Revlimid Prescribing Information Updated To Include Secondary Cancer Warning
Published: Mar 15, 2012 3:43 pm; Updated: March 16, 2012 8:55 am
The U.S. Food and Drug Administration has added a warning to the prescribing information for Revlimid stating that patients being treated with the drug have an increased risk of developing a second cancer.
The warning has been added in two parts of the prescribing information.
In the upfront ‘Warnings and Precautions’ section, text has been included stating that “Higher incidences of SPM [second primary malignancies] were observed in controlled trials of patients with multiple myeloma receiving Revlimid.”
Later in the document, the warning is expanded to explain that studies have shown that multiple myeloma patients treated with Revlimid (lenalidomide) as well as melphalan (Alkeran) and stem cell transplantation were more likely to develop a second cancer than those receiving comparable treatment without Revlimid. In particular, the Revlimid-treated patients were at higher risk of developing acute myelogenous leukemia and Hodgkin’s lymphoma.
The Food and Drug Administration (FDA) recommends in the prescribing information that physicians monitor patients being treated with Revlimid for the development of second cancers and take into account both the potential benefit of the drug and the risk of second cancers when considering treatment with Revlimid.
Revlimid is marketed by the U.S. pharmaceutical company Celgene (NASDAQ: CELG).
Concerns about a potential Revlimid-secondary cancer link first emerged at the American Society of Hematology annual meeting in December 2010, when results were presented from three trials that showed higher rates of reported second cancers among myeloma patients treated long-term with Revlimid therapy compared to other patients in the same studies.
Despite extensive follow-up research and investigation, concerns about Revlimid and secondary cancer persist. They are reflected, for example, in the recent International Myeloma Working Group consensus statement on maintenance therapy, which cites the risk of secondary cancer in its discussion of maintenance therapy with Revlimid (see related Beacon news).
The recent change in the U.S prescribing information for Revlimid was preceded earlier this year by a change in the European prescribing information for the drug. The European change reflects the results of a safety review by the European Medicines Agency, which was concluded last September (see related Beacon news).
The warning added to the European prescribing information is more extensive than the warning added by the FDA. In particular, the European agency added three paragraphs to the section on “other 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 second cancers versus what was observed in the trial control groups.
The third paragraph then states, “The risk of occurrence of [second 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.”
The U.S. Food and Drug Administration began its own safety investigation of Revlimid – and also thalidomide (Thalomid), which is chemically similar to Revlimid – in April 2011. An FDA representative contacted by The Beacon was unable at this time to clarify whether the recent change in Revlimid’s prescribing information reflects the conclusion of the agency's investigation.
Neither the FDA nor European authorities have thus far made any changes to the prescribing information for Thalomid related to secondary cancers.
[Update 8:55 am Eastern, March 16, 2012 - An FDA spokeswoman has told The Beacon that "We have updated the Revlimid labeling with the latest information. We continue to monitor the safety of the product, but we have not changed the Thalomid labeling with regard to this concern."]
At the 2011 American Society of Hematology meeting this past December, Dr. Antonio Palumbo of the University of Torino in Italy summarized results of a retrospective analysis of the risk of secondary cancer associated with Revlimid and thalidomide treatment (see related Beacon news).
The results of the analysis indicate that treatment with Revlimid in and of itself may not increase the risk of secondary cancers.
Instead, there may be an interaction between treatment with melphalan and treatment with Revlimid (or thalidomide) that increases a patient’s risk of developing secondary cancers.
Dr. Palumbo also presented data showing that the risk of developing secondary cancers when treated with Revlimid is generally lower than the risk of a number of serious side effects that can occur during common myeloma treatment regimens.
For more information, see the text that was added to the U.S. and European prescribing information for Revlimid, which is included below, or the full U.S. prescribing information and the full European prescribing information.
Additionally, please see the complete compilation of Beacon articles with information on the Revlimid safety controversy.
Addition To The U.S. Prescribing Information For Revlimid
Second Primary Malignancies (SPM): Higher incidences of SPM were observed in controlled trials of patients with multiple myeloma receiving Revlimid.
Patients with multiple myeloma treated with lenalidomide [Revlimid] in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide.
Addition To The European Prescribing Information For Revlimid
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 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.
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Thanks for posting this very timely article! I am currently 20months post stem cell transplant and have been on Revlimid Maintenance 5mg for about 17 months. I am scheduled to continue Rev 5mg to my 2yr SCT anniversary. Hopefully that will not bring a new diagnosis as suggested in this article lol
Thanks for all the amazing information on your site!
One of the things about safety surveillance post marketing in the USA that critically impacts this information is that it is completely voluntary. What that means is that the incidence of the SPM is likely far higher than has been reported. And even more importantly, those voluntary reports trigger an increased incidence review as well as labelling change.
IOW's once the FDA approves a product reporting AE's (adverse events) are not mandatory. Life threatening AE's are typically reported. However, the true incidence of the AE is never known, as there is no denominator once the product is on the market. Ergo, the incidence you see in the package label comes from the clinical trials (known denominator) when the product was approved.
Never again is the true incidence of the AE known, as the denominator is unknown once it is mass marketed.
This point is underscored by the fact that SPM has not been reported with thalidomide, and the likely reason is that the patient population for lenalidomide is far greater and has had far broader and higher clinical use than thalidomide, thus triggering the increased incidence of SPM with lenalidomide vs. thalidomide. NOT that thalidomide doesn't also carrry the same risk, merely that it has not been used widely enough for increased frequency reporting to have been triggered.
Which is why I am highly skeptical of this quote:
"Palumbo..presented data showing that the risk of developing secondary cancers when treated with Revlimid is generally lower than the risk of a number of serious side effects that can occur during common myeloma treatment regimens."
While it may be accurate statistically, how can Palumbo, compare the relative life threatening risk of myelosuppression vs. SPM?..please...stat wise he can, but when it comes to clinical significance..pshaw!
All of which brings us back to risk vs. benefit. When I expressed concern regarding SPM with the nephrologist at Mayo, he quipped, your risk of dying from MM is far higher than a SPM, making the latter risk a moot point.
Is it a benefit to survive longer with SPM and MM vs. MM?...what is the quality of life....how many more treatments, how much radiation and chemo for the SPM along with the MM?
Is there data showing overall survival is significantly greater with Revlimid maintenance to incur the risk of SPM or are we once again talking about PFS that is not sustainable with the additional risk of SPM?
hmmmm, thoughts worth pondering.......when it comes to risk vs. benefit
Thanks for the article, Beacon Staff, and for the analysis, Suzierose! That's interesting that you wonder if Thalidomide might also have the risk of SPM's. These cancer drugs are so amazing in what they can do to stop the growth of cancer cells that it doesn't surprise me that the side effects could be equally strong. I remember that my oncologist was worried about the results of the study for Revlimid in spring of 2011. He had scheduled me for a year of maintenance chemo on Revlimid, and didn't want to continue it beyond that after finding out that news (the feeling was mutual since I found the therapy difficult at times, and was almost at the end of the year.) I suppose that at least the SPM's are relatively rare, so if you need the treatment for active MM that would take priority.
Does anyone know if Velcade is known to have similar problems of a very low incidence of secondary cancers?
Thank you for your feedback, Julie. We're glad to be of help.
Suzierose -- Your concerns about potential under-reporting of secondary cancers are well taken. The best comparisons of secondary cancer rates are most likely the ones that are done between patients in different arms of clinical trials that carefully track patient outcomes for extended periods of time.
There is an overall survival benefit to Revlimid in the CALGB trial of maintenance treatment with Revlimid. The other major ongoing Revlimid maintenance trials thus far have shown progression free survival benefits, but not overall survival benefits.
Nancy - The data presented by Dr. Palumbo at ASH last December suggest that thalidomide and Revlimid are associated with similar secondary cancer risks in patients who also have received treatment with melphalan. An earlier study of thalidomide maintenance therapy, using the extensive Myeloma IX trial data from the UK, did not observe a difference in secondary cancer rates between patients treated with thalidomide and those not treated with thalidomide. However, the analysis does not appear to have differentiated between patients who did, or did not, take melphalan as well as thalidomide.
Here is a link to the full text of the UK analysis:
http://bloodjournal.hematologylibrary.org/content/early/2011/10/20/blood-2011-06-357038.full.pdf
There has been some research looking at secondary cancer and Velcade. However, the data are not as rich as those for Revlimid and thalidomide, because Velcade is not used nearly as frequently as the other drugs for maintenance therapy.
We covered some initial research on the Velcade-secondary cancer link in our ASH coverage last December. Here is a link to the relevant article:
http://www.myelomabeacon.com/news/2011/12/12/ash-2011-multiple-myeloma-update-day-two/
Nancy S.
Hope you are doing well today. This study was presented at ASH 2011 with respect to Velcade. They say no increased secondary cancer risk with Velcade.
http://ash.confex.com/ash/2011/webprogram/Paper37551.html
Mark
Thanks Beacon Staff and Mark for the info. I am doing really well right now, and am getting my annual medical exams and related tests appropriate for my age group and gender too, which includes cancer screenings. Also, get my blood testing done every three months now at the cancer centre, which includes the electrophoresis and light chain tests...a standing appointment! So, if anything else were to crop up, would have a decent chance of finding that out too! Am grateful not to be in need of any chemo therapy at the present time, but if I were, would be armed with more knowledge now than I had before.
I've been following the research into Velcade and secondary cancers closely, and I've often noted a disconnect between what the data presented in the analyses say, and what the researchers conclude.
Consider this relatively detailed analysis from ASH:
http://ash.confex.com/ash/2011/webprogram/Paper39543.html
The researchers conclude: "Bortezomib-based therapy for MM does not appear to be associated with an increased risk of either hematologic or solid tumor second primary malignancies, with incidence rates consistent with SEER data for incidence rates in the overall US population." (I've expanded some of the acronyms in the statement.)
Now, look at the data. There are four studies. One of them has Velcade in both arms of the trial. The other has thalidomide (and other things) in one arm and Velcade (and other things) in the other arm. Only two of the trial are comparisons of Velcade alone or with other stuff versus other stuff with no Velcade.
And, in those two trials that give the cleanest insight into whether Velcade might cause an increase in secondary cancers, the incidence of secondary cancers is highest in the Velcade arms of the trials.
I agree that the numbers are not big enough to show statistical significance. But I don't see how the numbers support the view that Velcade "does not appear to be associated with an increased risk" of secondary cancer.
Hi Nancy and Julie,
Thanks for the feedback Julie!
Nancy, I am 90% confident that SPM is a class effect for IMID's like lenalidomide/thalidomide..i.e. not a lot of wondering. Lenalidomide lacks the neurologic and sedation side effects of thalidomide. Just as carfilzomib has less neuropathy than bortezomide. I suspect that thalidomide would need to be used over a longer period of time since lenalidomide is up to 50K (not a typo) more potent than lenalidomide and has not been as widely used or as long a period. Celgene knew they needed a different analog of thalidomide and they created one to get away from the horrific history of thalidomide and limb defects as well as 100K dead babies in womb, worldwide.
We also know that new tumors need a vascular system or what is called angiogenesis to form secondary/primary tumors. Lenalidomide is 2-3 times as potent as thalidomide in suppressing vascular endothelial growth factor (VEGF) which is need for angiogenesis or vascular blood supply for tumor to thrive. So, thalidomide is less potent, (i.e. doesn't squash angiogenesis like lenalidomide) yet we have not seen SPM. What we do know is that the VEGF suppression of thalidomide was sufficient to induce limb defects, i.e. limbs needed the vascular supply for development. Which supports far more limited use in terms of the patient population treated with thalidomide when it comes to SPM.Has thalidomide ever been used as maintenance therapy ever?
There is one other variable of note here and that is BMSCT. In these trial designs they appear to be singling out melphan.(which does destablize DNA) Although, the risk of SPM in organ transplant patients is twice that of the general population. So we could speculate this is an issue of not just lenalidomide but that the the use of melphan in conjunction with BMSCT plays a role in developing SPM's as well. Another twist is that we know phosphorylation of P53 results in it's inactivation, and lenalidomide phosphorylates p53 typically subsequent to DNA damage as does thalidomide.
Just a few thoughts on what to me is a serious concern. Choices, choices, choices....that is what MM comes down to. No two patients respond the same nor have the same cellular disease process. So, there is simply no one right answer. You just gotta sit at the high roller table, kiss the dice, roll,play....and then there is HOPE.
This time it comes out of Canada..Nancy:
"Studies using small molecule inhibitors of the p53-MDM2 interaction such as nutlin and RITA (Reactivation of p53 and induction of tumor cell apoptosis) have shown the potential for pharmacological activation of p53 by disrupting the p53-MDM2 interaction as a new and promising anticancer strategy [4]–[8]."
http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0030215
TerryH.
I concur that it is prudent to recognize that the jury is still out on bortizomib and SPM.
Most often times we do not know what the major AE's will be or their frequency until after the drug is on the market for typically a minimum of five years, if it did not show up in the clinical trial. The reason being that the patient population is not large enough, there are few co-mordities in clinical trials, and critically important is that reporting of AE's is voluntary. Most physicians/nurses simply do not sit down and fill out the paperwork as it is a hassle and involves lots of follow-up paper as well. Which is a long way of emphasizing that what does get reported as AE's are the tip of the iceberg generally. And that is why the timeline is typically 5 years before an increased frequency report is triggered from the manufacturer and is mandatory to report. Which means that by the time we get labelling changes such as we see here in this article, there are likely many more patients treated with lenalidomide who whole lot of were NOT reported with SPM, and the incidence is probably much higher than what is now able to statistically say is clinically significant.
.....yep...makes for a serious pause in terms of relevant impact of this article....especially when you consider how much combo therapy is a staple of MM therapy.
Having said that there are 3 and 5 day incident triggers for death and/or life threatening AE's that are mandatory for physicians/murses to report.
There does appear to be a 'common' link though (even if not yet statistically proven) among the agents used with MM that show SPM..and that is they are DNA destablizers...i.e. alklyators, IMIDs...
All of which is to say that my concern about possible SPM's from protesome inhibitors is far less for that reason.
Nevertheless, vigilance is important...after all the first reports were no neuropathy with carfilzomib..and now we are seeing trials where neuropathy is being reported...nowhere near as severe/frequent as with bortizomide...but it is still occuring, vs. nonexistent.
Isn't dealing with Myelona enough? My doc wanted me to take Revlimid for 3 yrs. I told him no 8 months and still stand by my feelings about Rev and the causing of secondary cancers. I have bazile cell skin cancer that has been taken off of me 7 times. Don't I have enough cancers to complain about. It will be 1 year since my sct in April and I just want 1 year of not seeing any doc's. LOL
Donna...ICAM!!!
I had an stem cell replant 4/1/11, Yes I followed the DR Recomdation to take Revlimid Maintance drugs for an 2 year period. With in 7 month the turmor started to grow where I had never had them before. I have 4 tumors that have developed in my body. If I could re do I would not do Revlimid mainttance. I do not think their is enough study results and long term follow up study that support their maintance idea. I think that they are more concerned in selling additional drug rather than investigating the effect of long term drug over dose upon ones body after stem cell.
I had my stem cell transplant in Nov. 2011 & have been hesitant about taking Revlimed as maint. drug due to the high risk of DVT. After reading these articles, I am really thinking about saying no. Is there any data which suggests the length of time it extends ones long term remission? My wife had AML & its not something I care to experience on top of MM.....
I am new to this but had my doubts about Revlamid from the start. My first appointment with the doctor in February 2011 was preceded by a visit from a "customer advocate" from the oncology group who pushed me into signing an agreement with the Revlamid drug company (Celdene?) Of course it was completely absolving them from responsibilty and lying about me having been told about the side effects and potential problems with this drug. Cost? She didn't know but had an anecdote about " some rich guy recently who had to pay $3,000 up front but the rest was covered." The doctor had no information(came in late with no files, no computer) and was also a salesman for this drug, telling me on a subsequent phone call that if I were his brother, I would be in his office now and signing a Revlamid agreement.
My second opinion doctor came to our first meeting with a full file, answers to my questions, information about blood tests, an order for a skeletal xray and answers
about treatments and prognosis. I started treatments 2 days later with Velcamid and Dex (steroids). All my results so far are really good (I understand that can change!) My question is, at 62 yrs old, if I start Revlamid and risk secondary and serious side effects, should I not be thinking about quality of life rateher than length of life? Thanks for any advise.
Sorry, I was diagnosed i Februray 2012 not 2011
I just celebrated my 2nd anniversary of being in remission. I have been on Rev for the past 2 years and just had my checkup in March of 2012 and all my numbers are normal. There is really no reason for this post other than I need to write something. So far the Rev has been good to me but it seems like I am at the crossroad of stopping or going beyond 2 years. Keep the faith because it is all we have!!