The use of pembrolizumab (Keytruda) in combination with dexamethasone and either lenalidomide or pomalidomide is associated with an increased risk of death in patients with multiple myeloma, according to an alert from the Food and Drug Administration.

The FDA issued the alert on Aug. 31 to inform the public, health care professionals, and oncology clinical investigators of the risk, which became apparent during the course of two now-halted clinical trials.

Pembrolizumab is not approved for the treatment of multiple myeloma, but was being evaluated for this purpose, in combination with other treatment, in the phase 3 randomized, controlled KEYNOTE-183 and KEYNOTE-185 trials. The FDA statement is based on a review of data from these two trials.

Among 249 patients in KEYNOTE-183, which evaluated pomalidomide and low-dose dexamethasone with or without pembrolizumab in patients with relapsed and refractory multiple myeloma who had received at least two prior lines of therapy, the relative risk of death was increased more than 50% among those in the pembrolizumab-containing investigational arm, compared with the control arm (hazard ratio, 1.61).

Among 301 patients in KEYNOTE-185, which evaluated lenalidomide and low-dose dexamethasone with or without pembrolizumab in patients with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplant, the relative risk of death was nearly doubled in the pembrolizumab-containing investigational arm, compared with the control arm (hazard ratio, 2.06).

“On July 3, 2017, the FDA required that all patients in these trials be discontinued from further investigation with this drug, because interim results from both trials demonstrated an increased risk of death for patients receiving Keytruda when it was combined with an immunomodulatory agent as compared to the control group,” according to the statement . “Merck & Co., Inc. [the maker of Keytruda] was made aware of the issue through an external data monitoring committee recommendation and suspended the trials to enrollment on June 12, 2017.”

The FDA statement and actions by Merck do not apply to patients using the drug for approved indications, which include melanoma, lung cancer, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high (MSI-H) cancer.

“Patients on Keytruda for an approved use should continue to take their medication as directed by their health care professional,” according to the FDA, which noted in its statement that the agency will be working directly with sponsors and investigators of other ongoing trials of the drug and other PD-1/PD-L1 cancer drugs to “determine the extent of safety issues.”

In a separate statement , Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research further stressed that the FDA is “actively examining the data from the Keytruda trials and working directly with Merck to better understand the true cause of the safety concerns.”

“The FDA will take appropriate action as warranted to ensure patients enrolled in these trials are protected and that doctors and clinical trial researchers understand the risks associated with this investigational use. We are communicating now, given the serious nature of the safety issue, to remind doctors and patients that Keytruda is not approved for the treatment of multiple myeloma and should not be given to patients in combination with any immunomodulatory agents, including Revlimid (lenalidomide) and Pomalyst (pomalidomide), for the treatment of multiple myeloma,” she said.

Health care professionals and consumers are encouraged to report adverse events and side effects related to Keytruda or similar product to FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/MedWatch/report , or by calling 800-332-1088 to request a reporting form.

sworcester@frontlinemedcom.com

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