Revlimid Maintenance Therapy: Three Major Studies Clarify The Benefits And Risks
The results of the three major clinical trials investigating Revlimid maintenance therapy were published yesterday in three separate articles in the New England Journal of Medicine.
The articles were accompanied by an editorial summarizing the study findings and discussing their significance for the treatment of multiple myeloma patients.
All three clinical trials involved newly diagnosed multiple myeloma patients. The patients in the trials first underwent initial treatment that in some cases included Revlimid (lenalidomide). In two of the three trials, the initial treatment also included a stem cell transplant.
After the initial treatment, patients were randomly assigned to take either Revlimid or a placebo on a regular basis until they relapsed. This kind of extended treatment, given after a more intensive initial course of therapy, is known as maintenance therapy.
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All three trials found that Revlimid maintenance therapy significantly delays the progression of multiple myeloma. In younger newly diagnosed myeloma patients who had undergone a stem cell transplant, for example, Revlimid maintenance therapy nearly doubled the time to relapse.
Only one of the three trials, however, found that Revlimid maintenance therapy improved the overall survival of patients. In the other two trials, patients who were on Revlimid maintenance therapy typically lived no longer than those who took the placebo.
In addition, all three trials revealed that the patients taking Revlimid were significantly more likely to experience a second cancer than those who took a placebo.
Prior to the publication of yesterday’s articles, findings from the three trials already had been presented and discussed at several conferences in recent years. The findings are therefore well known among myeloma specialists (and long-time Beacon readers).
Nevertheless, publication of the results in a major peer-reviewed medical journal is a clear signal that the medical community views the findings as significant and relevant to the treatment of myeloma patients.
At the same time, the publication of the articles in unlikely to settle the important questions many physicians and patients still have about the value of maintenance therapy with Revlimid.
Among those questions, perhaps the most important is whether delaying disease progression is worthwhile when it requires long-term treatment, often with side effects, with an uncertain benefit in terms of overall survival.
Details Of The Three Trials
The trial results that were published yesterday were from three multi-center Phase 3 clinical trials being carried out in the United States and in Europe.
Two of the trials, known as the CALGB and IFM trials, were carried out with younger newly diagnosed multiple myeloma patients who also underwent a stem cell transplant as part of their initial myeloma therapy.
Patients in the third trial, known as the MM-015 study, were newly diagnosed myeloma patients as well. However, they were at least 65 years of age and not eligible for a transplant.
CALGB Study
The CALGB trial registered patients between April 2005 and July 2009 at centers across the United States. Patients had to be newly diagnosed and under the age of 70 years. A specific induction treatment was not required for the trial. All patients had to undergo a stem cell transplant after their initial treatment.
After their transplants, patients in the trial were randomly assigned to receive either 10 mg of Revlimid (231 patients) or a placebo (229 patients) as daily maintenance therapy. The study was “double blind,” meaning that neither patients nor their physicians knew which patients were receiving Revlimid and which were receiving a placebo.
In December 2009, an interim analysis of the trial results showed a statistically significant difference in the rate of disease progression between the two patients groups. The study was therefore unblinded, and patients who had been receiving the placebo were given the option to start taking Revlimid. Of 128 patients eligible to make this switch, 86 chose to do so.
Patients who received Revlimid maintenance therapy during the study stayed on the maintenance regimen until their disease progressed.
IFM Study
The IFM trial was conducted in France, Switzerland, and Belgium, registering patients between July 2006 and August 2008. Participants in the trial had to be newly diagnosed myeloma patients under the age of 65.
Most of the participants were initially treated with one of two treatment regimens: Velcade (bortezomib) and dexamethasone (Decadron), or vincristine (Oncovin), doxorubicin (Adriamycin), and dexamethasone. About a quarter of the patients also had their initial treatment augmented with additional combination therapy involving the DCEP regimen: dexamethasone, cyclophosphamide (Cytoxan), etoposide, and cisplatin.
After their initial therapy, patients underwent a stem cell transplant. One fifth of the patients also went on to receive a second transplant.
After patients had completed their transplants, they received two 28-day cycles of treatment consisting of 25 mg of Revlimid, administered on days 1 to 21 of each cycle. Then, patients were randomly selected to receive either 10 mg Revlimid daily (307 patients) or a placebo (307 patients) until disease relapse. As in the CALGB trial, the administration of Revlimid and the placebo was double blind, and was intended to continue until disease relapse.
In July 2010, the study was unblinded after a data analysis showed a statistically significant benefit to Revlimid treatment in terms of delaying disease progression. However, no patients were switched from the placebo-treated group to the Revlimid treated group.
In January 2011, an interim analysis of the trial data revealed a significant difference in the rates of second cancer between the two patient groups. The researchers leading the study therefore decided to halt all further dosing of Revlimid during the trial.
MM-015 Study
The third and final trial, the MM-015 study, was conducted in Europe, Australia, and Israel. Patients were recruited from February 2007 until September 2008, and they had to be 65 years of age or older and transplant ineligible.
Each MM-015 trial participant was randomly assigned to one of three treatment groups.
The first group (154 patients) – denoted “MP” – received nine 4-week cycles of treatment with melphalan (Alkeran), prednisone, and a placebo as initial therapy, followed by “maintenance” therapy with a placebo.
The second group (153 patients) – denoted “MPR” – received nine 4-week cycles of treatment with melphalan, prednisone, and Revlimid (10 mg on days 1 to 21 of the cycle), followed by “maintenance” therapy with a placebo.
The third group (152 patients) – denoted “MPR-R” – received the same upfront treatment as the second group (melphalan, prednisone, and Revlimid), but received Revlimid as maintenance therapy. The Revlimid maintenance dose was 10 mg on days 1 to 21 of a 28 day cycle.
As in the CALGB and IFM trials, the dosing of Revlimid and a placebo in the MM-015 also was double blind. The trial was unblinded in May 2010 after a data analysis showed patients receiving Revlimid maintenance therapy had a longer time to disease progression than patients on placebo. As in the IFM trial, however, no patients were switched during the trial from the placebo group to the Revlimid group.
Progression-Free Survival
Patients receiving Revlimid maintenance in all three studies experienced significantly longer progression-free survival times than patients who did not receive Revlimid maintenance therapy.
CALGB Study
In the CALGB-study, patients on Revlimid maintenance had longer progression-free survival times and rates, even after the study was unblinded in December 2009 and patients in the placebo group were allowed to begin Revlimid maintenance.
(Click here or on the image to the right to see a graph of the key CALGB progression-free survival results.)
At a median follow-up time of 34 months, 37 percent of patients receiving Revlimid maintenance had progressed or died, compared to 58 percent of patients who did not receive Revlimid maintenance.
The three-year progression-free survival rate was 66 percent among patients receiving Revlimid maintenance, compared to 39 percent among patients not receiving Revlimid maintenance.
The median time to disease progression was 46 months for patients on Revlimid maintenance, compared to 27 months for patients not receiving Revlimid maintenance.
IFM Study
When the study was unblinded at a median follow-up time of 30 months, the median time to disease progression was almost double (41 months) for patients on Revlimid maintenance, compared to patients not receiving Revlimid maintenance (23 months).
The three-year progression-free survival rate was 59 percent among patients receiving Revlimid maintenance, compared to 35 percent among patients not receiving Revlimid maintenance.
At a median follow-up time of 45 months, the four-year progression-free survival rate was still significantly higher for patients receiving Revlimid maintenance (43 percent) than for patients who did not receive Revlimid maintenance (22 percent).
MM-015 Study
As previously reported for the MM-015 study, the median progression-free survival time from the start of the trial was significantly longer for patients receiving Revlimid maintenance (MPR-R, 31 months) than for patients receiving MPR (14 months) or MP (13 months).
When the researchers compared progression-free survival times from the start of maintenance therapy, they found that the median was 26 months with Revlimid maintenance, compared to 7 months without maintenance.
The progression-free survival benefit associated with Revlimid maintenance, however, was not found to be statistically significant in patients over the age of 75 years: median progression-free survival times in this patient population were 19 months with MPR-R, 12 months with MPR, and 15 months with MP.
Overall Survival
The CALGB study showed an overall survival benefit for patients treated with Revlimid maintenance, but the other two studies did not.
CALGB Study
After a median follow-up time of 34 months, 85 percent of the patients receiving Revlimid maintenance and 77 percent of the patients in the placebo group were still alive.
(Click here or on the image to the right to see a graph of the key CALGB overall survival results.)
The estimated three-year overall survival rate was higher for the Revlimid group (88 percent) than the placebo group (80 percent), even though most of the placebo group began Revlimid maintenance when the study was unblinded.
A subgroup analysis showed that patients treated with Revlimid induction therapy had significantly longer survival if they received Revlimid maintenance, compared to those who received a placebo. The same analysis also showed that Revlimid maintenance did not provide a survival advantage for: patients who were treated with thalidomide induction therapy; patients who had elevated beta-2 microglobulin levels; or patients who achieved a complete response prior to the start of maintenance therapy or placebo.
IFM Study
Unlike the CALGB study, the estimated four-year overall survival rate was similar for the Revlimid maintenance (73 percent) and placebo (75 percent) groups. The study investigators pointed out that these rates are high and could be due to the use of intensive treatment as well as effective therapies at relapse.
(Click here or on the image to the right to see a graph of the key IFM overall survival results.)
The researchers also stated that a longer follow-up is needed to fully assess the effect of Revlimid maintenance on overall survival.
The investigators of the CALGB study wrote in their article that the difference in survival results between the CALGB and IFM trials may be due to differences in induction and consolidation therapies, the use of one versus two transplants, and the discontinuation of maintenance therapy. They suggested that longer follow-up and additional studies might clarify the difference in results.
MM-015 Study
As was the case with the IFM study, Revlimid maintenance did not extend overall survival in the MM-015 study.
After a median follow-up time of 30 months, the estimated overall survival time was 42.5 months for the MPR-R group and was not yet reached for the MPR and MP groups.
The three-year overall survival rate was similar for all three treatment groups. Specifically, the survival rates were 70 percent for the MPR-R group, 62 percent for the MPR group, and 66 percent for the MP group.
Second Cancers
In all three studies, patients receiving Revlimid maintenance experienced higher rates of second cancer than patients not receiving Revlimid maintenance.
The rate of second cancer in these studies is a key reason U.S., Canadian, and European authorities recently added warnings to Revlimid’s prescribing information about the risk of second cancer associated with the drug (see related Beacon news articles).
In the CALGB study, 8 percent of patients receiving Revlimid maintenance experienced secondary cancers, compared to 3 percent of patients who did not receive Revlimid maintenance. Of the 8 percent in the Revlimid maintenance group, 4 percent were blood-related cancers and 4 percent were solid tumors (excluding non-melanoma skin cancers).
In the IFM study, the researchers observed 32 cases of second cancers in 26 patients receiving Revlimid maintenance and 12 cases in 11 patients not receiving Revlimid maintenance. Based on these cases, they calculated that 3.1 percent of patients receiving Revlimid maintenance developed a second cancer each year and 1.2 percent of patients not receiving Revlimid maintenance developed a second cancer each year.
In the MM-015 study, the rate of second cancers at three years was reported to be 7 percent for patients receiving MPR-R, 7 percent for patients receiving MPR, and 3 percent for patients receiving MP.
Implications Of The Three Studies
As one might expect, the authors of the three studies are relatively positive, overall, about the benefits of Revlimid maintenance therapy.
The MM-015 investigators, for example, write in their conclusion that “MPR-R is an effective treatment for patients with newly diagnosed multiple myeloma who are ineligible for transplantation.
Similarly, the authors of the IFM article believe that their data, along with the CALGB data, “support the use of [Revlimid] maintenance therapy” after stem cell transplantation in patients with myeloma.
The IFM investigators also add, however, that the “impressive benefits” of Revlimid maintenance therapy “must be weighed against the increased risk” associated with that therapy.
An independent perspective on the three articles that were published yesterday is available in the form of an editorial that accompanied the articles. The editorial was written by Professor Ashraf Badros of the University of Maryland’s Greenbaum Cancer Center.
Prof. Badros notes in his editorial that the three studies provide “compelling evidence” that Revlimid maintenance therapy delays relapse. He adds, however, that there still are important questions relevant to this therapy that need to be answered.
For example, is delaying disease relapse actually what is important when testing a maintenance therapy?
With maintenance therapy, delaying relapse is achieved by continuously treating patients with a drug that, for some patients, will involve frequent side effects. Thus, even if the therapy results in some additional overall survival, will it be enough to be worthwhile given the side effects patients experience during the maintenance therapy?
Similarly, can physicians be certain there actually is a survival benefit to maintenance therapy? Is it possible that, by treating a patient continuously with low-dose Revlimid, the patient’s myeloma evolves such that, when relapse occurs, the disease is more resistant to treatment and there is no net survival benefit to the maintenance therapy?
Prof. Badros finds it difficult to come to a clear conclusion at the end of his editorial. “Whether these data establish a new standard of care for myeloma may be debatable,” he writes. He then starts a concluding sentence that sounds like a strong endorsement of Revlimid maintenance therapy … until one gets to a key qualifying statement at the end.
“The data on progression-free survival,” he said, “provide support for the use of [Revlimid] maintenance therapy after careful assessment of the risks and benefits.”
For more information, see the studies (CALGB, IFM, and MM-015) and the accompanying editorial in the New England Journal of Medicine (abstracts).
Note: The graphs that are included with this article are from the original journal articles and are copyrighted property of the Massachusetts Medical Society. For copyright reasons, only a limited number of graphs have been included. The ones that have been selected were chosen because they more fully describe important data, and because they permit more complete comparisons of important results from the different trials.
Related Articles:
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Sustained Complete Response To Initial Treatment Associated With Substantial Survival Benefit In Multiple Myeloma
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Early Use Of Radiation Therapy Associated With Shorter Survival In Multiple Myeloma
Thanks for the summary of the three trials involving maintenance chemo, Beacon Staff. For those of us who have already been on that program, it is a warning to look out for any secondary cancers. One should still get one's routine checks, as suggested by a primary physician. The PFS and OS stats are sobering , but it is food for thought for patients currently trying to decide what to do next.
We are unclear whether this applies to someone who is in remission? My husband reached cr after six cycles of rev/dex and a stem cell transplant. We spoke to two specialists, they both recommended No Maintenance. He has been drug free for two and a half years. These new studies don't specify how the patients were doing at start of maintenance therapy. Does anyone have any further information? Thanks in advance
Thanks for your comments, Nancy and Mswartz.
To answer your question, Mswartz, in the CALGB and IFM studies involving patients who underwent stem cell transplants, patients were put on the maintenance regimen if their disease was not progressing after the stem cell transplant.
In other words, patients such as your husband, who had a complete response after transplantation, were put on the maintenance treatment in those two trials. The same holds for patients who had only a partial or even a minimal reponse.
Beacon Staff, perhaps you could answer one more question for me. EJ elected not to go on Revlimid maintenance after his SCT. Eventually he knows his disease will return, and he may go on revlimid at that time. Is the risk of secondary cancers as high at this point? or does no one know?
Thank you.
Lyn
Hello Christa's Mom,
As far as we know, there aren't data available right now to answer your question directly. No study that we're aware of has looked to see if the risk of developing a second cancer when taking Revlimid changes depending on how many previous treatment regimens the patient has been given.
Also, in terms of the studies that have linked treatment with melphalan with Revlimid causing second cancers, it is not known whether the time between the two treatments matters.
Intuitively, one might think that the longer it's been since a patient received melpalan therapy, the less that therapy should increase the chance that Revlimid will cause a second cancer. There are no studies, however, that have tested that hypothesis.
All that having been said, please keep in mind that the risk of developing a second cancer seems to go up the longer a patient takes Revlimid. That's why the risk is discussed primarily for patients taking the drug as maintenance therapy, which can extend out over several years.
The risk doesn't appear to be as relevant in those cases -- perhaps like EJ's at some point in the future -- when a physician might be considering intensive Revlimid therapy for a relatively short period of time to get a relapsed myeloma patient's disease back under control.
Good luck!
Has there been any commentary about the fact that all 3 studies involved Revlimid maintenance following the use of melphalan, either as induction therapy or as part of an SCT? Revlimid maintenance can, of course, be initiated after other treatments that don't involve melphalan. The FDA warning seems to cover all uses of Revlimid maintenance whereas the studies aren't that broad.
The NEJM does a good job breaking down analysis of the trial data which the FDA (a consumer regulator body) also did and placed a warning on the lenalidamide label after concluding:
"Treatment with lenalidomide (Revlimid) for newly diagnosed multiple myeloma is associated with almost a threefold increased risk of developing secondary primary malignancies, the agency announced on May 7. The finding was based on three postapproval trials of lenalidomide as maintenance therapy in newly diagnosed patients.
"Specifically, these trials showed there was an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma," the FDA said. No increase was seen in incidence of nonmelanoma skin cancers and solid tumors"
With regard to this news posting stating:
"the initial treatment also included a stem cell transplant".
It concerns me that a stem cell transplant therapy(SCT) is called initial therapy. While ALLOlogous (SCT) is therapy autologous is not. Autologous SCT is pre-emptive rescue. Rather, it is high dose chemotherapy(HDT). that is the treatment and the stem cell transplant is a salvage process essential to save the patient whose bone marrow has been treated by the high dose chemotherapy to the point the marrow no longer can function biologically to sustain life. This distinction while well known to the medical community is often times not clear to patients.
It would also be helpful for clarity to have the criteria defined for" younger" when the statement says:
"known as the CALGB and IFM trials, were carried out with younger newly diagnosed multiple myeloma patients"
Given that for CALGB the criteria were: "under the age of 70 years..and for IFM it was Is 'younger" relative to MM-015 patients having to be 65 years or older?
These variables are important as most non-medical readers do not consider 'young' as being the age of what is usually described as senior citizens. Specifically, in the case of CALGB the median age was 57 which means that 50% of the 460 patients in CALGB were over 57 years of age and the IFM study is titled as a trial in elderly patients here:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726063/
For clarity then it would be very helpful to first state what the median age of patients with MM is if the trial is going to be described as being one for younger patients especially as we are now seeing the disease occur many patients under 50 years of age, and that age group is not predominate in the trials.
Many of the readers at Myeloma Beacon are patients and sometimes it can be confusing/ difficult to discern how the trial design and outcomes are being described particularly with all the caveats and nuances within the terms( younger/SCT) are being used; given how the medical community understands those terms relative to lay persons/patients.
Seems that these studies pose more questions than answers: younger pt / older pt, Melphalan / no Melphalan , sct/no sct, cr/someone with active disease. Etc. How can all of these patients be lumped together in one study? There are way too many variables for any broad base conclusions!
Hello everyone ... hope your weekends have started well!
Holt:. The FDA update does not discuss the possibility that the second cancers associated with Revlimid might be due to an interaction between treatment with melphalan and treatment with Revlimid. There was research at ASH, based on a broad retrospective analysis of data from many different trials, suggesting this might be the case. The research is discussed near the end of this Beacon article:
http://www.myelomabeacon.com/news/2011/12/21/ash-2011-multiple-myeloma-update-day-four/
For whatever reason, the FDA chose not to discuss the research in its update. It may be because the FDA prefers to emphasize results from placebo-controlled trials like the ones discussed here, and they do not make it possible to determine if an interaction between melphalan and Revlimid is the issue because almost all patients in the trials were treated with melphalan.
Note, though, that the warning language in the revised prescribing information for Revlimid does note that the second cancers were seen in patients who had been treated with melphalan and received a stem cell transplant.
Suzierose: Your point about being clearer about the age of the patients in the studies is a good one, and we'll be more careful in that regard in the future. We got caught in the trap that you alluded to, namely, that the medical profession refers often refers to myeloma patients under the age of 65 or 70 as "younger myeloma patients."
On the issue of describing stem cell transplantation as a treatment, we recognize that the real treatment when a patient undergoes an autologous stem cell transplant is the high-dose chemotherapy that takes place before the transplantat. However, as you know, the vast majority of autologous stem cell transplants are done with high-dose melphalan as the initial chemotherapy. So saying simply "stem cell transplant" rather than "high-dose melphalan followed by an autologous stem cell transplantat" is shorthand that we use to avoid making sentences (and entire articles) too long.
Mswartz: The common thread across the three studies is that they examine the benefits -- and risks -- of Revlimid maintenance treatment. All three studies also demonstrate that Revlimid maintenance therapy provides a benefit in terms of prolonging progression-free survival That is why the studies are often grouped together and discussed at the same time.
You are certainly correct that the studies raise a lot of questions. And that can be frustrating. But I think we can all agree that it is better that these studies have been completed, and that they look at different patient populations, because it means that the decisions we make can be better informed decisions.
Just because more information makes decisions difficult doesn't mean the additional information is bad.
Thanks for all the feedback and questions!
Thanks Beacon Staff. The referenced article is very helpful.
I was on the study right after sct. I did not fair well with 5 mg of Revlimid.I was started just 3 months after sct, and I had the mucous and all the problems with reactions to Revlimid. I had the rash in the scalp, the sore mouth where everything "burned" to eat. Even water tasted like I was drinking the hottest hot sauce available. So they stopped the study and took me off of the Revlimid unit I get more immunity and then will reset with 10 mg for maintenance. I will start back on the maintenance regime in a couple of weeks. Reading the information above, worries me. I, to this day do not know what I was facing in the form of what the cancer was doing to me. I only know that I was told I have this disease and I have this route of treatment. I guess that since I had taken 25mg of Revlimid prior to sct and was in remission with that course of treatment, the Dr. figured that I should be able to handle the lower maintenance dose. I do know that I was staged as III (three) and was told that sct was my only option. I have also been told that Revlimid is my only medication to continue my remission that I am currently in. The Dr. said that if the issues continue with the Revlimid, then there is no other option. Is there any other treatment other than the Revlimid regime listed above?