European Regulators Conclude Revlimid Safety Review, Say Drug's Benefit-Risk Balance Remains Positive
Published: Sep 23, 2011 8:26 am; Updated: Sep 23, 2011 3:05 pm
The European Medicines Agency announced earlier today that its Committee for Medicinal Products for Human Use has completed its safety review of Revlimid. The review was started earlier this year after several studies showed an increased risk of new cancers in newly diagnosed multiple myeloma patients being treated with Revlimid (lenalidomide) and other treatments.
The Agency's Committee has concluded that "the benefits of Revlimid, particularly improved survival, continue to outweigh the risks but recommended that the prescribing information for Revlimid be updated with a warning and advice to doctors on the risk of new cancers."
The recommended change to Revlimid's European prescribing information involves the addition of three paragraphs to the section on "special warnings and precautions for use."
The first two paragraphs note that, in both previously treated as well as newly diagnosed multiple myeloma patients, treatment with Revlimid has been associated with a three- to four-fold increase in the rate of secondary cancer versus what was observed in the trial control groups.
The third paragraph then states, "The risk of occurrence of [secondary cancers] must be taken into account before initiating treatment with Revlimid. Physicians should carefully evaluate patients before and during treatment using standard cancer screening for occurrence of second primary malignancies and institute treatment as indicated."
Dr. Vincent Rajkumar, a multiple myeloma specialist from the Mayo Clinic, said that he agrees with the European regulators' statement, but noted that the statement only applies to the approved use of Revlimid, which is for patients who have received at least one prior myeloma therapy. “In addition to the approved indication, I think the benefits also outweigh the risks for the use of Revlimid for the treatment of newly diagnosed myeloma,” said Dr. Rajkumar.
“However, we need more data to determine if this is the case for Revlimid as post-transplant maintenance therapy,” Dr. Rajkumar added. “That is the setting in which an increased risk of second cancers has been noted; and that is the area of controversy.”
Neither the recommended change to the prescribing information nor the European Agency's announcement about its safety review mention any link between the risk of secondary cancers and the duration of treatment with Revlimid.
The investigators of a key French trial of Revlimid in newly diagnosed patients following stem cell transplantation had previously reported concern that there might be such a link (see related Beacon news). Dr. Michel Attal, lead investigator of the French trial, told The Beacon that there is a clear trend toward a higher rate of second cancers in patients taking Revlimid for more than two years; however, the difference in second cancer rates is not statistically significant at this time.
Dr. Attal personally believes that the data from the French trial are sufficient to justify limiting the length of Revlimid treatment after transplants. At the same time, he recognizes that further clinical trials -- "with different induction, transplant, and consolidation therapies" -- will be needed to more conclusively demonstrate the need to limit the length of Revlimid therapy.
The U.S. Food and Drug Administration (FDA) is also conducting a safety review of Revlimid as well as thalidomide (Thalomid), which is chemically similar to Revlimid (see related Beacon news). The FDA's review is not yet complete.
An FDA spokesperson explained to The Beacon that, after the FDA completes its review, it will work with the company that markets Revlimid, Celgene Corporation, "to determine the appropriate next steps with regards to Revlimid's safety labeling."
For more information, see the full text of the European Medicines Agency announcement, as well as the text of the recommended change to Revlimid's European prescribing information, which are included below. Additionally, please see the complete compilation of Beacon articles with information on the Revlimid safety controversy.
Text of the European Medicines Agency Announcement
European Medicines Agency concludes that benefit-risk balance of Revlimid remains positive
The European Medicines Agency has confirmed that the benefit-risk balance for Revlimid (lenalidomide) remains positive within its approved patient population but advises doctors of the risk of new cancers as a result of treatment with the medicine.
Revlimid is used in combination with dexamethasone [Decadron] (an anti-inflammatory medicine) to treat adult patients with multiple myeloma whose disease has been treated at least once in the past.
Revlimid was reviewed following the results of three new studies showing a higher rate of new cancers in patients with newly diagnosed multiple myeloma who were being treated with Revlimid and received other treatments concomitantly. The studies showed a four-fold increase in the number of new cancers in patients being treated with Revlimid, including solid tumours and cancers of the blood and the immune system. Although the studies were carried out in patients for whom Revlimid is not currently indicated, the Agency’s Committee for Medicinal Products for Human Use (CHMP) was concerned that the results could also be relevant for the approved patient population.
The Committee weighed the benefits of Revlimid against the risks in the approved patient population. The Committee reviewed all available data on new cancers in the approved population, including data from studies and post-marketing data. It concluded that the risk of new cancers, such as skin cancers and some invasive solid tumours, was observed in studies in the approved population. The Committee also reviewed available data from the three studies in newly diagnosed multiple myeloma patients.
The Committee concluded that the benefits of Revlimid, particularly improved survival, continue to outweigh the risks but recommended that the prescribing information for Revlimid be updated with a warning and advice to doctors on the risk of new cancers.
Doctors are also reminded that the current review of the benefits and risks of Revlimid only covers the approved patient population. The Committee’s conclusion does not cover its use outside of the current authorised indication.
The Committee’s opinion has now been forwarded to the European Commission for the adoption of a decision.
Notes
- Multiple myeloma is a cancer of the plasma cells in the bone marrow.
- The Committee observed in studies in the approved population that there were 3.98 cases of new cancer for every 100 patient-years in patients receiving Revlimid compared with 1.38 cases in those not receiving Revlimid (patient-years is the sum of the lengths of time all patients have been under treatment).
- Revlimid has been authorised in the EU since 14 June 2007.
- See the Revlimid European public assessment report.The review of Revlimid was carried out under Article 20 of Regulation (EC) No 726/2004/EC and was requested by the European Commission in March 2011. This type of procedure is triggered for medicines that have been authorised via the centralised procedure, which is managed by the European Medicines Agency.
- The prescribing information will be updated with data on newly diagnosed multiple myeloma patients showing the four-fold increase in the number of new cancers in patients being treated with Revlimid.
Recommended Addition To The European Prescribing Information For Revlimid
Second Primary Malignancies
An increase of second primary malignancies (SPM) has been observed in clinical trials in previously treated myeloma patients receiving lenalidomide [Revlimid] / dexamethasone (3.98 per 100 patient-years) compared to controls (1.38 per 100 patient-years). Non invasive SPM comprise basal cell or squamous cell skin cancers. Most of the invasive SPMs were solid tumour malignancies.
In clinical trials of newly diagnosed multiple myeloma, a 4-fold increased incidence of second primary malignancies has been observed in patients receiving Revlimid (7.0%) compared with controls (1.8%). Among invasive SPMs, cases of AML [acute myeloid leukemia], MDS [myelodysplastic syndromes] and solid tumours were observed in patients receiving Revlimid in combination with melphalan [Alkeran] or immediately following high dose melphalan and ASCT [autologous stem cell transplant]; cases of B-cell malignancies (including Hodgkin's lymphoma) were observed in the clinical trials where patients received Revlimid in the post ASCT setting.
The risk of occurrence of SPM must be taken into account before initiating treatment with Revlimid. Physicians should carefully evaluate patients before and during treatment using standard cancer screening for occurrence of second primary malignancies and institute treatment as indicated.
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
- FDA Approves Once-Weekly Dosing And Revised Safety Information For Kyprolis
- Once-Weekly High-Dose Kyprolis Yields Deeper Responses And Longer Remissions Than Twice-Weekly Kyprolis (ASCO & EHA 2018)
- Two Darzalex Clinical Trials Halted; Little Impact Expected On Drug’s Use In Multiple Myeloma
Just for clarity.
Is Dr Rajkumar stating that it is post SCT that secondary malignacies are seen INDEPENDENT of whether the population was newly diagnosed MM or previously treated, if the therapy post SCT includes lenalidomide?
Such that patients should be concerned about secondary malignacies only if they are using lenalidomide post SCT?
Contrary to what Dr Rajkumar says is the specific area of concern is that the European investigators state:
"Revlimid was reviewed following the results of three new studies showing a higher rate of new cancers in patients with newly diagnosed multiple myeloma who were being treated with Revlimid and received other treatments concomitantly. The studies showed a four-fold increase in the number of new cancers in patients being treated with Revlimid, including solid tumours and cancers of the blood and the immune system. Although the studies were carried out in patients for whom Revlimid is not currently indicated"
The about statement does not indicate that Post SCT is the variable of difference...can Dr. Rajkumar perhaps explain how his focus is not contradictory to the study review results?
Hi suzierose,
Both the European statement and Dr. Rajkumar refer to three recent studies that first highlighted an increased risk of developing a second cancer following Revlimid treatment.
Two studies showed that recently diagnosed myeloma patients treated with long-term, low-dose Revlimid directly after stem cell transplantation (what is known as maintenance therapy) developed second cancers at a higher rate than patients in the same study who received a placebo instead of Revlimid maintenance.
Another study also found newly diagnosed elderly patients treated with melphalan and prednisone followed by long-term Revlimid maintenance also developed second cancers at a higher rate than those who received a placebo.
Here's a summary of the initial findings from those three studies:
http://www.myelomabeacon.com/news/2010/12/10/studies-support-revlimid-lenalidomide-maintenance-therapy-for-multiple-myeloma-patients-ash-2010/
After reviewing all of the Revlimid safety data, the European statement says that the benefits outweigh the risks when Revlimid is used according to its approved indication, after at least one prior myeloma treatment - that would include relapsed/refractory patients, even those who were previously treated with a stem cell transplant.
Dr. Rajkumar stated that he believes Revlimid is also safe for newly diagnosed (previously untreated myeloma patients); however, he said that more data is needed to determine whether the benefits of Revlimid maintenance therapy directly after stem cell transplantation outweigh the risks.
For more of the history behind this safety investigation, you can check out the rest of the Beacon articles on the Revlimid safety controversy:
http://www.myelomabeacon.com/tag/secondary-cancer/
Thank you for the reply.
This study presented at 2011 ASCO by Rossi appears to confirm the three studies cited by European review.
With all due respect to Dr. Rajkumar, based on the abstract the newly diagnosed patients were not post SCT, as indicated by the abstract.
http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=84524
Hi suzierose,
Since the three studies presented at ASH last year, many of the Revlimid studies have been reevaluated for safety, the one you cite being one of those. That study, however, is not one of the ones that Dr. Rajkumar was referring to. He was referring to the IFM and CALGB studies discussed in the link we provided in our previous comment. In both of those studies newly diagnosed patients received a stem cell transplant followed by Revlimid maintenance.
Which brings us full circle to the initial question,
Should newly diagnosed patients be concerned about secondary malignacies only if they are using lenalidomide post SCT, given the data presented at ASCO?
That would be Dr. Rajkumar's opinion.
Things this study did not look at was medications taken (ie: cyclophosphamide/melphlan/etc) or amount of radiation given (both by skeletal or treatment) . Or was this included and I did not see it. Thank you
I am wondering is it possible for the Beacon Staff to initiate a forum on this topic?
There just seems to be some inconsistencies here.
Perhaps, it is as simple as the CALGB & IMF 2005-02 newly diagnosed populations who had recently undergone SCT vs. BIRD and MM-15 who were newly diagnosed but had not undergone SCT, in terms of Dr Rajkumar's remarks.
Or it could be that ASH was in Dec 2010 vs the newer data was presented at IMW in May2011 and ASCO in June 2011, providing additional studies which support the European review.
I even considered that Rajkumar's remarks may have been made at ASH but the article clearly states this is his opinion regarding the European Regulators Safety review..despite trial MM 015 also having done a retrospective analysis of 1,798 newly diagnosed patients in 9 trials where they concluded it was revilimid plus an alkylating agent (melphan) that showed the higher incidence of secondary cancers in the newly diagnosed without SCT.
I hope you agree that it would be helpful to have a forum on this latest news.
Thanks so much for your time.
I'm not sure I understand why you find Dr. Rajkumar's statement so controversial, suzierose.
The strongest evidence yet regarding any potential link between lenalidomide and secondary malignancies is the recent evidence from the several large trials that directly and prospectively compared the impact of (a) maintenance treatment with lenalidomide to (b) no maintentance treatment with lenalidomide.
As the EU regulatory authority noted, those trials showed a 3-4x increase in the risk of secondary malignancies in the patients treated with lenalidomide.
Allow me to emphasize: Those were controlled studies that prospectively allowed for a comparison of lenalidomide's impact on myeloma patients. The patients in these trials were randomly assigned to either the lenalidomide arms of the trials or the control arms of the trials.
I am sure that Dr. Rajkumar is well aware of the retrospective analyses that you mentioned. He attended the Paris IMW meeting as well as last year's ASH meeting and this year's ASCO meeting.
I suspect, however, that Dr. Rajkumar simply places greater weight on data from large, controlled studies.
Finally, you seem to have misinterpreted the EU decision. The EU regulatory authority did not say "lenalidomide is safe." It said that, in lenalidomide's approved indication -- relapsed or refractory myeloma patients -- the benefits of treatment with lenalidomide outweigh the risks.
The recommendation then goes on to explicitly note the increased risk of secondary malignancies associated with lenalidomide, and urges physicians to take that risk into account when making prescribing decisions and when tracking the progress of their patients.
Hi Dr T,
Thanks for taking the time to respond.
I did not view what Dr Rajkumar said as controversial rather I did not find it consistent, with the data from ASCO, IMW subsequent to the trials used by the European Regulatory Safety Committee.
Nor did I infer, imply or suggest that Rajkumar had not attended any meeting but rather noted the data at ASCO and IMW was subsequent to ASH.
I am aware, based on webcasts that Rajkumar attended the IMW and ASCO meetings as well as knowing he is the MM committee chair for ECOG. Thus his opinions are highly regarded by myself as well as many others. Neither have I asserted that the EU stated lenalidomide is not safe as I understand the term benefits vs. risk. OTOH a new warning on any agent is not indicative of enhanced safety. Indeed, secondary cancers are a significant risk when there is no overall survival benefit demonstrated in any current conventional therapeutic regimen, as PFS is the most common endpoint.
While randomized controlled studies are certainly the gold standard when it comes to clinical evidence as the basis for treatment a retrospective study, despite it's limitations by design, with close to 2 thousand newly diagnosed people (MM015) along with BIRD's 6 year median follow up of the same population clearly add credence to the European Regulatory Safety review's conclusions.
So the question is whether Rajkumar's opinion is the same based on the totality of the data to date or is it narrowly focused on only those studies in the European Regulatory Safety review. If so, why? Benefits can always outweigh risks but the quality of life with secondary cancer is not a minor issue nor adverse event.
And patients and clinicians have to make the best choices given the data available.
Overall, I think it merits discussing the broad perspective of what the European Regulatory Safety review concluded along with the studies subsequently reported on as it pertains to newly diagnosed patients which are not the approved population for Revlimid but often times are treated off-label, as off -label use is the most common when it comes to chemotherapy. Such that the explicit risk being taken into account by physicians and patients is the entire point of discusssion.
m brown, the European Medicines Agency Committee reviewed results from a variety of studies and data sources but did not provide any detail in their statement about whether they analyzed the risk of secondary cancers based on the types of other medications taken prior to or at the same time as Revlimid treatment.
suzierose, Dr. Rajkumar's remarks quoted in this article were provided on Friday after the European Committee released its findings and issued its statement. They are based on his experience with Revlimid and the data and analyses with which he is familiar.
Just to clarify, the MM-015 trial is a prospective trial conducted by Dr. Antonio Palumbo that includes 459 newly diagnosed myeloma patients 65 years and older. In this trial, Revlimid was given in combination with melphalan and prednisone. Patients in the Revlimid treatment groups were more likely to develop a second cancer, although Dr. Palumbo has suggested that may be because there were more patients with complex chromosomal abnormalities in the Revlimid groups.
Dr. Palumbo also conducted a separate retrospective analysis of 1,798 newly diagnosed myeloma patients from nine clinical trials. This analysis found that Revlimid given in combination with alkylating agents raises a patient's risk of developing a second cancer, but Revlimid in combination with dexamethasone -- the combination typically given to younger, newly diagnosed myeloma patients -- does not.
hello. plz can someone help me. i m female age 46 frm South Africa. ive been diagnosed with MM on
Sep 2011. my doc put me on chemo therapy cyclophosphamide, vincristine n adriamycin. On tues 3rd July i was told im not responding to treatmnt, cancer goin up n the doc now goin to put me on lenalidomide
i m very worrid abt side effects. what r my chances. has anyone els been on this treatment. plz help
Hi Noori, Sorry to hear that you are having this battle with MM. Many of us patients who post here have taken lenalidomide (Revlimid). You can find lots of information on this site by going to the 'search' box on the top right. Hope that the new treatments help you..best wishes to you! You can also post questions in the 'forum' section and you may receive additional feedback from forum participants, including (perhaps) one of the Beacon's Medical Advisors.
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