Study Finds Revlimid-Dexamethasone Is Effective And Safe For Relapsed / Refractory Myeloma In ‘The Real World’
A recent Greek study looks at the efficacy and safety of Revlimid plus dexamethasone for relapsed and refractory multiple myeloma patients in ‘the real world’ -- that is, in patients being treated in standard clinical practice rather than clinical trials.
The study's findings confirm that Revlimid (lenalidomide) plus dexamethasone (Decadron) is effective and safe in day-to-day use among relapsed myeloma patients.
The majority of the patients in the study (77 percent) responded to treatment with Revlimid and dexamethasone, with 20 percent achieving a complete response. According to the investigators, these results are comparable to those reported from clinical trials.
Importantly, the Greek researchers found that the number of prior lines of therapy and prior treatment with other novel agents, such as Velcade (bortezomib) or thalidomide (Thalomid), did not significantly affect response to the Revlimid-dexamethasone combination.
In addition, the Revlimid-dexamethasone combination appeared to be at least as safe and well-tolerated when used in standard clinical practice as in clinical studies.
Although nearly half of the patients in the current study (46 percent) developed low blood cell counts, the most common side effect of the treatment combination, it was less common in this study than in previously reported clinical trials (69 percent).
Likewise, Revlimid-dexamethasone was less often discontinued in standard clinical practice (39 percent of patients) than in clinical trials (58 percent).
Background
The introduction of novel agents such as thalidomide, Velcade, and Revlimid has significantly improved the survival of myeloma patients (see related Beacon news).
Two previous Phase 3 clinical trials, by French and American researchers, showed that Revlimid plus dexamethasone is more effective as a treatment for relapsed myeloma than dexamethasone alone, and numerous clinical studies have further studied the efficacy and safety of the combination.
Based on these findings from clinical trials, Revlimid in combination with dexamethasone has become a common treatment for patients with relapsed or refractory myeloma.
In the United States, the combination of Revlimid and dexamethasone is also one of the most common treatments for newly diagnosed multiple myeloma. This is not the case in most other countries, however, because the combination is not yet officially approved for use in newly diagnosed myeloma, and "off-label" prescribing is less common outside the U.S.
In the current study, Greek researchers sought to better understand the efficacy and safety of the Revlimid-dexamethasone regimen among relapsed and refractory myeloma patients treated during standard clinical practice in Greece.
Study Design
The researchers retrospectively analyzed data from 211 patients who had received Revlimid-dexamethasone treatment for relapsed or refractory myeloma at various treatment centers across Greece between June 2010 and December 2011.
All patients who were included in the analysis were at least 18 years of age and had not received prior treatment with Revlimid.
About 35 percent of patients received Revlimid-dexamethasone as second-line therapy, 30 percent as third-line therapy, and the rest as fourth-line to seventh-line therapy.
Among those who received Revlimid-dexamethasone as second-line therapy, 34 percent had previously received Velcade-based therapy, 15 percent thalidomide-based therapy (15 percent), and 8 percent a regimen containing both. The other 42 percent had received treatment with conventional chemotherapeutic regimens that did not include these novel agents.
Among those who received Revlimid-dexamethasone beyond second-line therapy, 77 percent had been treated previously with novel agent combinations and 23 percent with conventional chemotherapy.
About 26 percent of all patients had received high-dose melphalan (Alkeran) plus autologous stem cell transplantation before Revlimid-dexamethasone treatment.
Overall, 22 percent of study participants received Revlimid-dexamethasone within a year of diagnosis. Another 18 percent received the combination between one year and two years after diagnosis, while 60 percent were treated with it more than two years after diagnosis.
Nearly 78 percent of participants received Revlimid-dexamethasone until disease progression. The others received the combination for a fixed number of cycles. The median number of cycles was 12.
The majority of patients (72 percent) received an initial dose of 25 mg of Revlimid per day for 21 days in a 28-day treatment cycle. The share of patients who initially received 25 mg of Revlimid was higher among patients younger than 65 years (85 percent) than in older patients (65 percent).
The researchers point out that older patients frequently received a lower starting dose and started Revlimid-dexamethasone earlier in the course of the disease, probably because the combination is considered less toxic than other treatment options.
The median follow-up period was 13 months.
Results
More than three-quarters (77 percent) of the patients included in the study achieved a partial response or better on the Revlimid-dexamethasone regimen, with 20 percent reaching a complete response.
Median time to best response was five months.
Patients who received Revlimid-dexamethasone as second-line therapy achieved a complete response in a median of four months, while those receiving the combination beyond second-line therapy achieved the same in a median of 11 months.
However, further analysis showed that the number of previous therapies and previous treatment with novel agents (Velcade or thalidomide) did not affect the response rate or quality of response, which according to the investigators confirms the high efficacy of the Revlimid-dexamethasone combination in all lines of therapy.
The median duration of response was about 35 months.
There was a significant difference in duration of response, however, between patients who continued treatment until disease progression, and those who did not.
Patients who were treated with the Revlimid-dexamethasone combination until disease progression had a median duration of response which has not yet been reached, but which will be at least 50 months based on the latest available data.
In contrast, patients who discontinued therapy prior to progression had a median duration of response of 19 months.
According to investigators, these findings show that treatment discontinuation has a sizable negative effect on duration of response. They therefore recommend that treatment be continued until disease progression.
The initial dose of Revlimid was also found to predict duration of response, with higher initial dose being associated with a longer duration of response.
Side effects were observed in 69 percent of patients, and 13 percent of patients required hospitalization.
The most common side effect was low blood cell counts (46 percent of patients), which was significantly lower than the rate reported in previous randomized clinical trials of the Revlimid-dexamethasone combination (69 percent).
About 11 percent of patients suffered from various infections, 6 percent developed blood clots in the deep veins, and 3 percent suffered from peripheral neuropathy (pain, tingling, and loss of sensation in the extremities). The rate of neuropathy was similar to the rates reported in previous randomized clinical trials.
The rate of blood clots was much lower than in previous randomized clinical trials, which the investigators explain by the fact that the vast majority of patients in their study (93 percent) received medication for the prevention of blood clots.
About 39 percent of patients had to discontinue treatment because of side effects or disease progression. The researchers point out that the discontinuation rate was lower than that reported in clinical trials (58 percent), which they attribute to discontinuation criteria being stricter in clinical trials.
For further information, please see the study in Annals of Hematology (abstract).
Related Articles:
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
- Lather, Rinse, Repeat: Will It Work With BCMA-Targeted Therapies For Multiple Myeloma?
We've made a few minor edits to the initial version of this article that was published earlier this evening. The edits all focus on the information presented about the duration of response to treatment with the Revlimid-dexamethasone combination.
In particular, we've updated the text to make clear just how significant the difference in duration of response was between the patients in the study who were treated with Revlimid+dexamethasone until disease progression, versus those who stopped treatment prior to disease progression.
The difference in duration of response between these two groups of patients is rather significant, and we felt the text in the article should fully capture that difference.
I think that this is an interesting study for at least two reasons. One was that the patients had not previously been given any Revlimid as treatment. The Revlimid/dex combo worked quite effectively for those patients. i am also interested as to whether there is a study for relapsed patients that have been treated by revlimid alone. Compared to dexamethasone alone, the combo proved more effective (quote from article below). In the 'real world' I think that revlimid is also used alone in relapse situations. it certainly is used alone in 'maintenance' situations. Another question....what was the definition of 'relapse'? If it was a quantifiable M-spike, what was the value of that?
'Two previous Phase 3 clinical trials, by French and American researchers, showed that Revlimid plus dexamethasone is more effective as a treatment for relapsed myeloma than dexamethasone alone, and numerous clinical studies have further studied the efficacy and safety of the combination.
Based on these findings from clinical trials, Revlimid in combination with dexamethasone has become a common treatment for patients with relapsed or refractory myeloma.'
Thanks Beacon Staff, for any more info about this work.
As a patient who has had 2 auto transplants and is currently in CR on Revlimid maintenance, I wonder if adding Dex to the regime would be a good idea?
Thanks, everyone, for the comments.
Jon, given that you have achieved a complete response with Revlimid alone, we suspect most myeloma specialists would recommend you continue with just the Revlimid. Have you discussed adding dex with your physician and, if so, what did they say?
Nancy, you're right that Revlimid is very often administered alone as maintenance therapy. However, if it's being used as a treatment for a patient experiencing a relapse, we believe it's more typically used in combination with dexamethasone.
As best we can tell, there has been only one significant study done looking at single-agent Revlimid as a treatment for relapsed myeloma. The full results of the study can be viewed (free) here:
http://bloodjournal.hematologylibrary.org/content/114/4/772.long
Here are the key parts of the abstract: "Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance ... Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively."
The patients in this study had more advanced myeloma than those in the Greek study, so comparisons are not that easy. However, eyeballing the results of the two studies would suggest -- not surprisingly -- that Revlimid combined with dexamethasone yields a higher response rate than Revlimid alone.
There also is a published case report of a relapsed myeloma patient who was treated with single-agent Revlimid and experienced a complete response. Here's a link to the abstract:
http://www.mjhid.org/article/view/10378
Thanks Beacon Staff for the reference papers. The second one, about a 71 year old woman who had no detectable lesions after six months on revlimid, is interesting!
The first paper , from 2009, was interesting too. The dose of lenalidomide given was 30 mg. per day, which is higher than the norm I think. The definition of 'relapse' was having greater than 0.5 g/dl of M Protein in the blood serum.
There is a higher than average risk of blood clots , DVT's, with myeloma itself, and even more with taking Revlimid, and higher yet with taking Revlimid plus Dex. Thus the patients took anticoagulants to ward off DVT's.
So it's all good to know, and I am filing it away for future talks with my oncologist. It's very helpful to have the Beacon here to learn more, since any of us could relapse out of a remission. I am sure that many of us have the MRD that we don't really want to think much about! I have had a couple of blood tests that worry us, and am being closely monitored at this time!
Another interesting study and thorough analysis by the Beacon Staff. Good job! Three points: the standard of care in US after initial induction therapy for MM, with or without an auto stem cell transplant, is now to recommend Revlimid maintenance, without dex, to most patients. When patients become refractory on this regimen, just adding dex does not make much sense. Switching to a proteasome inhibitor, like Velcade or Kyprolis, with dex, is a more effective option, as is entering a trial of investigational meds.
Also, with high risk MM on dx, I believe the data supports the use of initial combination novel agent therapy, with dex, followed by an ASCT. The response rates and side effect profile are superior to cytotoxic therapy, and more targeted. So I have to disagree with the comments by Mark after the review two days ago.
Finally, I am surprised that there is no mention in this study of secondary cancers, which have been quite controversial in the literature. I'm interested in any comments! Thank you.
Question similar to Jon's. I have reached partial remission (0.2M-spike) without transplant and am currently taking 5 mg of Revlimid daily. Should I up the dose of Revlimid and add dex or wait til disease progression?
Thanks,
Coach Hoke
Am I to understand correctly that about 40% of this study patients discontinued treatment and about 60% of trial patients discontinue?
Also is their a number for elderly patients(over 70) for discontinuing treatment who are prescribed Rev/Dex for their initial treatment?
Thanks.
Bob Davis
Thanks for the additional comments, everyone. This is a great discussion.
Nancy, yes, as you mentioned, the Revlimid dose in the trial that investigated single-agent Revlimid was higher than usual (30mg/day). And, as you mention, it is standard for patients being treated with Revlimid to take some sort of preventative treatment against blood clots (baby aspirin is common, but other agents are used as well).
Jan, I’m not sure we’d go so far as to call maintenance therapy with Revlimid (with or without dex) as the “standard of care” in the U.S. for patients after their initial round of treatment. It's certainly common. But the NCCN guidelines recommend several options for patients following initial treatment, with or without a transplant, ranging from "observe" to "maintenance" to (in the case of transplant patients) a second transplant.
In our experience, doctors will generally discuss the possibility of maintenance with patients, and some doctors feel strongly it should be pursued. But many patients do not go on to maintenance therapy after their initial therapy.
Note, as well, that the most recent International Myeloma Working Group statement on maintenance therapy was not able to come to consensus on Revlimid maintenance. See this article for the details:
http://www.myelomabeacon.com/news/2012/02/01/experts-publish-consensus-statement-on-maintenance-therapy-in-multiple-myeloma/
You're right, Jan, that it's interesting that the Greek researchers do not address secondary cancers in their article. This is a concern with Revlimid maintenance therapy, as discussed in a number of articles The Beacon has published on the subject:
http://www.myelomabeacon.com/tag/secondary-cancer/
We suspect the subject is not discussed in the Greek study because it may have been challenging to track secondary cancers in this kind of retrospective, real-life study.
Coachhoke, talk with your doctor about the dose of Revlimid you're taking and the possibility of adding dex. You may be on the lower dose of Revlimid because your doctor is concerned about your blood counts (especially your white blood counts), or for other reasons (for example, the possibility of blood clots that Nancy mentioned). We're not too sure your physician will be keen on adding dex to your treatment mix -- that doesn't seem to be too common once a patient has been on Revlimid alone -- but you never know.
Bob, yes, 39 percent of the patients in the study permanently discontinued treatment with Revlimid. Cause of discontinuation appears to have been split about 50/50 between side effects and disease progression. That was about the same split seen in the clinical trial, which, yes, had a higher discontinuation rate close to 60 percent (58 percent).
Thanks Beacon Staff for the replies. Yes, I did use low dose (baby) aspirin while on chemotherapy drugs, and even afterwards for quite a while, and luckily did not have any DVT's. There are stronger anticoagulants available of course, by prescription, for anyone who is indicated to need a stronger level of care for their blood! I took Revlimid maintenance for a year, first at 10 mg. and then after complete remission at 5 mg. I wasn't on any 'dex' at the time, just during the induction chemo phase with Velcade.
Was the dose of dexamethasone mentioned in the Greek study?
I am initiating maintenance therapy very soon, & there is a debate as to what dose of Dex I should take with the 25mg Rvelimid & how frequently I should take the Dex per week. One physician's assessment is 20mg on days 1,2 5,6 (of a 7 day week) & the other from a well known MM center is just 20mg one day per week. This is a 3 week on & 1 week off protocol.
Thanks.
Good question, George. As it turns out, the paper does not explicitly mention the dose of dexamethasone the patients took.
However, it does provide one clue. It says that patients included in the study had to receive the Revlimid-dexamethasone combination "according to the standard clinical practice and the terms described in the approved marketing license."
In other words, the regimen had to be administered as recommended in the European prescribing information.
And here's what the European prescribing information says about dosing:
"The recommended starting dose of lenalidomide [Revlimid] is 25 mg orally once daily on days 1-21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on days 1-4, 9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily on days 1-4 every 28 days."
So that's probably what the starting dosing was for the patients in the study.
I am in my 3rd month of Revlimid. I haven't had the Dex with it but I am still being treated with Cyclophosmadide/Dex monthly which hopefully ceases next week as I have been on it monthly since last November.The Rev has crunched my Paraprotein, taking it from 40 to 25 in the first fortnight and now, after 3 months,has it down to 8, the lowest it has been since diagnosis nearly 4 years ago, including a SCT in 2011. After initially on 25mg 3 weeks on,1 week off, my ONC has me back to 1week on, 2 weeks off due to very low blood counts,especially neuts. of around .6. What I would like to know is what percentage of patients are on just Rev. and no Dex and why some are on Dex with Rev. and others aren't. Also, my ONC says I don't show any historical signs of DVT so I don't take anything for it. Do you think that this is wise or should I just take some baby aspirin just in case? I don't think it would hurt would it.
Thanks for you very informative forum.
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