Melflufen plus Dexamethasone in Patients with RRMM Refractory to Pomalidomide and/or an Anti-CD38 Monoclonal Antibody

The HORIZON study is a phase 2 single-arm, multicenter study of patients with relapsed/refractory multiple myeloma who have had ≥2 prior lines of therapy, including an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI), and who were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. The study aimed to evaluate the efficacy and safety of melflufen, a novel peptide-drug conjugate that delivers an alkylating payload into tumor cells, plus dexamethasone. The primary end point was overall response rate (ORR) defined as the ORR plus partial response per the International Myeloma Working Group criteria and assessed by an investigator. Secondary end points included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. A post-hoc analysis was performed based on extramedullary disease, alkylator- and triple-class refractory multiple myeloma, progression within 1 year of stem-cell transplant, and high-risk cytogenetics, defined as patients with genetic subtypes t(4;14), t(14;16), deletion 17p, gain 1q(+1q), gain(1q21), t(14;20), or hypodiploidy.

A total of 154 patients received melflufen 40 mg (intravenously every 28 days) plus dexamethasone 40 mg/week or 20 mg/week if aged >75 years until progressive disease or unacceptable toxicity as of October 1, 2019. Patient ages ranged from 35 to 86 years with a median age of 64.5 years. Approximately one-third of patients had International Staging System stage 3. Extramedullary disease and high-risk cytogenetics were present in 32% and 38%, respectively. The median prior lines of therapy was 5 (range, 2-12), and all patients had prior exposure to IMiDs and PIs and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. A total of 71% were triple-class refractory to ≥1 IMiDs plus PI plus an anti-CD38 monoclonal antibody.

Patients with at least 20 weeks of follow-up were included in the analysis (n = 125). The ORR was 29% in the intention-to-treat (ITT) population, and the clinical benefit rate was 44%. The median DOR was 5.5 months in the ITT population, and the median PFS was 4.2 months. Median OS was 11.6 months for the ITT population. Among the 42 patients with extramedullary disease and 47 with high-risk cytogenetics, the ORR was 24% and 21%, median DOR was 5.5 and 3.2 months, median PFS was 2.9 and 3.1 months, and median OS was 6.5 and 9.3 months, respectively. In the 93 patients who were triple-class refractory and the 76 patients who were refractory to a prior alkylator, the ORR was 26% and 21%, respectively. The median DOR was 4.4 and 4.2 months, median PFS was 3.9 and 3.8 months, and median OS was 11.2 and 9.7 months for the triple-class and alkylator-refractory patients, respectively. Finally, among 26 patients who progressed within 1 year of autologous stem-cell transplantation, the ORR was 19%, and the median DOR, PFS, and OS were 7.5 months, 3.5 months, and 8.1 months, respectively.

Any-grade treatment-emergent adverse events (TEAEs) occurred in 100% of the 157-patient ITT population. Grade 3/4 TEAEs occurred in 89% of patients, with thrombocytopenia and neutropenia being most common and occurring in 76% and 79% of patients, respectively. Nonhematologic grade 3/4 TEAEs, such as pneumonia (10%) and hypophosphatemia (4%), occurred in 46% of patients. The discontinuation rate related to TEAEs was 14%. Finally, serious adverse events, such as pneumonia (9%), febrile neutropenia (5%), and thrombocytopenia (3%), occurred in 40% of patients. No treatment-related deaths occurred during the study.


  • Abstract and Poster EP945. EHA 2020. June 12, 2020. HORIZON (OP-106): Melflufen plus dexamethasone in relapsed/refractory multiple myeloma (RRMM) refractory to pomalidomide and/or an anti-CD38 monoclonal antibody – primary and subgroup analysis.

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