LENALIDOMIDE INCREASES RISK OF SECONDARY MALIGNANCIES 

May 7, 2012 — The US Food and Drug Administration (FDA) has updated its safety review regarding the risk for secondary primary malignancies in patients with newly diagnosed multiple myeloma who received lenalidomide (Revlimid, Celgene).

New safety information has been added to the warnings and precautions section of lenalidomide's label, informing both healthcare providers and patients of the risk for a secondary primary malignancy. In particular, patients face a greater risk for acute myelogenous leukemia (AML), myelodysplastic syndromes (MDS), and Hodgkin lymphoma.

Healthcare providers need to monitor patients closely for the development of a secondary cancer. The FDA also advises that both the potential benefit of lenalidomide and the risk for a serious adverse event need to be weighed when considering treatment with this agent.

The label change is a follow-up to the April 2011 FDA communication about the agency's ongoing safety review of lenalidomide. At that time, the FDA alerted the public and the healthcare community that they were aware of results of clinical trials that were conducted inside and outside the United States that showed an increased incidence of certain second primary malignancies in patients treated with this agent.

At that time, the FDA did not recommend delaying, modifying, or restricting the use of lenalidomide in the treatment of conditions for which it is indicated. The FDA also noted that they believed that the "benefits of Revlimid continue to outweigh the potential risks" and recommended that patients continue to follow the advice of their healthcare providers.

The European Medicines Agency concurred with this assessment. In September 2011, the agency concludedthat the benefit/risk balance for lenalidomide was positive for the currently approved patient population, despite its association for an increased risk for cancer development. At that time, the agency advised that the prescribing information for the drug be updated with a warning and that clinicians be advised about the risk for new cancers developing in treated patients.

Clinical Data

At this time, lenalidomide is approved for use in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. It also has an indication for the treatment of patients with transfusion-dependent anemia resulting from low- or intermediate-risk MDS associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.

A pooled analysis of the 3 prospective, randomized clinical trials, conducted in patients with newly diagnosed multiple myeloma, showed 65 second primary malignancies among 824 patients in the group that received lenalidomide. This was compared with 19 second primary malignancies among 665 patients in the treatment groups that did not include lenalidomide maintenance (7.9% vs 2.8%; P < .001).

This was nearly a 3-fold increase in the number of new malignancies, and overall, 30 second primary hematologic malignancies (3.6%) were reported in the lenalidomide treatment groups (22 MDS/AML, 5 Hodgkin lymphoma, 3 B-cell acute lymphoblastic leukemia) compared with 2 cases of AML (0.3%) in the groups that did not receive the agent.

However, according to the current data, there does not appear to be a difference in the incidence of nonmelanoma skin cancers or solid tumors.

The FDA also assessed a retrospective pooled analysis of second primary malignancies from 2 clinical trials that were conducted in 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 who received lenalidomide/dexamethasone and placebo/dexamethasone, respectively.

The higher incidence rate of second primary malignancies in the group receiving lenalidomide was largely accounted for by the higher incidence of nonmelanoma skin cancers (2.4 vs 0.91 per 100 person-years, respectively), the FDA notes.

In the pooled analysis, patients who received lenalidomide also received treatment for a longer time (467 person-years vs 218.7 person-years, respectively). When adjustments were made for differences in observation time on-study, the incidence rate of invasive nonmelanoma skin cancers was not substantially different between the 2 groups (1.71 vs 0.91 per 100 person-years, respectively).

The FDA recommends that healthcare providers encourage patients to read the medication guide when they receive their prescription and to report adverse events involving lenalidomide to the FDA MedWatch program.