The results of the phase III OCEAN study (NCT03151811) published earlier this year gave the myeloma research community a moment to ponder. This global trial randomized patients with relapsed/refractory multiple myeloma (RRMM) with two to four prior lines of therapy and lenalidomide refractoriness to receive either melphalan flufenamide (melflufen) plus dexamethasone (mel/dex) or pomalidomide plus dexamethasone (pom/dex). The trial was expected to back the accelerated approval of melflufen that was initially granted in February 2021 by the U.S. Food and Drug Administration (FDA), based on data from the phase II HORIZON trial (NCT02963493). Melflufen is a peptide-drug conjugate developed as a delivery vehicle for melphalan to myeloma cells, with more predictable pharmacokinetics than melphalan hydrochloride. However, the OCEAN trial drew wide public attention in July 2021 after the FDA announced a partial hold on all trials involving melflufen due to preliminary overall survival (OS) data favoring the control arm in an intention-to-treat analysis (hazard ratio [HR], 1.1; 95% CI, 0.8-1.4). Shortly thereafter, the manufacturer requested a voluntary withdrawal of the drug from the U.S. market.
The authors of the OCEAN study provided complete data for readers to consider and offer their own perspectives on outcomes. First, they showed that the study met its primary end point, demonstrating a significantly higher progression-free survival (PFS) in the melflufen arm, with an HR of 0.79 (95% CI, 0.64-0.88; p=0.03). Second, the authors argued that the five-month difference in median OS between the two arms (19.8 months with mel/dex vs. 25 months with pom/dex) was not statistically significant, and that data were not sufficiently mature. Third, they presented results of an exploratory post-hoc analysis in which patients without prior exposure to high-dose melphalan (HDM; ~50%) seemed to derive OS benefit from treatment with melflufen (HR, 0.78; 95% CI, 0.55-1.1; p=0.2), whereas those with prior transplant are shown to be negatively affected by the drug. The authors postulated this may be due to decreased hematopoietic reserve and/or development of resistance mechanisms to alkylators following HDM treatment, and they concluded that the role for melflufen may be limited to non-transplanted patients with RRMM.
This hypothesis certainly merits further investigation. However, even if it is prospectively validated in an adequately powered study of non-transplanted patients with RRMM, the underwhelming results of the OCEAN study in the larger context of current and forthcoming RRMM therapies make it difficult to justify using melflufen in clinical practice. This is especially true for hematologists practicing in affluent countries where novel therapies are increasingly available, and where doublets such as pom/dex are no longer considered to be standard of care in this setting because multiple triplets have demonstrated superiority over doublets in head-to-head trials (e.g., APOLLO, ICARIA, ELOQUENT-3).
In Brief
Following the publication of the OCEAN trial, the manufacturer of melflufen announced in early 2022 it would rescind its voluntary withdrawal of the drug from the U.S. market, leading to speculation about whether the longer-term OS follow-up from the OCEAN trial and/or other melflufen studies may have shown benefit in certain RRMM subsets. However, the key question is whether there is a role for melflufen in the rapidly evolving MM therapeutic landscape presently ruled by chimeric antigen receptor T-cell therapies, T-cell redirection therapies, CelMods, and novel small molecules.
Competing Interests
Dr. Thibaud and Dr. Usmani indicated no relevant conflicts of interest.
