HORIZON (OP-106): Melflufen Plus Dexamethasone in 55 Patients With Relapsed/Refractory Multiple Myeloma With Extramedullary Disease-Subgroup Analysis

Context Prognosis for patients with RRMM and EMD is poor (Mangiacavalli et al. Ann Hematol. 2017;96:73). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumor cells. Melflufen plus dexamethasone showed meaningful efficacy and manageable safety in RRMM (HORIZON, NCT02963493; Richardson et al. J Clin Oncol. 2021;39:757-767). Objective To evaluate patients with EMD in HORIZON. Methods Patients with RRMM had ≥2 prior lines of therapy (e.g., immunomodulatory agent, proteasome inhibitor) and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Patients received melflufen 40 mg (intravenous; day 1 of each 28-day cycle) and dexamethasone 40 mg/week until progressive disease/unacceptable toxicity. The primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Results As of January 14, 2020, 55 of 157 patients treated had EMD (49% soft tissue; 51% bone-related plasmacytoma). Median age was 64 years (range, 43–82); 35% had high-risk cytogenetics; 33% had International Staging System stage III; median prior lines of therapy was 5 (range, 2–12); 60% were refractory to prior alkylators; and 91% had triple-class refractory MM. In patients with EMD and overall, respectively, ORR was 23.6% and 29.3%; median DOR was 5.5 and 5.5 months; median PFS was 2.9 and 4.2 months; and median OS was 6.5 and 11.6 months. In patients with EMD who achieved ≥ partial response (PR; n=13) and ≥ stable disease (n=28), respectively, median PFS was 17.3 and 5.3 months, and median OS was 18.5 and 13.6 months. Interpretation of ≥ PR results may be limited due to low event number. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 78% of patients with EMD and 89% overall. In patients with EMD, the most common grade 3/4 TEAEs were anemia (42%), thrombocytopenia (40%), and neutropenia (38%). No treatment-related deaths were reported. Conclusions In HORIZON, melflufen plus dexamethasone showed encouraging activity and no new safety concerns in the largest cohort of patients with RRMM with EMD reported to date. These data support further evaluation of melflufen plus dexamethasone in RRMM with EMD.