answer important maintenance-related questions. For those practitioners who prescribe maintenance therapy or those patients who wish to receive maintenance therapy outside of a clinical trial, it is the responsibility of the medical provider to counsel the patient about the risks/benefits so that an informed decision can be determined."
You might find these recent counterpoint discussions from Drs. Berenson, Vesole and Siegel on the subject of maintenance therapy to be insightful:
"Counterpoints: Do Patients With Multiple Myeloma Need Maintenance Treatment?," Clinical Advances in Hematology & Oncology, March 2015 (full text via OBR Oncology)
Excerpts:
Dr. Berenson:
"It is our recommendation that all patients who do not show disease progression should receive maintenance therapy with the same agents used during their treatment. One exception is chemotherapeutic agents, which should be discontinued. Maintenance agents are typically administered at lower doses or less frequently than therapeutic doses, or in combination with corticosteroids. For instance, bortezomib is given every other week instead of 4 times monthly and IMiDs are continued along with corticosteroids if corticosteroids were part of the patient’s treatment regimen."
Drs. Vesole & Siegel:
"For better or worse, almost all US-based transplant centers have incorporated lenalidomide [Revlimid] maintenance therapy into their treatment algorithm after autologous transplantation, even though it is not approved by the US Food and Drug Administration for this indication and is not recommended by the IMWG or the UK Myeloma Forum. Although it is clear that PFS is improved, it remains to be determined whether this results in improved OS or quality of life, and whether it is indicated for high-risk patients, after consolidation, or in MRD-negative patients ...
Therefore, at this time maintenance therapy should continue to be considered only in the context of clinical trials whose goal is to answer important maintenance-related questions. For those practitioners who prescribe maintenance therapy or those patients who wish to receive maintenance therapy outside of a clinical trial, it is the responsibility of the medical provider to counsel the patient about the risks/benefits so that an informed decision can be determined."
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
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