Update On Benefits And Risks Of Revlimid Maintenance Therapy (IMW 2013)
Further findings from two clinical studies of Revlimid maintenance therapy were presented at the 14th International Myeloma Workshop (IMW) in Kyoto, Japan, earlier this month.
Both studies involved newly diagnosed multiple myeloma patients who received maintenance therapy with Revlimid (lenalidomide).
Results from both studies, which were published in the New England Journal of Medicine last May, indicate that Revlimid maintenance therapy significantly increases progression-free survival compared to a placebo (see related Beacon news). One of the studies also found that Revlimid maintenance therapy improved overall survival of patients.
Both studies also found that patients who received Revlimid maintenance therapy were at an increased risk of developing secondary cancers, compared to patients who received a placebo.
At the IMW meeting, Dr. Philip McCarthy from the Roswell Park Cancer Institute presented updated results on the efficacy and long-term safety data from the so-called CALGB study. He reported that patients receiving Revlimid maintenance therapy following stem cell transplantation continue to have better progression-free and overall survival than patients receiving a placebo after transplantation.
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Dr. Michel Delforge from the University Hospital in Leuven, Belgium, presented updated long-term safety data from the so-called MM-015 trial. He reported that Revlimid maintenance therapy continues to be well tolerated by myeloma patients who are ineligible for stem cell transplantation. The latest results show that the rate of new or worsening severe side effects is low.
The updated data from both studies also show that the risk of developing secondary cancers continues to be higher in patients receiving Revlimid maintenance therapy. However, both studies also show that the risk of progression and death is higher in patients receiving the placebo.
Based on these findings, Dr. Delforge concluded that the benefit-risk profile of Revlimid remains favorable and Dr. McCarthy suggested that the risk of secondary cancers should be evaluated within the context of the risk of disease progression.
Results of a third trial on Revlimid maintenance, the so called IFM trial, were also published in the New England Journal of Medicine last May. However, no updates about that trial were given at IMW.
CALGB Study
The CALGB study is a Phase 3 trial that recruited newly diagnosed patients under the age of 70 from centers across the United States between 2005 and 2009. All patients in this trial received a stem cell transplant following initial treatment.
The patients then received either 10 mg of Revlimid daily or a placebo as maintenance therapy.
In December 2009, an interim analysis showed that patients receiving Revlimid maintenance therapy had significantly better progression-free survival. Patients in the placebo group were therefore given the option to start taking Revlimid maintenance therapy.
The median time to disease progression was 46 months for patients on Revlimid maintenance, compared to 27 months for those who received a placebo.
The results published last year showed that after a median follow-up of 34 months, fewer patients who received Revlimid maintenance therapy progressed or died compared to patients who received a placebo (37 percent versus 58 percent).
Revlimid maintenance therapy also improved overall survival. After a median follow-up time of 34 months, 85 percent of the patients receiving Revlimid maintenance therapy and 77 percent of the patients in the placebo group were still alive. The estimated three-year overall survival rate was higher for the Revlimid group (88 percent) than the placebo group (80 percent).
Overall, 8 percent of patients receiving Revlimid maintenance therapy experienced secondary cancers, compared to 3 percent of patients who received a placebo. Among the Revlimid maintenance group, 4 percent developed blood-related cancers and 4 percent developed solid tumors (excluding non-melanoma skin cancers).
CALGB Updated Efficacy And Safety Data
During his presentation at IMW, Dr. McCarthy reported that after a median follow-up time of 48 months, the median time to progression for patients who received Revlimid maintenance therapy remains longer than the median time to progression for patients in the placebo group (50 months versus 27 months, respectively).
In addition, overall survival continues to be better for patients receiving Revlimid maintenance therapy. The median overall survival has not been reached for patients receiving Revlimid maintenance therapy, compared to 73 months for patients receiving a placebo.
The most recent data also indicate that fewer patients who received Revlimid died, compared to patients who received a placebo (19 percent versus 34 percent).
Dr. McCarthy also pointed out that the rate of secondary cancers remains higher in patients who received Revlimid maintenance. Overall, 13 percent of patients who received Revlimid developed a secondary cancer, of which 5 percent developed blood cancers, 5 percent developed solid tumors, and 3 percent developed skin cancers.
Of the patients who received a placebo, 4 percent developed secondary cancers.
Despite the increased risk of second cancers, the results showed that patients who received Revlimid maintenance therapy had significantly longer median time to progression, secondary cancer, or death (47 months versus 27 months, respectively).
Dr. McCarthy stated that further analysis of the CALGB data will focus on identifying any potential associations between genetic changes, side effects, and outcomes as well as evaluating risk factors associated with second cancers.
MM-015
The second study, known as the MM-015 study, was conducted in Europe, Australia, and Israel. Patients who were at least 65 years of age and transplant ineligible were recruited for the study from February 2007 until September 2008.
Patients were divided into three treatment groups.
The first group received treatment with melphalan (Alkeran), prednisone, and a placebo as an initial therapy (MP). These patients subsequently received another placebo as maintenance therapy.
The second group received initial treatment with melphalan, prednisone, and Revlimid, followed by a placebo as maintenance therapy (MPR).
The final group received the same initial treatment as the second group, but also received Revlimid as maintenance therapy (MPR-R).
The results published last May showed that the median progression-free survival was significantly longer for patients in the MPR-R group (31 months), compared to patients in the MPR group (14 months) and the MP group (13 months).
However, unlike the CALGB trial, this study did not show that Revlimid maintenance significantly improved overall survival.
The rate of secondary cancers at three years was 7 percent for patients receiving MPR-R, 7 percent for patients receiving MPR, and 3 percent for patients receiving MP.
MM-015 Updated Safety Data
In his presentation at IMW, Dr. Delforge focused on the long-term safety of Revlimid maintenance therapy.
He described the safety profile of continuous Revlimid maintenance therapy as predictable and manageable.
He reported that after a median follow-up of 53 months, few new or worsening severe side effects were observed during Revlimid maintenance therapy. The most common were blood-related and included low platelet counts (9 percent), low red blood cell counts (8 percent), and low white blood cell counts (7 percent).
Overall, 18 percent of the patients discontinued treatment due to side effects.
The rate of secondary cancers continues to be higher in patients receiving Revlimid: 11 percent for patients receiving MPR-R, 11 percent for patients receiving MPR, and 8 percent for patients receiving MP.
During the maintenance phase of the study, more patients in the MPR-R group developed secondary cancers (11 percent), compared to patients in the MPR group (3 percent) and MP group (2 percent). The majority of secondary cancers in the MPR-R group were blood-related cancers, such as acute myeloid leukemia.
According to Dr. Delforge, the four-year probability of developing a second cancer was 13 percent for patients receiving MPR-R, 10 percent for patients receiving MPR, and 4 percent for patients receiving MP.
The four-year probability of disease progression or death, on the other hand, was significantly lower for patients receiving MPR-R (70 percent), compared to patients receiving MPR (93 percent) and patients receiving MP (95 percent).
For more information, please see Dr. McCarthy’s and Dr. Delforge’s presentation slides, which they have made available for download and viewing as a courtesy to The Beacon’s readers.
Related Articles:
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- 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
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
Thanks for the summary of the 'revilimid maintenance' trials. One question I have is, in the CALGB study, was the revlimid maintenance given on an ongoing basis, or was it stopped after a certain length of time (e.g. one or two years)? What I am wondering is, if the patient was in a remission, for how long were they given revlimid maintenance after a stem cell transplant?
I am also interested in the answer to Nancy's question about how long to stay on the maintenance therapy. Also if the patient was in complete remission before transplant & 3 months after transplant do they even do maintenance & for how long. Our daughter is 32 & I am concerned about the side effects , although if it holds off relapse longer. It's hard because no one can tell you for sure what is the best course. It all seems up in the air a little.
Hi Nancy and Terri,
Thanks for your questions.
In all three of the major Revlimid maintenance therapy trials -- CALGB, IFM, and MM-015 -- patients who were to be given maintenance therapy were randomly selected to receive it. This means they were given maintenance therapy even if they had achieved CR or sCR as a result of their induction therapy and, in the case of the CALGB and IFM trials, their stem cell transplants.
In addition, the initial trial protocols called for the patients to be given maintenance therapy until relapse, or until they could not tolerate the maintenance therapy.
The protocol was modified somewhat in the IFM trial, which decided to halt maintenance therapy beyond two years due to concern that the risk of secondary cancer seemed to increase beyond that point.
The NCCN guidelines for myeloma, although listing Revlimid maintenance as a highest level recommendation, do not speak to the issue of which patients specifically should be given maintenance therapy, or for how long it should be given.
The Mayo guidelines recommend that physicians "Consider lenalidomide maintenance therapy in patients after ASCT for a maximum of 2 years."
Five months following ASCT at the Cleveland Clinic, my 51 y/o wife has begun her Revlimid therapy. "Very good partial remission" No more M nor Amyloid! (We had our choice between Mayo and Cleveland - She just felt more comfortable with our sweet Cleveland Doctor
We were very happy with our choice.) I asked about the Mayo guidelines of Revlimid two-year max. Cleveland said they had no such rule. We were told they've had progression-free, post-transplant patients on Revlimid for over eight years.
Ya know what? I'm not going to question anymore, or worry about it for a while. I'll bring it up again in two years. Yep. That's what we'll do. (We will also do a lot more traveling as well!) See ya at Stuckey's...or the worlds largest candle store, or Alaska, or something.
Thank you to all on G110, the Taussig Cancer Institute, and the Cleveland Clinic.
Having had my stem cell abt 6 weeks ago I know my doc plans on revlimid maint I would like to hear from someone as to what the side effects are how acute or tolerable?
Hello Sharon,
I found out I had MM Stage 3 of 3 80% cancer cells when I went to the dentist Feb. of 2012. I did 9 treatments of Revlimid(25mg) Velcade(Shot in belly) and Dex(80 then 40 mg) drugs. I did not get neuropathy. I did an auto stem cell transplant in Nov 2012. I went into CR. I was put on 15mg of Revlimid everyday in Feb 2013 for maintenance. The side effects I find are fatigue(SCT). And I am sick alot from a lower immune system (Revlimid). I have middle back pain and shoulder pain. MRI"S show no damage but I do have lesions thru out my whole body.I also take an IV of Zomeda to strengthen my bones. I will update in a year!
Rick--I love your attitude.
Robin--I started maintenance after 2 SCT's. 15 mg Rev. After 4-5 months, I became neutropenic, so was cut down to 10 mgs daily. That was a year ago and I've been fine.
Like Robin, I had Stem Cell Replacement(BMT) in Nov 2012. I also am at stage 4 Chronic Kidney Disease due to the light chain damage - I take less of all drugs since my kidneys cannot clear them out of my blood as well as healthy kidneys. They started me on 5 mg Revlimid every other day in February and I have had no problems. No noticeable side effects at all. They are increasing my dosage to 10 mg Revlimid every other day starting tomorrow. My kidney Dr. had 4 suggestions: 1. take a benedryl at night if I have trouble sleeping. 2. do light bicycling action to relieve cramps 3. stretching can also help if you get cramps. 4. He is testing my magnesium level to make sure that is not causing cramps. 5. If neuropathy bothers my feet, I put aspercream on them.
Sharon, I had ASCT in March 2011. I'd had a CR after initial chemo (three rounds of Velcade, Doxil and dex) and that continued at my 100-day follow up. Six months after the transplant (September 2011) I began 10mg Revlimid for 21 days, then 7 days off. I found it made me nauseous, fatigued and lowered my mood at about 14 days. After some experimentation I reduced the dose to 5mg, but still had side effects toward the end of the 21-day cycle. Then I went to 14 days on and 7 off and that seemed to help for a while. Buy March or April 2013 I felt like I was getting more side effects and went off Revlimid then, and have not gone back, but I'm thinking about doing so later this month. My hematologist is a big fan of Revlimid and he also said the side effects don't recur for some patients. My transplant surgeon also feels Revlimid is proven effective for maintenance, and would be happy if I could keep taking it any way I could tolerate it.
I'm a bit troubled by the secondary cancer rate, particularly since I had a CR and continue to show no measurable signs of disease. I watch my blood tests carefully and if there's any sign of an uptick I'll certainly go back on or ask to try something else, such as injected Velcade.
Diag 05/09
IGG-Kappa MM Stage 3.
I am one of the very small group to develop
Second Primary Malignancy,
Solid Tumor, Colon.
Just recently discovered.
I am currently awaiting colon surgery.
HUGE unknown path ahead....
Any experienced patients or providers able to give insite?
In March 2013, I had a stem cell transplant at the Seattle VA for MM. Three months later I was in complete remission. Since then, my oncologist has had me on maintenance Revlimid, 5 mg every morning. The only side effect seems to be some fatigue, especially in my brain. I simply don't think as clearly as I used to. Of course, that could be from chemo treatments prior to and during the SCT, not necessarily from the Revlimid.
Physically, I feel good. Last summer, I completed four triathlons -- two Olympic distance (won age group in both) and two 70.3. I am now signed up for the Boise 70.3 and the Coeur d'Alene Ironman, both in June. To train for those, I swim, bike, and run every day, for about 2 hours on average. Sometimes this level of training pretty well wipes me out, but, then, I'm 68 years old, so that might have something to do with it. I can't say the Revlimid is interfering with my lifestyle much, and I continue in CR. Life is good. All the best to the rest of you. Be strong.