FDA Warns of Death Risk in Ongoing Multiple Myeloma Clinical Trial

A warning from the FDA highlights that an increased rate of death has been observed in patients with multiple myeloma who are undergoing treatment with the FDA-approved agent melphalan flufenamide (Pepaxto) in combination with dexamethasone in the phase 2 OCEAN clinical trial (NCT03151811).¹

Considering the impact on overall survival (OS) in patients who are enrolled, the FDA has required suspension of the study’s enrollment. However, patients who are deriving benefit from the study combination are permitted to continue treatment.

Melphalan flufenamide received accelerated approval from the FDA in February 2021 for the treatment of adult patients with relapsed or refractory multiple myeloma, who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody. The approval was based on findings from the phase 2 HORIZON trial (NCT02963493), which showed a clinically meaningful efficacy in the patient population along with a manageable safety profile.²

A total of 157 patients were assessed in the study for the primary end point of investigator-assessed overall response rate (ORR), as well as the secondary end point of duration of response (DOR), progression-free survival (PFS), OS, and safety. Treatment with melphalan flufenamide and dexamethasone were received by 131 patients from the intention to treat (ITT) population.¹

At data cutoff, 26 patients remained in the study and were evaluable for efficacy. The ORR observed was 29% (95% CI, 22%-37%) in the overall population, which included 1 stringent complete response (sCR), 17 very good partial responses (VGPRs), 28 partial responses (PRs), and 25 minimal responses for a clinical benefit rate (CBR) of 45% (95% CI, 37%-53%). In the triple-class refractory population, the ORR was 26% (95% CI, 18%-35), which included 13 VGPRs, 18 PRs, and 16 patients with minimal responses, which calculated to a CBR of 39% (95% CI, 31%-49%).

Investigators of the HORIZON study measured DOR only in patients who achieved a PR or better on treatment with melphalan flufenamide in combination with dexamethasone. In all patients who received treatment, the median DOR was 5.5 months (95% CI, 3.9-7.6), and the DOR was 4.4 months (95% CI, 3.4-7.6) in the triple-class refractory population.

Survival outcomes were also reported for the combination of melphalan flufenamide and dexamethasone, showing a median PFS of 4.2 months (95% CI, 3.4-4.9) in the overall population and a median PFS of 3.9 months (95% CI, 3.0-4.6) in the triple-refractory group. In terms of OS, the median was 11.6 months (95% CI, 9.3-15.4) and 11.2 months (95% CI, 7.7-13.2), respectively.

In terms of safety, all patients in the study experienced treatment-emergent adverse events (TEAEs), and 90% had grade ≥ 3 TEAEs. Of the grade ≥ 3 TEAEs observed, the most common included hematologic in nature were thrombocytopenia (76%), and anemia (43%). The most common nonhematologic treatment-emergent grade 3/4 events were pneumonia, and hypophosphatemia.

Serious TEAS were also observed in 39% of patients with pneumonia (9%) and febrile neutropenia (5%) being the most common.

After demonstrated clinical benefit and being approved by the FDA, continued approval of the agent for this indication in contingent on confirmation of benefit in the OCEAN study, which is designed as a randomized, controlled, open-label study that compares the efficacy and safety of melphalan flufenamide in combination with dexamethasone to the combination of pomalidomide (Pomalyst)and dexamethasone in approximately 495 patients with relapsed or refractory multiple myeloma who are refractory to lenalidomide.

The primary end point of OCEAN is PFS, and the secondary end points are ORR, DOR, OS, and safety/tolerability.

The OCEAN trial is under ongoing evaluation by the FDA to assess it safety, and to explore marketing of the drug going forward. Clinicians and their patients are being encouraged by the FDA to report adverse events and other issues that occur during the study to the MedWatch Adverse Event Reporting Program.

_Reference:

_{1. FDA alerts patients and health care professionals about clinical trial results showing an increased risk of death associated with Pepaxto (melphalan flufenamide). News release. FDA. July 28, 201. Accessed July 28, 2021. https://bit.ly/3zPs0vD}

_{2. FDA approves Oncopeptides' PEPAXTO® (melphalan flufenamide) for patients with relapsed or refractory multiple myeloma. News release. Oncopeptides, AB. February 26, 20201. Accessed July 28, 2021.}

_{3. Richardson PG, Oriol A, Larocca A, et al. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol. 2021;39(7): 757-767. doi: 10.1200/JCO.20.02259}