The FDA has issued an alert that evidence from the phase 3 OCEAN study of melphalan flufenamide, which was recently approved for use in combination with dexamethasone in patients with relapsed or refractory multiple myeloma, has indicated that the doublet resulted in an increased risk of death in this population.
The FDA has issued an alert that evidence from the phase 3 OCEAN study (NCT03151811) of melphalan flufenamide (melflufen; Pepaxto), which was recently approved for use in combination with dexamethasone in patients with relapsed or refractory multiple myeloma, has indicated that the doublet resulted in an increased risk of death in this population.1
In the multicenter, open-label phase 3 trial, investigators examined melphalan flufenamide plus dexamethasone vs pomalidomide (Pomalyst) plus dexamethasone in patients with relapsed or refractory multiple myeloma who had received 2 to 4 prior lines of therapy and were resistant to lenalidomide (Revlimid) in the last line of therapy.2
In the statement, the regulatory agency encouraged that the progress of patients who are receiving melphalan flufenamide be assessed and that the risks of continued administration be discussed with each recipient in the context of other options.
“Due to the detrimental effect on overall survival [OS] in the OCEAN trial, FDA is requiring the manufacturer suspend enrollment in the trial,” according to the alert. “FDA has also suspended enrollment in other ongoing [melphalan flufenamide] clinical trials.”
Notably, patients who are deriving clinical benefit from melphalan flufenamide can continue to receive treatment on the OCEAN trial if they have been informed about the potential risks and they sign a revised written informed consent.
The FDA will continue to assess findings from the trial and shared potential plans to hold a public meeting in the future to further discuss these safety data and explore the continued marketing of the drug. Oncopeptides AB, the drug developer, shared plans to submit complete findings from the trial to the 2021 International Myeloma Workshop meeting.3
To be eligible to enroll to OCEAN, patients needed to be at least 18 years of age, have documented disease progression, measurable disease, a life expectancy of at least 6 months, and an ECOG performance status of 0 to 2.2
If patients had primary refractory disease; evidence of mucosal or internal bleeding, or platelet transfusion refractory; previous exposure to pomalidomide; a known intolerance to immunomodulatory drugs (IMiD); a known infection that required parenteral or oral anti-infective treatment within 14 days of randomization; or another malignancy diagnosed or requiring treatment within the past 3 years, they were excluded.
Study participants were randomized to receive either melphalan flufenamide at 40 mg on day 1 plus dexamethasone at 40 mg on days 1, 8, 15, and 22 of each 28-day cycle or pomalidomide at a daily dose of 4 mg for days 1 through 21 plus the same schedule of dexamethasone. Notably, patients who were 75 years of age or older received a reduced 20-mg dose of dexamethasone on days 1, 8, 15, and 22, irrespective of the arm they were randomized to.
Treatment was administered until progressive disease, intolerable toxicity, or decision to discontinue. Dose modifications and delays were permitted based on tolerability.
The primary end point of the trial was progression-free survival (PFS) per independent review committee assessment. Key secondary end points included overall response rate (ORR), duration of response (DOR), and OS, as well as safety and tolerability.
At a data cutoff of February 3, 2021, a total of 495 patients had been randomized and were included in an efficacy analysis.4
Results indicated that the median OS in those who received melphalan flufenamide/dexamethasone was 19.7 months (95% CI, 15.1-25.6) vs 25.0 months (95% CI, 18.1-31.9) in those who were given pomalidomide/dexamethasone (HR, 1.104; 95% CI, 0.846-1.441); this was indicative of a detriment in survival in the investigative arm vs the control arm.
Additional safety and efficacy analyses of OCEAN are ongoing.
Previously, in February 2021, the FDA granted approval to melphalan flufenamide for use in combination with dexamethasone in adult patients with relapsed/refractory multiple myeloma, who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor (PI), 1 IMiD, and 1 CD38-directed monoclonal antibody.5
The decision was supported by findings from the phase 2 HORIZON trial (NCT02963493), which enrolled a total of 157 patients with relapsed/refractory multiple myeloma who had previously received 2 or more lines of therapy, were exposed to an IMiD and a PI, and were refractory to pomalidomide and/or daratumumab (Darzalex). Notably, patients had either triple-refractory disease and/or extramedullary disease (EMD) and/or high-risk cytogenetic characteristics.
Patients received melphalan flufenamide at a dose of 40 mg on day 1 plus dexamethasone at a dose of 40 mg on days 1, 8, and 15. Again, patients aged 75 years or older received dexamethasone at a reduced dose of 20 mg. Treatment was given in 28-day cycles until patients experienced disease progression or intolerable toxicity.
The primary end point of the trial was ORR, and secondary end points comprised clinical benefit rate, progression-free survival, OS, DOR, time to response, time to next treatment, safety, and health-related quality of life.
Results showed that the combination induced an ORR of 23.7% in this heavily pretreated population. Moreover, the DOR was 4.2 months in these patients. The doublet was also found to have activity in patients with extramedullary disease (41%).
Grade 3 or 4 toxicities that were most frequently reported with the doublet included neutropenia (79%), thrombocytopenia (76%), and anemia (43%). The most common grade 3 or 4 non-hematologic toxicity was pneumonia (10%).6