Abstract
Despite the availability of new therapies that have led to improved outcomes for patients with multiple myeloma, most patients will eventually relapse. With triplet and even quadruplet combination therapies becoming standard in the first and second line, many patients will have few treatment options after second-line treatment. Melflufen (melphalan flufenamide) is a first-in-class peptide–drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. Once inside the tumor cells, melflufen is hydrolyzed by peptidases to release alkylator molecules, which become entrapped. Melflufen showed anti-myeloma activity in myeloma cells that were resistant to bortezomib and the alkylator melphalan. In early phase studies (O-12-M1 and HORIZON [OP-106]), melflufen plus dexamethasone has demonstrated encouraging clinical activity and a manageable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma, including those with triple-class refractory disease and extramedullary disease. The Phase III OCEAN study (OP-104) is further evaluating melflufen plus dexamethasone in patients with relapsed/refractory multiple myeloma. The safety profile of melflufen is characterized primarily by clinically manageable hematologic adverse events. Melflufen, with its novel mechanism of action, has the potential to provide clinically meaningful benefits to patients with relapsed/refractory multiple myeloma, including those with high unmet needs.
Highlights
Despite improved outcomes in patients with multiple myeloma following the advent of proteasome inhibitors, immunomodulatory agents (IMiDs), and anti-CD38 monoclonal antibodies, the majority of patients with multiple myeloma will eventually relapse [1,2]
This review describes the historical development of melflufen, its mechanism of action, and the ongoing clinical development program for melflufen in multiple myeloma
Given that current standard-of-care regimens utilize triplet and quadruplet combination regimens in the first and second lines, there will likely be a large unmet need for patients with multiple myeloma that is refractory to multiple agents in the second line and beyond [2,3,15]
Summary
Despite improved outcomes in patients with multiple myeloma following the advent of proteasome inhibitors, immunomodulatory agents (IMiDs), and anti-CD38 monoclonal antibodies, the majority of patients with multiple myeloma will eventually relapse [1,2]. New therapies with novel mechanisms of action that are tolerable are needed for third-line treatment and beyond, for patients with relapsed and/or refractory multiple myeloma who have disease that is refractory to standard-of-care agents including IMiDs, proteasome inhibitors, and anti-CD38 antibodies. The US Food and Drug Administration granted accelerated approval to selinexor in July 2019, a selective inhibitor of exportin 1, in combination with dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received ≥4 prior lines of therapy and whose disease is penta-refractory (i.e., ≥2 proteasome inhibitors, ≥2 IMiDs, and ≥1 anti-CD38 monoclonal antibody) [20]. In the Phase II DREAMM-2 study, belantamab mafodotin, an anti-BCMA antibody–drug conjugate, has demonstrated single-agent activity and a manageable safety profile in patients with relapsed/refractory multiple myeloma who had received ≥3 lines of therapy and were refractory to an IMiD, a proteasome inhibitor, and an anti-CD38 antibody (n = 196) [26]. This review describes the historical development of melflufen, its mechanism of action, and the ongoing clinical development program for melflufen in multiple myeloma
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