The peptide-drug conjugate melphalan flufenamide (melflufen) “showed clinically meaningful efficacy” in patients with heavily pretreated relapsed and refractory multiple myeloma (RRMM) in the phase 2 HORIZON trial, researchers reported inthe Journal of Clinical Oncology.

“Melflufen, when combined with dexamethasone, has the potential to fill this unmet medical need by providing a novel mechanism of action, clinically meaningful efficacy, and manageable safety in patients with RRMM,” the researchers stated, adding that melflufen could be “an important therapeutic option.”

According to the researchers, melflufen targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells.

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“Unlike previous aminopeptidase-targeting therapies that directly inhibit aminopeptidase activity, melflufen takes a novel approach by leveraging increased aminopeptidase activity to selectively direct potent cytotoxic agents into tumor cells,” the researchers explained.

“Melflufen and its metabolites trigger robust and irreversible DNA damage, have antiangiogenic effects, induce apoptosis — resulting in potent antitumor activity in myeloma cells, including those with resistance to melphalan, bortezomib, and dexamethasone — and, importantly, retain activity in myeloma cells with absent or impaired p53 function,” they continued.

The HORIZON trial ( Identifier: NCT02963493) included 157 patients with disease refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. The median age of the study population was 65 years, and the patients had received a median of 5 prior lines of therapy.

The patients received melflufen at 40 mg intravenously on day 1 of each 28-day cycle, in combination with once-weekly oral dexamethasone at 40 mg.  The primary endpoint was overall response rate.

The overall response rate was 29%, with a 26% response rate in the 76% of patients with triple-refractory disease.

In the treated population, the median duration of response was 5.5 months, and the median progression-free survival was 4.2 months. The median overall survival was 11.6 months.

In the triple-refractory population, the median progression-free survival was 3.9 months, and the median overall survival was 11.2 months.

The majority of patients reported at least 1 treatment-emergent adverse event (TEAE). The most common grade 3 or worse TEAEs were neutropenia (79%), thrombocytopenia (76%), and anemia (43%).

Serious TEAEs occurred in about half of the patients (49%), the most common of which were pneumonia (9%) and febrile neutropenia (5%).

Based on these results, melflufen is being investigated further in the phase 3 OCEAN (OP-103) trial ( Identifier: NCT03151811) in patients in earlier relapse.

Disclosures: This clinical trial was supported by Oncopeptides AB. Please see the original reference for a full list of authors’ disclosures.


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