There have been several additional developments in the past few weeks related to concerns about a potential link between Revlimid and secondary cancers.

A group of myeloma researchers issued a joint statement on the issue; the European Medicines Agency has begun an investigation into Revlimid’s risks and benefits; and there are subtle signs – but no official confirmation – that the U.S. Food and Drug Administration may be conducting its own investigation into Revlimid and its safety.

As the Beacon announced last week, a group of myeloma researchers has issued a statement regarding the occurrence of secondary cancers after treatment with Revlimid ^[1] (lenalidomide).  (See related Beacon ^[2] news.)

The group of researchers was called together as an advisory board arranged by Celgene, the company that markets Revlimid.  The advisory board includes a number of leading European myeloma researchers as well as the lead investigators of all three clinical trials that have reported data showing higher rates of secondary cancer among patients receiving Revlimid maintenance therapy.

Members of company-sponsored advisory boards typically are reimbursed by the sponsor for their travel expenses and are paid an honorarium for their time.  Celgene has not yet responded to a Myeloma Beacon inquiry asking whether members of this advisory board were compensated by the company.

The advisory board’s statement says that the risk of developing a secondary cancer after exposure to Revlimid depends on whether the patient is newly diagnosed or relapsed / refractory, and on whether the patient has received certain types of chemotherapy.

The statement notes, for example, that an increased risk of secondary cancer has only been seen in newly diagnosed patients who are treated with DNA-damaging chemotherapy at the same time or prior to Revlimid therapy.  This will often be the case, however, as a number of chemotherapies commonly used to treat myeloma patients are known to damage DNA, including cyclophosphamide ^[3] (Cytoxan), melphalan ^[4] (Alkeran), busulfan ^[5] (Myleran),  cisplatin (Platinol), and etoposide (VP-16).

“The missing bullet in the [advisory board’s statement] is that a significant increase in second cancers has been noted in patients receiving post-transplant lenalidomide [Revlimid] maintenance compared with those receiving placebo in both Phase 3 studies reported so far,” said Dr. S. Vincent Rajkumar from the Mayo Clinic in response to the board’s statement.  “This finding needs to be studied closely to determine whether 1) the risk is real, 2) there are confounders, and 3) the risk is related to duration of such therapy.”

Three studies have shown that Revlimid used as maintenance therapy after stem cell transplantation or in combination with melphalan and prednisone ^[6] in newly diagnosed patients significantly increases progression-free survival.  However, the board notes that an increase in overall survival in these studies has not yet been shown.

The advisory board also states that results of 11 Celgene-sponsored clinical trials indicate that Revlimid does not appear to increase the risk of secondary cancers when it is used to treat relapsed / refractory patients, regardless of whether the patients have been treated with DNA-damaging chemotherapy.

The board’s statement concludes by saying that, until more follow-up data is available, Revlimid should be used in clinical trials studying the rate of secondary cancers and in “defined clinical indications.”  Dr. Philip McCarthy, one of the advisory board members and lead investigator of the U.S.-based trial studying Revlimid maintenance therapy, clarified that “defined clinical indications” should be interpreted as approved and commonly accepted uses of Revlimid.

In Europe, Revlimid is officially approved for use with dexamethasone ^[7] (Decadron) in myeloma patients who have received at least one prior therapy.  It is uncommon for the drug to be used differently in Europe due to government and insurance restrictions.

In the United States, Revlimid’s officially-approved use is the same as in Europe.  However, it frequently is used in the U.S. as first-line therapy, and it also is used as single-agent maintenance therapy for select patients, particularly those who are at high risk of relapsing.

In a separate development, the European Medicines Agency on March 18 announced ^[8] that it would begin reviewing the benefits and risks of Revlimid due to its potential link to secondary cancers.  The agency will assess whether current safety and efficacy data impact the balance between the benefits and risks of Revlimid’s approved use.

Such a review is uncommon but not unheard of.  Last year, the European Medicines Agency (EMA) – which acts as a kind of Europe-wide equivalent to the U.S. Food and Drug Administration – conducted similar reviews of about 5 percent of EMA-approved medicines.  Celgene representatives have told the Beacon that they expect the review will take 3 to 6 months to complete.

The Agency’s review could result in no changes for the use of Revlimid in Europe; changes to the drug’s official prescribing information, such as the addition of warnings or restrictions; or a suspension or revocation of Revlimid’s approval for use in Europe.  The most common result of such investigations is a change in the drug’s official prescribing information.

In the meantime, the Agency recommends that European physicians and patients continue to use Revlimid according to its approved use until the Agency’s review is complete.  It does not recommend delaying, modifying, or restricting use of Revlimid.  It also recommends that clinical trials studying other uses of Revlimid should continue enrollment and treatment of participants.

Finally, in a separate but related development, the Beacon has received subtle, and admittedly indirect, evidence that the U.S. Food and Drug Administration (FDA) may be carrying out an investigation similar to the one recently initiated by the EMA.

Specifically, when the Beacon recently inquired as to whether the FDA was conducting a similar investigation, a spokesperson responded that “there is nothing that [the FDA] can say publicly on this topic at this stage.”

In addition, Celgene's press representatives have not responded to several email and phone requests for comment on whether there is an ongoing FDA investigation into Revlimid and its safety.

More data on the Revlimid maintenance studies are expected to be published at the upcoming International Myeloma Workshop in May and the American Society of Clinical Oncology meeting in June.  The International Myeloma Working Group will also meet in May and may issue recommendations related to the issue.