Combined with dexamethasone, melflufen may be efficacious among patients with heavily pretreated relapsed and refractory multiple myeloma (MM), according to research published in the Journal of Clinical Oncology.

While novel therapies have improved outcomes in patients with MM over the past several decades, treatment resistance remains a significant problem in this patient population. Many patients resistant to primary treatment show multidrug resistance as early as the second line of therapy, and patients with triple-class refractory disease are in urgent need of novel therapy options.

Melflufen (melphalan flufenamide), a first-in-class peptide-drug conjugate that has been established to selectively release alkylating agents into cancer cells, previously showed promise in a phase 1/2 study of relapsed and refractory MM. The conjugate may be active even in cells with impaired p53 function. For the phase 2 HORIZON study ( Identifier: NCT02963493), researchers further evaluated the safety and efficacy of melflufen in relapsed and refractory MM.

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Of the 157 patients included in the intention-to-treat population, 119 patients (76%) were considered triple-class refractory. The median patient age was 65 years (range, 35-86), 57% of patients were men, the median number of prior lines of therapy was 5 (range, 2-12), and 38% of patients had high-risk cytogenetics. In addition, 59% of patients were refractory to previous alkylator therapy.

The median follow-up was 14 months. In the all-treated population, the overall response rate was 29%, the median duration of response was 5.5 months, the median progression-free survival was 4.2 months, and the median overall survival was 11.6 months. In the triple-class refractory group, the overall response rate was 26%. One stringent complete response was noted in the all-treated population; no complete responses were noted.

Grade 3 or worse adverse events were noted in 96% of patients, including neutropenia (79%), thrombocytopenia (76%), and anemia (43%). The most common grade 3 or worse nonhematologic event was pneumonia (10%).

“In conclusion, the results from HORIZON suggest that melflufen has the potential to be an important therapeutic option in [relapsed and refractory] MM by providing a novel mechanism of action, clinically meaningful efficacy, and manageable safety when combined with dexamethasone in heavily pretreated patients,” the authors wrote.

Disclosure: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Richardson PG, Oriol A, Larocca A, et al. Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma. J Clin Oncol. Published online December 9, 2020. doi:10.1200/JCO.20.02259