The U.S. Food and Drug Administration (FDA) announced last week that it is investigating the safety of the multiple myeloma drugs Revlimid and thalidomide.  The Beacon covered this development in an earlier article ^[1].  More details are provided here about why the FDA is conducting the investigation and the possible outcomes of that investigation.  These questions and answers have been developed in consultation with the FDA.

Why is the FDA investigating the safety of Revlimid and thalidomide?

In December, intermediate results from three clinical trials studying long-term use of Revlimid ^[2] (lenalidomide) showed that multiple myeloma patients who received Revlimid may be at an increased risk for developing a second cancer, as compared to patients who received a placebo.

In two of these studies, Revlimid was used as maintenance therapy after stem cell transplantation.  In the third study, Revlimid was used in combination with melphalan ^[3] (Alkeran) and prednisone ^[4] for elderly, newly diagnosed myeloma patients.  Neither of these uses is currently approved by the FDA, although they are still legal – and not uncommon – uses in the United States.

Revlimid is currently approved by the FDA for use with dexamethasone ^[5] (Decadron) to treat multiple myeloma patients who have already received another treatment.  It is also approved to treat certain patients with a group of blood disorders known as myelodysplastic syndromes ^[6].  No evidence so far has suggested a connection between these approved uses of Revlimid and elevated rates of second cancers.

Given that recent studies have suggested Revlimid maintenance therapy may put patients at higher risk of developing second cancers, the FDA is reviewing all approved and investigational uses of Revlimid, including use in multiple myeloma and also myelodysplastic syndromes.

No studies have suggested that thalidomide may be linked to higher rates of second cancers.  However, since thalidomide ^[7] (Thalomid) is chemically similar to Revlimid, the FDA is also reviewing the safety of thalidomide.  It is standard procedure for the FDA to investigate related compounds if the safety of one is in question.

Are reviews such as this one common?

Once a drug is approved by the FDA, safety reviews are not common.  However, the FDA continues to monitor all drugs after they are approved, and it will investigate the safety of a drug if any data emerge suggesting the drug may not be as safe as believed when it was first approved.

How long can the review be expected to take?

Reviews such as this typically take a few months.  The FDA may be waiting on data from some of the ongoing clinical trials to allow it to complete its review.

Who typically conducts these reviews?

Safety reviews are typically conducted by FDA staff, who may consult with temporary Special Government Employees, members of the Oncologic Drugs Advisory Committee (ODAC), and potentially other individuals without conflicts of interest if they are needed to understand the data and situation at hand.  The ODAC is the committee of outside scientific experts that advises the FDA in regard to the approval of new oncology drugs and changes to the approved use of already marketed oncology drugs.

What are the possible outcomes of this review?

According to the FDA, the agency may conclude that there is no safety problem, that further investigation is needed, or the agency can modify the prescribing information or the approved uses of Revlimid and thalidomide.

Although it is theoretically possible that the FDA could revoke its approval for the sale and use of Revlimid or thalidomide, these drugs have demonstrated clear benefits for multiple myeloma patients, so such an outcome is considered highly unlikely.

If a link is found between Revlimid or thalidomide and second cancers, a warning could be placed on their official prescribing information, their use as maintenance therapy might not be approved by the FDA, or a cap might be placed on the length of time they are recommended to be used.

Until the FDA review is complete, should patients continue taking Revlimid and thalidomide?

The FDA recommends at this time that patients taking Revlimid or thalidomide should continue to take their medications as prescribed by their physician.  The agency even went as far as to say that they believe the benefits of Revlimid outweigh the safety concerns.

Will this review have any impact on pomalidomide’s anticipated approval as a multiple myeloma treatment?

Pomalidomide ^[8] (CC-4047) is also chemically related to Revlimid and thalidomide.  It is in Phase 3 clinical trials as a potential multiple myeloma treatment and is expected to be submitted to the FDA for approval in the near future.  The FDA, however, is prohibited from commenting on how its investigation into the safety of Revlimid and thalidomide may impact the application for approval of pomalidomide or any other drugs that may now, or in the future, be under review by the FDA.

For more information, see the Beacon’s announcement about the FDA investigation ^[1] and the rest of the Beacon articles about the Revlimid controversy ^[9].