Multiple myeloma patients participating in the international MM-015 study will continue to receive Revlimid maintenance treatment, despite concern that there might be a link between such treatment and a higher risk of developing second cancers.  Celgene, the manufacturer of Revlimid, confirmed yesterday that no changes are currently planned for the trial protocol.

In a statement provided to The Myeloma Beacon, Dr. Antonio Palumbo, chief of the Myeloma Unit at the University of Torino in Italy and lead investigator of the MM-015 study, suggested that the benefits of Revlimid (lenalidomide) maintenance therapy outweigh the potential increased risk of a second cancer:

“Without maintenance, the risk of myeloma relapse at two years is 50 percent, and the risk of a second cancer at two years is 1 percent.  Relapse of myeloma should be considered quite similar to the occurrence of a second cancer.  Therefore, the cumulative risk of myeloma relapse plus a second cancer is 51 percent.

With lenalidomide [Revlimid] maintenance, the risk of myeloma relapse at 2 years is 25 percent, and the risk of a second cancer at two years is 4 percent.  The cumulative risk of myeloma relapse plus a second cancer is 29 percent.

Patients should be informed of the benefit/risk ratio of both options.”

Concerns that Revlimid maintenance therapy might increase a multiple myeloma patient’s risk of developing a second cancer emerged in December when results from the MM-015 study and two other studies showed more reported cases of second cancers in patients receiving Revlimid maintenance than those receiving a placebo.

Since then, investigators of the French IFM 2005-02 study announced an amendment to the study’s treatment protocol in which Revlimid dosing would be discontinued.  Investigators of the U.S.-based CALGB 100104 study announced that their trial would continue as originally planned.

Although the rate of second cancers was higher in the Revlimid arms of the MM-015 trial, Dr. Palumbo said the rate was not significantly different from the rate of second cancers observed in the general public.

According to Dr. Palumbo, 1.66 percent of participants receiving melphalan (Alkeran), prednisone, and Revlimid followed by Revlimid maintenance (MPR-R) or placebo (MPR) developed a second cancer per year of follow-up.  This was significantly higher than the 0.66 percent of participants receiving melphalan and prednisone (MP) without any Revlimid therapy who developed a second cancer during each year of follow-up.

Within the general population, at least 1.82 percent of people 65 years and older would be expected to develop cancer each year, Dr. Palumbo said.  The rates of second cancers in the MM-015 study would indicate that Revlimid, used in this manner, does not increase the risk of second cancer.  However, it is not clear how carefully the MM-015 participants were tracked for second cancers, particularly once they relapsed.

Although the overall rate of second cancers was within the expected range, Dr. Palumbo said that the 1 percent rate of acute myeloid leukemia (AML) and myelodysplastic syndromes per year of follow-up was higher than expected.

An RBC Capital Markets report from last week said, “Celgene also believes that there was an imbalance of patients with high-risk cytogenetics [chromosomal abnormalities] in the Revlimid arms versus control in MM-015.  Specifically, there were nine patients who had a rare ‘triple mutation’ that confers higher risk to AML and all were in the Revlimid arm.  Of the five cases of AML, cytogenetics was available for three, and all three had the triple mutation.”  A spokesperson from Celgene confirmed this information in discussions with The Beacon earlier today.

For more information about the secondary cancer concern, please see the previous Beacon news coverage on the topic.