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 ^[1] (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 ^[2] 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 ^[3] (Thalomid), which is chemically similar to Revlimid (see related Beacon ^[4] 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 ^[5].

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 ^[6] [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 ^[7] [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.