Hi everyone,
Abstracts for the upcoming ASH meeting have been made public, and they include the first significant results reported for the IFM clinical trial that has been testing
- Having a stem cell transplant, or
- Not having a stem cell transplant
as part of initial treatment for newly diagnosed myeloma patients.
I initially thought that this abstract reported results for both the French and U.S. arms of the trial, which is collectively known as the IFM/DFCI trial. However, apparently this abstract only covers the French (IFM) part of the trial.
Summary of key results:
Progression free survival was significantly better for patients who underwent transplantation upfront. Overall survival at three years, however, is no different between the two groups of patients.
The authors believe these results confirm that stem cell transplantation should remain the standard of care for newly diagnosed myeloma patients.
Here is the relevant abstract:
391 Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: A Phase III Study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial)
Michel Attal, Valerie Lauwers-Cances, MD, Cyrille Hulin, MD, Thierry Facon, Denis Caillot, Martine Escoffre, Bertrand Arnulf, Margaret MACRO, MD, Karim Belhadj, MD, Laurent Garderet, MD, Murielle Roussel, MD, Claire Mathiot, MD, Herve Avet-Loiseau, Nikhil C. Munshi, MD, Paul G. Richardson, MD, Kenneth C. Anderson, M.D, Jean Luc Harousseau and Philippe Moreau
High dose chemotherapy plus autologous transplantation (ASCT) is considered a standard of care for newly diagnosed myeloma patients younger than 65 years of age. The high complete response rate (CR) achieved with the triplet combination of immunomodulatory drugs + proteasome inhibitors + dexamethasone has led investigators to propose this strategy upfront without immediate ASCT. The aim of this study was to determine if, in the era of new drugs, ASCT was still required in the initial management of young patients.
We conducted a randomized trial comparing conventional dose treatment (RVD arm= 8 cycles of lenalidomide, bortezomib and dexamethasone, plus stem cell mobilization after 3 cycles of RVD utilizing high dose cyclophosphamide and G-CSF) to RVD with ASCT (Transplant arm= 3 induction cycles of RVD, followed by stem cell collection, and then ASCT conditioned with melphalan 200 mg/m2, followed by 2 cycles of RVD as consolidation).
Maintenance treatment with lenalidomide (10 to 15 mg/d) was used in both arms for one year. In the RVD arm, ASCT was planned at time of relapse.
From November 2010 to November 2012, 700 previously untreated French and Belgian patients were equally randomized between arms. Randomization was stratified according to ISS stage (I vs II vs III) and FISH analysis (standard vs high risk = del 17p or t(4;14) or t(14;16)). The primary study end point was progression-free survival (PFS). Two pre-specified interim analysis were to be performed at 33% and 69% of the estimated total number of events. The second interim analysis was performed in June 2015 (346 events= 197 in the RVD arm, 149 in the transplant arm). These results were submitted to an independent data management and safety committee, who recommended completing the trial, and continuing follow-up (without cross over before progression), since the difference in PFS between the 2 groups had reached the pre-specified level of significance for stopping the study.
As of June 8, 2015, median follow up was 39 months. All patients had discontinued treatment (completion of planned therapy= 66%, disease progression= 16%, adverse events= 10%). Patient characteristics of each group were similar and no significant differences were found with regard to age (median=58 years), ISS stage (I=233, II=341, III=126), Ig isotype, beta-2-microglobulin (median=3.5 mg/L), and cytogenetics (high risk=90 patients).
In the transplant arm, 93% of patients underwent ASCT and 5 toxic deaths occurred during mobilization or in the actual transplant phase (1.4%).
ASCT was found to improve PFS (stratified p value for log-rank test < 0.0002; HR= 1.5, 95% CI= 1.2-1.9). The 3-year post-randomization PFS rate was 61% in the transplant arm versus 48% in the RVD arm. The PFS benefit observed in the transplant arm was uniform across all the following subgroups: age (≤ or > 60 years), sex, Ig isotype (IgG or others), ISS stage (I or II or III), cytogenetics (standard or high risk), and response after the 3 first cycles of RVD (complete response or not).
The 3-year post randomization rate of overall survival was extremely high (88%) and similar between the 2 study groups (stratified p value for log rank test=0.25).
The complete response rate was significantly higher in the transplant arm compared to the RVD arm: 58% versus 46%, respectively (p<0.01). Forty-one second primary malignancies among 39 patients were recorded (Transplant arm=23, RVD arm=18).
In conclusion, these results demonstrate that ASCT should remain a standard of care for young patients with de novo myeloma, and suggest that RVD plus ASCT could be a future reference strategy in this setting.
Further follow-up is needed, as the number of deaths is still low in both arms. The parallel US trial, which uses a similar design but importantly administers maintenance lenalidomide continuously until progression in both arms, is ongoing.
https://myelomabeacon.org/resources/mtgs/ash2015/abs/391/
Forums
Re: Initial results: key stem cell transplant clinical trial
Thanks for posting this study. As a side note, I think the disclosure statement at the bottom of the paper is longer than the paper itself!
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Mark11
Re: Initial results: key stem cell transplant clinical trial
CherylG, this looks like an important study. I continue, however, to be befuddled by the relationship between progression free survival and overall survival, a topic that has been discussed here in the forum lots of times. But I never seem to grasp what this really means. Apparently, PFS is significantly better if one gets an upfront stem cell transplant. However, overall survival is the same whether you get the transplant or not. Can you try to explain this to me? I suspect that if anyone can help me understand, you are the one.
Re: Initial results: key stem cell transplant clinical trial
Hi Mrozdav,
Sorry, I just saw your question, and I probably won't be able to answer it tonight. What I can do now, however, is make sure we're on the same page as to some key definitions.
So, for an individual patient enrolled in a study like this one:
Progression-Free Survival = Time from diagnosis until the patient either (a) relapses, or (b) dies of any cause, whichever of those two comes first;
Overall Survival = Time from diagnosis until the patient dies
In studies involving newly diagnosed multiple myeloma patients -- particularly transplant-eligible newly diagnosed patients -- progression-free survival will mainly measure time from diagnosis until time of first relapse. This is because not many transplant-eligible newly diagnosed myeloma patients die before they relapse.
I should add that there can be some variation in the start time for these survival metrics. Sometimes the start time is the time of diagnosis, sometimes it's the time of enrollment in a study, and sometimes it's the start of treatment. Once again, in studies involving newly diagnosed patients, it doesn't make a huge difference which of those starting times is used: they're very similar to each other.
So what the results of this study show is that doing a transplant upfront, rather than waiting to do a transplant at first relapse, increases the time to first relapse. It does not, however, affect the share of patients who are still alive -- whether they have relapsed or not -- 3 years after diagnosis.
It is possible with longer observation, however, that early transplantation may be found to increase not only median progression-free survival, but also median overall survival.
I don't know if what I just wrote will really answer your question, but it may help us (and others) get on the same page about the definitions of the key variables that need to be discussed.
I hope this helps. Let me know, and we can continue the discussion!
Sorry, I just saw your question, and I probably won't be able to answer it tonight. What I can do now, however, is make sure we're on the same page as to some key definitions.
So, for an individual patient enrolled in a study like this one:
Progression-Free Survival = Time from diagnosis until the patient either (a) relapses, or (b) dies of any cause, whichever of those two comes first;
Overall Survival = Time from diagnosis until the patient dies
In studies involving newly diagnosed multiple myeloma patients -- particularly transplant-eligible newly diagnosed patients -- progression-free survival will mainly measure time from diagnosis until time of first relapse. This is because not many transplant-eligible newly diagnosed myeloma patients die before they relapse.
I should add that there can be some variation in the start time for these survival metrics. Sometimes the start time is the time of diagnosis, sometimes it's the time of enrollment in a study, and sometimes it's the start of treatment. Once again, in studies involving newly diagnosed patients, it doesn't make a huge difference which of those starting times is used: they're very similar to each other.
So what the results of this study show is that doing a transplant upfront, rather than waiting to do a transplant at first relapse, increases the time to first relapse. It does not, however, affect the share of patients who are still alive -- whether they have relapsed or not -- 3 years after diagnosis.
It is possible with longer observation, however, that early transplantation may be found to increase not only median progression-free survival, but also median overall survival.
I don't know if what I just wrote will really answer your question, but it may help us (and others) get on the same page about the definitions of the key variables that need to be discussed.
I hope this helps. Let me know, and we can continue the discussion!
Re: Initial results: key stem cell transplant clinical trial
Cheryl
Thank you for bringing this to our attention. Without seeing all data and the full paper it is difficult to assess fully.
I note that the number of ISS stage 3 patients is much lower than usually encountered in practice, although statistically the researchers found no significant differences with outcomes between the ISS stage stratified patient groups.
Transplant patients vary enormously in time to progression post transplant and some that do not have transplants have longer rates of progression. Individual characteristics and response to treatment remain unpredictable. A , high, similar 3 year over all survival for both arms does not suggest a longer time frame for follow up will necessarily show significant differences in over all survival between the groups because of this vast spectrum of individual responses based on so many factors, but we shall see.
The stratification included the accepted high risk genetics, but there is still uncertainty about patients wiith deletion 1p.32 who one large trial data in the UK suggested worse survival post ASCT. This study does not clarify this.
Edna
Thank you for bringing this to our attention. Without seeing all data and the full paper it is difficult to assess fully.
I note that the number of ISS stage 3 patients is much lower than usually encountered in practice, although statistically the researchers found no significant differences with outcomes between the ISS stage stratified patient groups.
Transplant patients vary enormously in time to progression post transplant and some that do not have transplants have longer rates of progression. Individual characteristics and response to treatment remain unpredictable. A , high, similar 3 year over all survival for both arms does not suggest a longer time frame for follow up will necessarily show significant differences in over all survival between the groups because of this vast spectrum of individual responses based on so many factors, but we shall see.
The stratification included the accepted high risk genetics, but there is still uncertainty about patients wiith deletion 1p.32 who one large trial data in the UK suggested worse survival post ASCT. This study does not clarify this.
Edna
Re: Initial results: key stem cell transplant clinical trial
Cheryl G.,
No, I think I continue befuddled, but I also think I may just be obtuse. I do not even know how to express my confusion. Is progression free survival a higher goal than overall survival? How can it be? If you get a stem cell transplant, but I do not , and we both survive for, let's say, five years, then what was the benefit of the stem cell transplant? Is the issue the quality of our lives during those five years, that it is better for transplant patients?
I am not being polemical here, just genuinely do not understand what the medical doctors/researchers are talking about.
No, I think I continue befuddled, but I also think I may just be obtuse. I do not even know how to express my confusion. Is progression free survival a higher goal than overall survival? How can it be? If you get a stem cell transplant, but I do not , and we both survive for, let's say, five years, then what was the benefit of the stem cell transplant? Is the issue the quality of our lives during those five years, that it is better for transplant patients?
I am not being polemical here, just genuinely do not understand what the medical doctors/researchers are talking about.
Re: Initial results: key stem cell transplant clinical trial
Dear Mrozdav
I do not think your questioning is unreasonable. You are not muddled, but the data on progression free survival and overall survival in multiple myeloma are different 'benchmarks' for clinicians in particular treating the disease.
Progression free survival is time to relapse after treatment, as each relapse can become more challenging to treat with drugs alone. That is why people often have more than one transplant.
I think this is how I understand things- although I may be wrong.
So with a transplant up front, which takes up a large initial time period post diagnosis, an average patient may have a longer period without first relapse. With drug treatment regimes alone the relapse may come earlier on average and then either different treatment regime, e.g. transplant or different drugs may delay next relapse. The overall affect it seems is that overall survival remains the same for the two treatment regimes.
As to quality of life- for the pre-transplant, transplant and early post transplant period quality of life is unlikely to be great for many as they report. But often is better over time.
With continuous drug regimes quality of life depends on the response to treatment and adverse affects that may arise from prolonged treatment hitting the bone marrow / body. Some do fairly well, others do not, even with the same regimes.
It is not easy to relate information to oneself at an individual level. There are more questions than answers.
Edna
I do not think your questioning is unreasonable. You are not muddled, but the data on progression free survival and overall survival in multiple myeloma are different 'benchmarks' for clinicians in particular treating the disease.
Progression free survival is time to relapse after treatment, as each relapse can become more challenging to treat with drugs alone. That is why people often have more than one transplant.
I think this is how I understand things- although I may be wrong.
So with a transplant up front, which takes up a large initial time period post diagnosis, an average patient may have a longer period without first relapse. With drug treatment regimes alone the relapse may come earlier on average and then either different treatment regime, e.g. transplant or different drugs may delay next relapse. The overall affect it seems is that overall survival remains the same for the two treatment regimes.
As to quality of life- for the pre-transplant, transplant and early post transplant period quality of life is unlikely to be great for many as they report. But often is better over time.
With continuous drug regimes quality of life depends on the response to treatment and adverse affects that may arise from prolonged treatment hitting the bone marrow / body. Some do fairly well, others do not, even with the same regimes.
It is not easy to relate information to oneself at an individual level. There are more questions than answers.
Edna
Re: Initial results: key stem cell transplant clinical trial
Hello Mrozdav,
As Edna has suggested, I think you understand things very well, and you are asking exactly the questions that should be asked.
Before I say anything else, let me make sure it's clear that this clinical trial is not testing transplantation versus no transplantation.
In the one group of patients, everyone received a transplant as part of their initial therapy.
In the other group of patients, no one received a transplant as part of their initial therapy. However, nothing prevents the patients in this second group from having a transplant at relapse.
I suspect that many (a majority? most?) of the patients in the second group will receive a transplant at relapse. The exception would be those who are not capable of having a transplant, or not permitted to have one.
Going back to your original question, most myeloma clinical trials focus on measuring progression-free survival because the data can be collected quicker, and because there is a belief that better progression-free survival leads to better overall survival.
I say "belief" because there are more and more clinical trials like the current one where differences in progression-free survival are not associated with differences in overall survival. We have seen this in two of the three key trials that looked at Revlimid maintenance therapy. We saw this in the ASCO study this summer that looked at Velcade consolidation therapy after transplantation. And we see it now in this study.
Yet, as you suggest, overall survival is really what all of us here should care about the most. I think this should particularly be the case when trying to decide between two options that have potentially very different quality of life outcomes, but comparable overall survival outcomes.
As Edna has suggested, I think you understand things very well, and you are asking exactly the questions that should be asked.
Before I say anything else, let me make sure it's clear that this clinical trial is not testing transplantation versus no transplantation.
In the one group of patients, everyone received a transplant as part of their initial therapy.
In the other group of patients, no one received a transplant as part of their initial therapy. However, nothing prevents the patients in this second group from having a transplant at relapse.
I suspect that many (a majority? most?) of the patients in the second group will receive a transplant at relapse. The exception would be those who are not capable of having a transplant, or not permitted to have one.
Going back to your original question, most myeloma clinical trials focus on measuring progression-free survival because the data can be collected quicker, and because there is a belief that better progression-free survival leads to better overall survival.
I say "belief" because there are more and more clinical trials like the current one where differences in progression-free survival are not associated with differences in overall survival. We have seen this in two of the three key trials that looked at Revlimid maintenance therapy. We saw this in the ASCO study this summer that looked at Velcade consolidation therapy after transplantation. And we see it now in this study.
Yet, as you suggest, overall survival is really what all of us here should care about the most. I think this should particularly be the case when trying to decide between two options that have potentially very different quality of life outcomes, but comparable overall survival outcomes.
Re: Initial results: key stem cell transplant clinical trial
Good morning:
Thank you very much for posting this information. I will have to research it in detail myself. Very timely.
I would like to make one observation to those interested in this thread. It looks like the medium duration on trial is something like three years. That is enough time to get a first read on PFS. PFS stats will be updated as more date comes in.
With regards to overall survival, however, we generally know from other studies that the OS for both arms will likely fall in the range of 5 to 7 years. As an aside, I hope that some of the new drugs in the pipeline push out those numbers for both arms, and that is a possibility. At this stage, it is way to early to make any reading on overall survival. A comment to the effect that there is no difference proven between the two arms could be misunderstood if not looked at in this context. This study will need probably at least two more years to get a very early read to make any reliable statistical call on OS between the two arms. The best the study can do at this point is to inform us on progression free survival.
Best Regards, JPC
Thank you very much for posting this information. I will have to research it in detail myself. Very timely.
I would like to make one observation to those interested in this thread. It looks like the medium duration on trial is something like three years. That is enough time to get a first read on PFS. PFS stats will be updated as more date comes in.
With regards to overall survival, however, we generally know from other studies that the OS for both arms will likely fall in the range of 5 to 7 years. As an aside, I hope that some of the new drugs in the pipeline push out those numbers for both arms, and that is a possibility. At this stage, it is way to early to make any reading on overall survival. A comment to the effect that there is no difference proven between the two arms could be misunderstood if not looked at in this context. This study will need probably at least two more years to get a very early read to make any reliable statistical call on OS between the two arms. The best the study can do at this point is to inform us on progression free survival.
Best Regards, JPC
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JPC - Name: JPC
Re: Initial results: key stem cell transplant clinical trial
Many thanks Cheryl,
I wonder why the USA DFCI arm of the trial isn't releasing any preliminary results for ASH, while the French IFM trial is?
It also appears that several studies were conducted alongside the DFCI/IFM trials. One IFM co-trial in particular analyzes the use of imaging in predicting PFS and OS. I found the PFS and OS stats with respect to PET/CT imaging at the 3-cycle-induction and pre-maintenance stages to be especially insightful.
P Moreau et al, "Prospective Evaluation of MRI and PET-CT at Diagnosis and before Maintenance Therapy in Symptomatic Patients with Multiple Myeloma Included in the IFM/DFCI 2009 Trial," ASH 2015 Annual Meeting abstract #395 (link to full abstract)
I wonder why the USA DFCI arm of the trial isn't releasing any preliminary results for ASH, while the French IFM trial is?
It also appears that several studies were conducted alongside the DFCI/IFM trials. One IFM co-trial in particular analyzes the use of imaging in predicting PFS and OS. I found the PFS and OS stats with respect to PET/CT imaging at the 3-cycle-induction and pre-maintenance stages to be especially insightful.
P Moreau et al, "Prospective Evaluation of MRI and PET-CT at Diagnosis and before Maintenance Therapy in Symptomatic Patients with Multiple Myeloma Included in the IFM/DFCI 2009 Trial," ASH 2015 Annual Meeting abstract #395 (link to full abstract)
Following 3 cycles of VRD, MRI remained positive in 93%, and PET-CT in 55% of the patients, respectively. Normalization of MRI after 3 months of induction therapy was not predictive neither for progression-free survival (PFS) (p = 0.99) nor for overall survival (OS) (p = 0.99). Normalization of PET-CT after 3 months of induction therapy was associated with a significant improvement in PFS (30-month PFS rate: 60% in patients PET-CT positive vs 79% in patients PET-CT negative, p = 0.04), but not OS (30-month OS rate: 82 % in patients PET-CT positive vs 93 % in patients PET-CT negative, p = 0.15).
Prior to maintenance therapy, MRI remained positive in 83%, and PET-CT in 21% of the patients, respectively. Normalization of MRI before maintenance was not predictive neither for PFS (p = 0.31) not for OS (p = 0.98). Normalization of PET-CT before maintenance was associated with a significant improvement in both PFS (30-month PFS rate: 54.4% in patients PET-CT positive vs 75.9% in patients PET-CT negative, p = 0.0004, figure 1) and OS (30-month OS rate: 69.9% in patients PET-CT positive vs 94.6% in patients PET-CT negative, p = 0.01, figure 2)."
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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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