Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

Abstract

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

Treatment of Multiple Myeloma and the Role of Melphalan in the Era of Modern Therapies—Current Research and Clinical Approaches

“…A recent multicenter, international, open-label, phase I–II study showed that melflufen is active in patients with relapsed and refractory MM (RRMM). These results demonstrate the feasibility of this scheme and support the initiation of additional clinical studies with melflufen in MM, both in combination with dexamethasone and in triplet with additional drug classes [ 139 , 140 ]. In a Phase I study, the established maximum tolerated dose was 40 mg melflufen plus dexamethasone.…”

Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen

“…It also demonstrated that melflufen is equally effective in melphalan-naïve and melphalan-refractory patients [52]. The second study, focusing on heavily pretreated RRMM, showed that melflufen combined with dexamethasone leads to clinical improvement in the triple-class RRMM population with an overall response rate of 26%, median progression-free survival of 3.9 months, and median overall survival of 11.2 months [53]. In this study, we demonstrated that melflufen is highly effective at targeting plasma cells, particularly in samples from RRMM patients, including those with poor prognostic markers, such as del 17p or t(4;14).…”

Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death

“…The next-generation melphalan pro-drug melflufen (melphalan flufenamide ethyl ester) is an alkylating agent that has shown its high efficacy. It was recently approved by the FDA for use in combination with dexamethasone in R/R MM patients [219]. Melflufen enters cells where it is targeted by aminopeptidases resulting in its trapping in organelles and membranes allowing its accumulation.…”