MM-171: Melflufen Plus Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Exposed or Refractory to Prior Alkylators: A Pooled Analysis of the O-12-M1 and HORIZON Studies

Abstract

Context Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen has a mechanism of action distinct from other alkylating agents (Slipicevic et al. AACR 2020. Abs. 1843). In the O-12-M1 (NCT01897714) and HORIZON (OP-106; NCT02963493) studies, melflufen plus dexamethasone showed meaningful efficacy and a clinically manageable safety profile in patients with RRMM (Richardson et al. Lancet Haematol. 2020;7:e395-e407; Richardson et al. J Clin Oncol. 2021;39:757-767). Objectives To conduct a pooled analysis of outcomes in patients exposed to prior alkylators in these studies. Methods The O-12-M1 and HORIZON studies included patients with RRMM who received ≥2 prior lines of therapy (LoTs) and had a primary endpoint of overall response rate (ORR). Secondary endpoints included progression-free survival (PFS) and safety. Data from the two studies were pooled and analyzed according to exposure and refractoriness to alkylators before study entry. Results Of 202 patients (HORIZON: n=157, cutoff January 14, 2020; O-12-M1: n=45, cutoff October 29, 2019), 178 (88%) had been exposed to alkylators. Patients exposed and refractory to alkylators in ≥2 LoTs had the highest number of patients refractory to an alkylator in the last LoT (61%), and 82% were refractory to an alkylator within 12 months of study entry. ORR was 33.9% in all patients exposed to alkylators in ≥1 prior LoT, not refractory (n=62); 23.3% in patients exposed and refractory to an alkylator in 1 prior LoT (n=43); 35.0% in patients exposed to alkylators in ≥2 prior LoTs and refractory in 1 LoT (n=40); and 9.1% in patients refractory to alkylators in ≥2 prior LoTs (n=33). PFS trended toward being shorter with higher exposure and refractoriness to prior alkylators. Results should be interpreted with caution due to limited patient numbers. Safety was not adversely impacted by prior exposure to alkylators; grade 3/4 adverse events were similar between patients exposed to prior alkylators (O-12-M1: 85%; HORIZON: 89%) and the overall population (O-12-M1: 84%; HORIZON: 89%). Conclusions Melflufen in combination with dexamethasone showed meaningful efficacy and a clinically manageable safety profile in patients with RRMM exposed/refractory to prior alkylators.