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

Introduction / Background / Significance: Background: Despite improvements in outcomes for patients with MM, most will relapse, and survival is poor (Kumar et al. Leukemia. 2017;31:2443). Because novel agents are incorporated into combination regimens in earlier lines of therapy, many patients with RRMM have few treatment options after the third relapse (Gandhi et al. Leukemia. 2019;33:2266). Melphalan flufenamide (melflufen) is an investigational first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. The safety and efficacy of melflufen plus dexamethasone were established in a phase 1/2 study in patients with RRMM who received ≥2 prior lines of therapy (Richardson et al. Blood. 2017;130[suppl, abstr]:3150). The aim of this study was to evaluate the efficacy and safety of melflufen plus dexamethasone in patients with RRMM in the pivotal, single arm, multicenter, phase 2 HORIZON study (NCT02963493).

Materials and Methods / Case Presentation / Objective: Materials and Methods: Patients who had RRMM, had received ≥2 prior lines of therapy (≥1 immunomodulatory agent [IMiD] and (≥1 proteasome inhibitor [PI]), and were refractory to pomalidomide and/or an anti-CD38 monoclonal antibody (mAb), received melflufen 40 mg (intravenous every 28 days) plus dexamethasone 40 mg/week (20 mg/week for patients aged ≥75 years) until progressive disease or unacceptable toxicity. The primary endpoint was overall response rate (ORR; ≥ partial response; investigator-assessed per International Myeloma Working Group criteria). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. A post-hoc analysis was conducted in patients with high-risk features including extramedullary disease (EMD) and triple-class–refractory MM.

Results / Description / Main Outcome Measure(s): Results: As of January 14, 2020, a total of 157 patients were treated; median age was 65 years (range, 35-86); 25% had International Staging System stage 3 disease; 38% had high-risk cytogenetics; and 35% had EMD. Patients had received a median of 5 (range, 2-12) prior lines of therapy; 80% were refractory to ≥1 anti-CD38 mAb; 59% were refractory to prior alkylator therapy; and 76% were triple-class refractory (≥1 IMiD + ≥1 PI + ≥1 anti-CD38 mAb). ORR was 29%; clinical benefit rate was 45%; median (m) DOR was 5.5 months (95% CI, 3.9-7.6); mPFS was 4.2 months (95% CI, 3.4-4.9); and mOS was 11.6 months (95% CI, 9.3-15.4). Among patients with EMD (n=55) and triple-class–refractory disease (n=119), ORR was 24% and 26%; mDOR was 5.5 and 4.4 months; mPFS was 2.9 and 3.9 months; and mOS was 6.5 and 11.2 months, respectively (Table). Any-grade and grade 3/4 adverse events (AEs) occurred in 100% and 94% of patients, respectively. The most common grade 3/4 AEs were neutropenia (79%), thrombocytopenia (76%), and anemia (43%). The most common nonhematologic grade 3/4 AE was pneumonia (10%). Overall, 17% of patients discontinued therapy due to an AE. Serious AEs occurred in 49% of patients, most commonly, pneumonia (9%) and febrile neutropenia (5%). There were no treatment-related deaths.

Conclusion(s): Conclusions: Melflufen plus dexamethasone showed efficacy with a manageable safety profile in heavily pretreated patients with RRMM, including patients with EMD and triple-class–refractory disease. Nonhematologic AEs were infrequent.