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

2020 Year in Review - Multiple Myeloma —February 1, 2021


Multiple Myeloma

Patients with relapsed/refractory multiple myeloma (RRMM) 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 were evaluated in a phase 2 single-arm, multicenter study known as HORIZON.

The study evaluated 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), which is defined as the ORR plus partial response per the International Myeloma Working Group criteria and assessed by an investigator. Progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety were secondary end points. 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.

As of October 1, 2019, there was a total of 154 patients who received melflufen 40 mg (intravenously every 28 days) plus dexamethasone 40 mg weekly or 20 mg weekly if they were aged >75 years until progressive disease or unacceptable toxicity. Patient ages ranged from 35 to 86 years; median age was 64.5 years. Approximately one-third of patients had International Staging System stage 3. Present in 32% and 38% of patients were extramedullary disease and high-risk cytogenetics, respectively. 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% of patients were triple-class refractory to ≥1 IMiDs plus PI plus an anti-CD38 monoclonal antibody.

Patients with ≥20 weeks of follow-up were included in the analysis (N = 125). In the intent-to-treat (ITT) population, the ORR was 29% and the clinical benefit rate was 44%. Median DOR was 5.5 months in the ITT population, and 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 ORRs were 24% and 21%, median DOR rates were 5.5 months and 3.2 months, median PFS rates were 2.9 months and 3.1 months, and median OS rates were 6.5 months and 9.3 months, respectively. In the 93 and 76 patients who were triple-class refractory and refractory to a prior alkylator, the ORRs were 26% and 21%, respectively. The median DOR rates were 4.4 months and 4.2 months, median PFS rates were 3.9 months and 3.8 months, and median OS rates were 11.2 months 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 median DOR, PFS, and OS rates were 7.5 months, 3.5 months, and 8.1 months, respectively.

In 100% of the 157-patient ITT population, any-grade treatment-emergent adverse events (TEAEs) occurred. In 89% of patients, grade 3/4 TEAEs occurred, with thrombocytopenia and neutropenia being most common and occurring in 76% and 79% of patients, respectively. In 46% of patients, nonhematologic grade 3/4 TEAEs, such as pneumonia (10%) and hypophosphatemia (4%), occurred. The discontinuation rate related to TEAEs was 14%. Finally, in 40% of patients, serious adverse events, such as pneumonia (9%), febrile neutropenia (5%), and thrombocytopenia (3%), occurred. 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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Last modified: February 3, 2021

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