Abstract CT154: Melflufen in patients (pts) with relapsed/refractory multiple myeloma (RRMM) refractory to daratumumab (dara) and/or pomalidomide (pom) (OP-106)
Authors: Richardson Paul G. , Oriol Albert , Larocca Alessandra , Otero Paula Rodriguez , Moreb Jan , Bladé Joan , Hassoun Hani , Cavo Michele , Alegre Adrián , Mazumder Amitabha , Maisel Christopher , Paner Agne , Leleu Xavier , Zonder Jeffrey A. , Harmenberg Johan , Thuresson Sara , Zubair Hanan , Mateos María-Victoria 
Published: August 2019

Abstract
Background: Melflufen is an alkylating peptide belonging to a novel class of peptidase-enhanced compounds. Aminopeptidases are heavily overexpressed and key for the transformation process in multiple myeloma (MM). Melflufen selectively targets MM through aminopeptidase-driven accumulation, leading to a 50-fold enrichment of alkylating metabolites vs melphalan (Chauhan et al. Clin Can Research. 2013).
In the Phase I/II O-12-M1 study, melflufen showed activity in pts with RRMM (overall response rate [ORR], 31%; median progression-free survival [PFS], 5.7 mo; median overall survival, 20.7 mo), with acceptable safety (Richardson et al. Blood. 2017).
The Phase II HORIZON study evaluates melflufen in pts exposed to IMiDs and proteasome inhibitors (PIs) and refractory to pom and/or dara.
Methods: Pts with RRMM must have received ≥2 prior lines of therapy and have been exposed to IMiDs and PIs and refractory to pom and/or dara. Pts receive 40 mg melflufen intravenously on Day 1 of each 28-day cycle + 40 mg weekly dexamethasone. The primary endpoint is ORR (≥ partial response; investigator assessed per International Myeloma Working Group criteria). Secondary endpoints include clinical benefit rate (CBR; ≥ minimal response), PFS, and safety. Pts are treated until progressive disease (PD) or unacceptable toxicity.
Results: As of 22 Oct 2018, 83 pts were treated. Median age was 63 y (35-86), median time since diagnosis was 6.5 y (0.75-25); 36% of pts were International Staging System (ISS) stage 3 and 61% had high-risk cytogenetics at study entry. Median no. of prior lines was 5 (2-13). All pts were pom or dara refractory, 60% were pom and dara refractory and 86% were double refractory (IMiD and PI). Also, 84% had received prior alkylator therapy (55% alkylator refractory); 69% had received ≥1 prior transplant.
Treatment was ongoing for 23% of pts and discontinued in 77% of pts due to PD (57%), adverse event (AE; 13%), or other (7%). Treatment-related grade 3/4 AEs were reported in 62 (75%) pts, mostly hematologic: neutropenia (61%), thrombocytopenia (59%), and anemia (25%). Treatment-related non-hematologic grade 3/4 AEs were rare (eg, infections in 7% of pts). Fourteen (16%) pts experienced treatment-related serious AEs, most commonly febrile neutropenia (n=5), neutropenia (n=3), and thrombocytopenia (n=2). No treatment-related deaths were reported.
In total, 82 pts were evaluable for response: ORR was 33% and CBR 39%. Benefit was observed for high-risk subgroups: ORR for pts with ISS stage 3, high-risk cytogenetics, and double- and dara-refractory disease was 24%, 22%, and 19%, respectively. Median PFS was 4.0 mo (95% CI, 3.3-5.1).
Conclusion: Melflufen has promising activity in heavily pretreated, multi-refractory late-stage pts with RRMM. Melflufen was generally well tolerated with infrequent non-hematologic AEs and low rates of discontinuation due to AEs.
Citation Format: Paul G. Richardson, Albert Oriol, Alessandra Larocca, Paula Rodriguez Otero, Jan Moreb, Joan Bladé, Hani Hassoun, Michele Cavo, Adrián Alegre, Amitabha Mazumder, Christopher Maisel, Agne Paner, Xavier Leleu, Jeffrey A. Zonder, Johan Harmenberg, Sara Thuresson, Hanan Zubair, María-Victoria Mateos. Melflufen in patients (pts) with relapsed/refractory multiple myeloma (RRMM) refractory to daratumumab (dara) and/or pomalidomide (pom) (OP-106) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT154.