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 MM. Melflufen selectively targets MM through aminopeptidase-driven accumulation, leading to a 50-fold enrichment of alkylating metabolites compared with melphalan (Chauhan et al. Clin Can Research. 2013).

In the phase 1/2 study O-12-M1, melflufen + dex had promising activity in RRMM (overall response rate, 31%; median progression-free survival, 5.7 mo; median overall survival, 20.7 mo), with acceptable safety (Richardson et al. Blood. 2017). This phase 1/2 study, OP-104 ANCHOR, is evaluating the triplet combination of melflufen and dex + BTZ or dara in RRMM.

Methods: Pts must have RRMM defined as refractory (or intolerant) to an IMiD and/or proteasome inhibitor (PI) with 1-4 prior lines of therapy. Pts who receive BTZ or dara cannot be refractory to a PI or have had prior anti-CD38 therapy, respectively. Melflufen (30, 40 or 20 mg intravenously [IV]) is administered on Day 1 of each 28-day cycle in one of 2 regimens selected based on prior therapy and investigator choice. Regimen A: BTZ 1.3 mg/m2 subcutaneous + dex 20 mg on Days 1, 4, 8 and 11 and dex 40 mg on Days 15 and 22. Regimen B: dara 16 mg/kg IV weekly (8 doses), every 2 w (8 doses), then every 4 w + dex 40 mg weekly. Pts are treated until disease progression or unacceptable toxicity. The phase 1 primary objective is to determine the optimal dose of melflufen and dex + BTZ or dara.

Results: As of 12 Nov 2018, 12 pts were treated: 3 in the BTZ combination with melflufen 30 mg and 9 in the dara combination with melflufen 30 mg (n=4) or 40 mg (n=5).

Regimen A (BTZ combination): Median age was 81 y, median no. of prior lines was 3, and 2 of 3 pts were refractory to last therapy. No dose-limiting toxicities (DLTs) were observed in the melflufen 30-mg dose level. Following 17 cycles, 2 pts had grade 3 treatment-related adverse events (AEs) of neutropenia and thrombocytopenia, and one pt had pneumonia pneumococcal. One pt had treatment-related serious AEs (SAEs). All pts achieved partial response (PR); all were ongoing on treatment.

Regimen B (dara combination): Median age was 63 y, median prior lines was 2, and 56% were last-line refractory. No DLTs were observed at either dose. Following 39 cycles, treatment-related grade 3 and grade 4 AEs, respectively, were neutropenia (n=6, n=0), thrombocytopenia (n=3, n=1), lymphocyte count decreased (n=3, n=3), and white blood cell count decrease (n=1, n=1). There were no treatment-related SAEs. Six of the 7 (86%) evaluable patients achieved ≥PR (4 very good partial responses [VGPRs] and 2 PRs); all patients were ongoing on treatment.

Conclusion: Interim results show that melflufen and dex + BTZ or dara is well tolerated in pts with RRMM. Early signs of efficacy are encouraging; the study is ongoing.

Citation Format: Ludek Pour, Yvonne Efebera, Miquel Granell, Roman Hajek, Albert Oriol, Jacques Delaunay, Katell Le Du, Jean-Richard Eveillard, Lionel Karlin, Vladimir Maisnar, Joaquin Martinez-Lopez, María-Victoria Mateos, Jan Moreb, Vincent Ribrag, Paul G. Richardson, Jan Straub, Catriona Byrne, Christian Jacques, Hanan Zubair, Enrique Ocio. Melflufen and dexamethasone (dex) plus bortezomib (BTZ) or daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) (OP-104) [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 CT080.