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FDA Issues Extensive Update About Revlimid And Second Cancers

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Published: May 7, 2012 8:15 pm; Updated: May 9, 2012 10:30 am

The U.S. Food and Drug Administration earlier today issued an extensive update regarding the risk of developing a second cancer while being treated with Revlimid.

The update comes on the heels of a change the Food and Drug Administration (FDA) made to the prescribing information for Revlimid (lenalidomide) in March of this year.

The change involved the addition of a warning that patients being treated with Revlimid have an increased risk of developing a second cancer (see related Beacon news).

Today’s update by the FDA includes more specific details of the agency's analyses of Revlimid and second cancers.


News articles about:
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- Revlimid

In the update, the FDA says that it continues to recommend that physicians monitor patients being treated with Revlimid for the development of second cancers, and that physicians take into account both the potential benefit of the drug and the risk of second cancers when they consider treating a patient with Revlimid.

The FDA also urges patients to contact their health care professional if they have any questions or concerns about Revlimid.

Revlimid is marketed by the U.S. pharmaceutical company Celgene (NASDAQ: CELG).  Representatives from Celgene did not respond to requests for comment on today's FDA update.

The new Food and Drug Administration’s analyses show that newly diagnosed multiple myeloma patients treated with Revlimid maintenance therapy after stem cell transplantation are three times more likely to develop a second cancer than patients who do not receive Revlimid maintenance.

Data from three ongoing clinical trials show so far that 7.9 percent of newly diagnosed patients receiving Revlimid maintenance have developed a second cancer, compared to 2.8 percent of patient who received a placebo.  Patients receiving Revlimid were more likely to develop acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin’s lymphoma.  The median time from start of Revlimid treatment till diagnosis of a second cancer was two years.

The analyses also show that relapsed and refractory myeloma patients treated with Revlimid and dexa­methasone (Decadron) are more likely to develop a second cancer than patients treated with dexamethasone alone.

Specifically, data from the two clinical trials that supported the FDA’s approval of Revlimid show that 3.98 percent of relapsed and refractory myeloma patients developed a second cancer during each year of treatment with Revlimid and dexamethasone, compared to 1.38 percent of patients treated with dexa­metha­sone and placebo.   A key contributor to the different rates of second cancer was a noticeably higher rate of non-melanoma skin cancer among the patients treated with Revlimid.

However, when FDA adjusted its analysis of non-melanoma skin cancer rates to account for differences in how long patients were observed on treatment during the clinical trials, it found that 1.71 percent of Revlimid-treated patients developed a non-melanoma skin cancer per year of treatment, as compared to 0.91 percent of patients who did not receive Revlimid.  The FDA stated that these two rates are statistically similar.

The FDA also suggested in today's update that the prescribing information for Revlimid has been further updated to reflect the agency's newly released analyses.  The Beacon has not been able to confirm with either the FDA or Celgene whether or not this actually is the case, and there is no evidence on the FDA's website of newly revised prescribing information for Revlimid. (See important update below.)

Today's FDA update follows an announcement last week by regulators in Ottawa that information about the risk of secondary cancer has been added to Revlimid’s Canadian prescribing information (see the related Health Canada announcement).

European regulators concluded their review of Revlimid and second cancers last September by reporting that “the benefits of Revlimid, particularly improved survival, continue to outweigh the risks” (see related Beacon news).

At the same time, the regulators moved to include in Revlimid's European prescribing information language about second cancers that is more detailed than what has been included thus far in the drug's U.S. and Canadian prescribing information.

The current European prescribing information for Revlimid, for example, states that "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%)."

For further coverage of developments related to Revlimid and second cancers, please see the compilation of Beacon articles about relevant research findings and announcements.

The full text of today’s FDA update can be found at the FDA website.  The key parts of the statement are included below for the convenience of the Beacon’s readers.

Update (May 9, 2012; 10:30 a.m.):  A spokesperson for the FDA has informed The Beacon that the agency is not currently planning additional revisions to Revlimid’s prescribing information beyond those made public by the FDA in March. Thus, the Revlimid prescribing information currently available on the FDA website is up to date.

The spokesperson further clarified that the FDA update discussed in the Beacon article above was intended, in part, to explain the agency’s rationale for the changes to Revlimid’s prescribing information published on the FDA website in March.

Key Text of FDA Drug Safety Communication:
Safety review update of cancer drug Revlimid (lenalidomide) and risk of developing new types of malignancies

Safety Announcement

The U.S. Food and Drug Administration (FDA) is informing the public of an increased risk of second primary malig­nancies (new types of cancer) in patients with newly-diagnosed multiple myeloma who received Revlimid (lenalidomide). Clinical trials conducted after Revlimid was approved showed that newly-diagnosed patients treated with Revlimid had an increased risk of developing second primary malignancies compared to similar patients who received a placebo. Specifically, these trials showed there was an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma.

This safety information has been added to the Warnings and Precautions section of the Revlimid drug label. The patient Medication Guide is also being updated to inform patients about this risk.

Healthcare professionals should consider both the potential benefit of Revlimid and the risk of second primary malignancies when deciding to treat patients with this drug, and monitor patients for this risk.

Patients should contact their healthcare professional if they have any questions or concerns about Revlimid …

Data Summary

FDA reviewed controlled clinical trials of Revlimid as maintenance therapy in patients with newly-diagnosed multiple myeloma and for the treatment of relapsed/refractory multiple myeloma, to evaluate the risk of developing a second primary malignancy with Revlimid.

Second primary malignancies in patients with newly diagnosed multiple myeloma

In three prospective, randomized trials, patients with newly-diagnosed multiple myeloma received initial chemotherapy or chemotherapy plus blood stem cell transplantation followed by treatment with Revlimid or a placebo. This treatment protocol was used to study the effect of Revlimid as maintenance therapy. A pooled analysis of the three ongoing trials, as of February 28, 2011, showed 65 second primary malig­nancies among 824 patients in the Revlimid treatment arms compared to 19 second primary malig­nancies among 665 patients in the treatment arms that did not include Revlimid maintenance (7.9% vs. 2.8%; p<0.001). This difference is almost a three-fold increase in new malignancies for the groups receiving Revlimid versus the groups that did not receive Revlimid. The second primary malignancies noted included acute myelogenous leukemia (AML), myelodysplastic syndromes (MDS), and B-cell malignancies. Overall, 30 (3.6%) second primary hematologic malignancies were reported in the Revlimid treatment arms (22 MDS/AML, 5 Hodgkin lymphoma, 3 B-cell acute lymphoblastic leukemia) compared with 2 (0.3%) cases of AML in the study arms not receiving Revlimid. The median time from start of Revlimid to a diagnosis of a second primary malignancy was two years. Based on the available data, there appears to be no difference in the incidence of non-melanoma skin cancers or of solid tumors between the patients who received Revlimid and those who did not.

Second primary malignancies in patients with relapsed/refractory multiple myeloma

A retrospective pooled analysis of second primary malignancies also was conducted on data derived from the two clinical trials that supported the initial FDA approval for relapsed multiple myeloma. These were multicenter, double-blind, placebo-controlled, parallel-group trials of Revlimid plus high-dose dexa­methasone therapy versus dexa­methasone alone in the treatment of patients with relapsed or refractory multiple myeloma. The incidence rates of developing a second primary malignancy during the treatment phase of these trials were 3.98 and 1.38 per 100 person-years for patients in the Revlimid / dexa­metha­sone and the placebo / dexamethasone groups, respectively. The higher incidence rate of second primary malignancies in the Revlimid / dexa­metha­sone group was largely accounted for by the higher incidence of non-melanoma skin cancers with Revlimid (2.4 vs. 0.91 per 100 person-years for the Revlimid / dexa­metha­sone and placebo / dexamethasone groups, respectively). The patients in the Revlimid / dexa­metha­sone group had longer on-study treatment time compared to the placebo / dexamethasone group (467 person-years vs. 218.7 person-years, respectively). When adjusted for the differences in observation time on-study, the incidence rate of invasive non-melanoma skin cancers was not substantially different between the two groups (1.71 vs. 0.91 per 100 person-years, respectively).

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  • Dan D said:

    As indicated on the warning, it appears that this increased risk is based on studies of newly diagnosed patients that received revlimid maintenance after a stem cell transplant.

    Supposedly, this increased risk may relate to the administration of mutagenic drugs such as the close relative to mustard gas - melaphan -- before transplant.

    In that regard, however, does anyone know -- and I suspect Suzie Rose will have a hunch -- whether there is ANY indication that giving revlimid as an upfront therapy with, say, dexamethasone, also increases the change of secondary malignancies?

    And more generally, is there any expectation at all that pomalidomide may pose less risk of secondary primary cancers? I tend to doubt it given that pomalidomide differs from revlimid -- and for that matter, thalidomide, by only a few atoms. Hence this may be a class effect.

  • Stan said:

    I'm confused.
    Is non-melanoma skin cancer playing a minor or major role in these secondary cancers? I'll accept a much higher risk of non-melanoma skin cancer than the other cancers.
    I will be buying extra sun screen tomorrow.

  • suzierose said:


    Unfortunately, these SPM's are the tip of an iceberg when it comes to lenalidamide.

    If I am not mistaken the trials they are speaking of were ones that used lenalidamide in combination with melphalan and prednisone, and that therapy was used as induction and/or consolidation post ASCT. Many of the SPM's were hematologic (leukemias and lymphomas) in those phase III trials

    Dan, my hunch is yes and that we are talking about length of therapy (or what they call maintenance) vs. whether there will be SPM's..as noted in the article the median length of therapy was 24 months for development of the SPM.

    My hunch is also based on one of the multiple mechanism(s) of action (MOA) of lenalidomide as an anti-angiogenesis agent via inhibition of VEGF. While it has not been shown in MM It has been established in breast, colon, and prostate cancers that agents which inhibit VEGF result in metastasis and more aggressive cancer. The increase in SPM's with lenalidomide would be consistent based on the same MOA that we now are seeing in newly diagnosed MM patients, this would include what you describe as 'upfront' therapy as the patient population is the newly diagnosed.

    Having said that however, we also need to recognize that cancer patients have an increased risk of SPM and so do transplant patients independent of any drug. IOW's when we look at the non-cancer and non-transplant populations the incidence of SPM is significantly less.

    Regarding pomalidamide, it is also an anti-angiogenesis agent (inhibits VEGF) as a member of the IMID class and this should be sufficient reason for ODAC to consider delay of approval vs. a protesome inhibitor. Particularly, given that lenalidomide is 50K times as potent as thalidomide and pomalidomide is 5x as potent as lenalidomide.

    Stan, what they are saying is that the patients have skin cancer that is NOT melanoma. Basal and squamous cell carcinomas of the skin are non- melanoma. Melanoma is now much better known but the most common skin cancers are basal and squamous carcinomas.

  • Dan D said:

    Interesting analysis SR: Thanks for your insights. I am thinking about starting upfront BiRd treatment: revlimid plus low-dose dex plus the antibiotic Biaxin -- which appears to be very promising - so this is timely and concerning.

    If VEGF inhibition does play a key role in SPMs -- as you suggest -- then revlimid may well be worrisome in any treatment context -- not just post-ASCT maintenance.

    That said, I was just looking at the summary for one restrospective study (linked here), and this does give room for optimism. The results suggest that Revlimid does NOT increase second cancers when used with dexamethasone, although it does so when administered with melphalan.

    So maybe VEGF downregulation by itself is generally insufficient to promote more aggressive disease or SPMs in the case of myeloma. After all, myeloma is a cancer OF the bone marrow, with metastasis being a very rare event.

    In other words, myeloma cells really need the bone marrow niche to flourish. Outside the bone marrow -- even in the blood -- myeloma cells are very unstable.

    But when you start alkylating and mutagenizing DNA -- as is the case when you add melphalan, now you may be inadvertently imposing a genetic screen for agressive cells, especially when VEGF is also suppressed.

    But who the f!@k really knows?

  • Dan D said:

    Whoops: I forget to add in my previous message the link to the earlier studies of SPMs in association with rev and various agents. Here it is:


  • Al Rojas said:

    Glad I made the decision to stay off Revlimid maintenance therapy when I did. About 9 months later my kappa free light chain started to rise. I chose to fight it with alternative medicine and so far so good.

  • Jesse White said:


    What alternative therapy do you follow?

  • Mary Austin said:

    Hi Al,
    I too would like to know what alternative therapies you follow. Chemotherapy two years ago has had a disaterous effect on peripheral neuropathy caused by Amyloidosis and only obtained partial remission. My consultant actually commented that it was a surprised I had actually got there. It sort of slipped out. So I would be interested to know what works for you. I am ironically amused when I read that Amyloidosis can cause nerve damage such as carpal tunnel syndrome and/or tingling and pins and needles in feet and legs. If only!!!

  • Ben S. said:

    The FDA's data actually showed a nearly TWO fold, not THREE fold, INCREASE of SPM's occurrence. I can't believe the wording in the announcement has been so inaccurate. Of course that's not to say it is not significant. I also wish FDA has been more specific on what chemotherapies in conjunction with ASCT preceded the Revlimid maintenance in the studies.

  • Tracy B. said:

    Hi,I am a new subscriber. Was diagnosed 2 years ago, which Multiple Myeloma at age 46 years old. Just read this article. I was on Revlimid/Dexmethasone for 2 years. Due to other health issues, I decided to not have the stem cell transplant. Currently on Velcade subcuteanous injection, and my m protein has dropped from 2710 in January to 400 in April. My oncologist, suggested the injections,so far just had one. Doing relatively well.
    Does this include patients who have not had a stem cell transplant and who took the Revlimid for maintenance therapy?

  • suzierose said:

    Hi Tracy,

    There are 3 sets of data, one with ASCT one without as well as maintenance therapy included with either of the former sets.

    One set of data shows that the combination of melphalan/lenalidamide with or without ASCT demonstrates a higher incidence of SPM's that are predominately hematologic (leukemias/lymphomas). This is a study of newly diagnosed MM patients without ASCT where the combination was used for induction. Note, this group of patients were > 65 and were not on maintenance therapy.


  • Dr. T said:

    @Ben S. - I'm not sure I see the error that you're claiming is in the FDA announcement. If you do the math for the newly diagnosed patients, the ratio of the secondary cancer rates is 2.76, which can reasonably be rounded up to three, which is what the FDA did.

    I'm also a little hesitant to place too much emphasis on claims that the cancers are tightly tied to specific other treatments. The number of secondary cancers that we're talking about already is rather low when we're comparing (a) people on Revlimid, to (b) people not on Revlimid.

    So when you start dividing groups (a) and (b) further, you're talking smaller and smaller numbers of observations, which means the ability to statistically distinguish between rates of secondary cancer becomes harder and harder.

  • suzierose said:

    Hi DanD,

    You mentioned BIRD. Here is the data that was presented at ASCO2011:

    "The BiRD study also explored this issue.5 BiRD was a small phase II trial involving 72 patients, median age 63 years, with newly diagnosed multiple myeloma. Patients were treated with lenalidomide, clarithromycin, and dexamethasone until progressive disease, stem cell transplantation, or unacceptable toxicity. At baseline, 8 patients had prior solid tumors, 2 had skin cancers, and 1 had lymphoma.
    At a median follow-up of 6 years, median progression-free survival was 70.8 months and median 4-year overall survival was 82.2%; median 5-year overall survival had not yet been reached. Follow-up at 5 years revealed five new primary solid tumors and no new hematologic malignancies."


    The interesting thing about BIRD is that the SPM's were solid tumors vs hematologic. Again keep in mind that cancer patients have a higher incidence of SPM to begin with and they do not say whether the resultant SPM's in BIRD were statistically significant given that 8 patients had prior solid tumors at baseline.

  • Stan said:

    Thanks for the correction. So now I have to learn about skin cancer??
    I have been ignoring my MM, and this website, for 4 months or so..nice break. But I think I have lost a few IQ points in the meantime.
    This article makes my head spin.
    Celgene stock has dropped a lot this last month, so that tells me the people in the know don't like the news.

  • suzierose said:

    @ Dr T..."The number of secondary cancers that we’re talking about already is rather low when we’re comparing (a) people on Revlimid, to (b) people not on Revlimid.
    So when you start dividing groups (a) and (b) further, you’re talking smaller and smaller numbers of observations, which means the ability to statistically distinguish between rates of secondary cancer becomes harder and harder."

    The doubling of SPM incidence in newly diagnosed MM patients treated concomittantly with lenalidomide/melphalan will likely grow as the numbers of patients treated expands given that melphalan hi dose chemotherapy is virtually a standard of care and lenalidomide has become a drug of choice for induction therapy. Additionally, the incidence is of sufficient concern to have warranted a label change and a second FDA update warning, all indicative of an incidence rate high enough for clinicians to exercise caution about the combination. Moreover, while it may be low statistically, the clinical impact is not as that means new drug regimens and therapy with additional toxicities in order to simply manage the SPM. .

    Which would bring us, full circle to the keypoint of risks vs benefits with MM therapy and that is survival. If therapy does not increase survival what is acceptable becomes highly individualistic and patient centered particularly once the patient knows that despite the increase risk of SPM the risk of dying from MM is far higher than the risk of SPM.

    Each patient though has to make that judgment and self assessment as to the clinical risks they are willing to submit to. For us MM patients, rolling the dice is not a choice but when and how is.

  • Dr. T said:

    @suzierose - It seems that I didn't explain myself well enough.

    I'm not arguing that we shouldn't believe that Revlimid causes an increase in second malignancies. I think the evidence is very clear that it does.

    What I am arguing is that the water is muddier when you start to talk about whether or not melphalan, stem cell transplants, or some other treatment plays a key role in "helping" Revlimid to cause second cancers.

    Those sorts of analyses require splitting the data we have into smaller and smaller subsets, which makes it harder to draw firm, statistically sound, conclusions from the data.

    And remember, it doesn't help that more and more people are being treated with Revlimid every year. The data that we need to really help us figure out the finer points of the secondary cancer issue are data from long-term clinical trials, where patients are being tracked and monitored carefully. Yet the number of new patients entering long-term Revlimid trials in any given year isn't particularly large.

  • Ben S. said:

    Dr. T:

    The rounding is OK, but the emphasis is on the word "increase." The group with Revlimid maintenance has 3 times as many SPM's as the group without, but has only 2 times of increased risk. I'm not splitting hairs. Since we are talking about human lives, a 3- or 2- fold *INCREASE* surely makes a huge difference.

  • suzierose said:

    @Dr T....OIC..we agree about the evidence for Revlimid increasing SPM

    Does the evidence get muddier, if we recognize the MOA of IMIDs? The data on VEGF inhibition is clear and lenalidomide is a VEGF inhibitor.


    Or, with regard to 'helping", based on RCT (double blind) IFM 2005 was unblinded in 2010 and stopped in 2011 due to SPM in lenalidomide arms. The trial sorts out "helping" given there were 3 arms, with melphalan, i.e.MPR-R, MPR, and MP as the incidence of all invasive SPM was significantly increased in the lenalidomide arms and were predominately hematologic. Or we could look at decades of data, where melphalan has been used in combination with numerous agents without resultant SPM.

    I agree the gold standard for conclusiveness of data does require RCT however that is not likely to be ethical given what has been demonstrated to date necessitating a label change.

    And we should not lessen our concern based on the incidence being low as one of the major reasons the incidence rate may remain low for SPM with lenalidomide is that the drug is on the market, all AE reporting is voluntary and we will not have a denominator for the general population. The only time we have a denominator is in a clinical trial as you are asserting, but then again that is why the low incidence is also the tip of an iceberg having triggered this warning.

    The history of safety surveillance for pharmaceuticals is that it typically takes 5 years post-marketing for the incidence to be high enough to result in a recall, due to the lack of a denominator. Which would make lenalidomide right in the ballpark as it was approved June 2006.

  • suzierose said:

    Beacon Staff,

    When you reported, in March, about the European MM physicians consensus meeting in Paris, MM020 had not reported. The trial is important as it has a maintenance lenalidomide arm without melphalan. Did the trial ever report?


  • tim marciniak said:

    Ok there is no real reason for this post other than I have to write something or go nuts. I will have been on Rev for 2 years this coming June and had my last checkup in March of 2012. So far my numbers are normal...for everything. I am now concerned about being on Rev for more than 2 years and will discuss this with my doctor. Man sometimes we get beat up but remember...every day is not a good day but there is good in every day.
    I appreciate reading other's opinions. It really helps, thanks.

  • Stan said:

    Tim--It sounds like we're in the same boat. I am currently liking my maintenance program of Rev. I hope to keep with it but this report is a little frightening. I have two transplants under my belt, 6 months of pre transplant Rev/dx and now have 6 months post transplant maintenance Rev.
    I'd like to see how University of Arkansas interprets these numbers.
    I wonder if Velcade is a very effective maintenance drug?
    I also wonder how odds would be affected if we stayed on the Rev, ate more vegetables and stayed out of the sun??

  • Mark said:

    Tim and Stan - I too am in the same boat as you gentleman. I have been on Rev for 28 months now post Allo, post Auto, and post initial RVD treatment (before Melphalan and transplants).
    My numbers could not be better, I have been in CR for 26 months. Where do we go from here? I am not sure, but I am thankful for my treatment and results so far. We can only hope for the best in what lies ahead.


  • Myeloma Beacon Staff said:

    The article has been updated with information an FDA spokesperson provided to The Beacon. The new section of the article is labeled with "Update" and can be found here.

  • Bob McMullen said:

    Sometimes it can be disturbing to research MM issues. I was only looking for information about taking 4x200 mg of Acylovir now that I am on 10 mg Revlimid. Diagnosed with early stage one MM in Oct. 2010 and put on Velcade until it lost effectiveness in Nov. 2011. Originally very happy to take my daily pill instead of visiting chemo ward for Velcade needle. And the Revlimid quickly brought all of the blood scores back to the acceptable control ranges. Obviously good news. BUT, now I am reading your comments about secondary cancers! Yippee. And still do not know if I should continue taking Acyclovir .... had a bought of shingles 3 months after diagnosis when on Velcade.

  • Myeloma Beacon Staff said:

    Hi suzierose,

    As best we can tell, no results of the MM-020 trial have been reported yet. Celgene has publicly reported that it expects interim results of the trial to be made public sometime in the second half of this year.

  • Bev said:

    I'm a bit confused by this story. Originally, I thought this was a new warning about secondary cancers. New, as in "2012". I mentioned this article to my husband's oncologist today, and he was unable to confirm any new warnings. He reminded me to always check the original date of anything I read online. So, this evening, I did just that, and I see that this story is actually not "new" news, but rather published on May 9, 2010.

  • Myeloma Beacon Staff said:

    Thanks, Bev, for your comment and question.

    We made an error when we were entering the date information for the update to the article. The year should have been entered as 2012, not 2010. We've corrected the error, and we're sorry for the confusion it created.

    The FDA announcement was made this Monday, May 7, 2012. As mentioned at the end of our article, the announcement is available at the FDA website at this page:


    Good luck!