Effect of Melphalan/Melphalan for Injection on Multiple Myeloma

Multiple myeloma (MM) is the second most common hematologic malignancy, and although an established curative therapy for MM has not yet been established, standard first-line treatments for newly diagnosed MM currently include novel proteosome inhibitors and immunomodulatory drug triplet-based regimens that have demonstrated effective and sustained minimal residual disease (MRD)-negative responses. Melphalan for injection/Melphalan flufenamide is a peptide-drug conjugate prodrug of melphalan, an alkylating cytotoxic chemotherapy drug used to treat multiple myeloma.

Melphalan for injection is an example of taking an established active MM chemotherapy and modifying it to be more targeted in terms of drug delivery. It is a peptide-drug conjugate that interacts with aminopeptidase to specifically release active alkylating agents into cancer cells, avoiding normal cells.

Melphalan for injection is used primarily to treat patients who have received four prior treatments for myeloma. Accelerated approval is based on results from the HORIZON study, which showed an overall response rate of 29% and a median duration of response (mDoR) of 5.5 months in the intention-to-treat population, and an overall response rate of 24% and an mDoR of 4.2 months in the U.S. Food and Drug Administration (FDA)-approved indication subgroup. Adverse events were mainly hematological indicators. While these results do not appear to be serious, they are consistent with what would be expected in a large pretreated patient population and are similar to results with other approved drugs.

The OCEAN confirmatory trial, a study of injectable melphalan or pomalidomide in patients with lenalidomide-refractory RRMM, has reportedly met its primary endpoint of improved progression-free survival compared with pomalidomide. However, in July 2021, the FDA issued an alert stating that injectable melphalan in the OCEAN trial was associated with an increased risk of death and partially shelved the injectable melphalan study. While the details are unclear at this time, subgroup analyzes are underway to determine whether certain patient groups benefit more or less in terms of survival. Several other studies are ongoing, the results of which are yet to be determined.

After discussions withFDA, based on data from the OCEAN Phase III study in October 2021, Melphalan for injection was withdrawn from the U.S. market. Based on existing published data and clinical experience, injectable melphalan may be a valuable tool in the myeloma physician's armamentarium, but it will largely not be clinically available until early signs of death are addressed.