ANCHOR: melflufen plus dexamethasone and daratumumab or bortezomib in relapsed/refractory multiple myeloma: final results of a phase I/IIa study

Abstract

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, demonstrated clinical benefit in combination with dexamethasone in triple-class refractory multiple myeloma (MM). The phase I/IIa ANCHOR study evaluated melflufen (30 or 40 mg) and dexamethasone (40 mg with daratumumab; 20 mg followed by 40 mg with bortezomib; dose reduced if aged ≥75 years) in triplet combination with daratumumab (16 mg/kg; daratumumab arm) or bortezomib (1.3 mg/m2; bortezomib arm) in patients with relapsed/refractory (RR)MM refractory to an immunomodulatory agent and/or a proteasome inhibitor and who had received one to four prior lines of therapy. Primary objectives were to determine the optimal dose of melflufen in triplet combination (phase I) and overall response rate (ORR; phase IIa). In total, 33 patients were treated in the daratumumab arm and 23 patients received therapy in the bortezomib arm. No dose-limiting toxicities were reported at either melflufen dose level with either combination. With both triplets, the most common grade ≥3 treatment-emergent adverse events (TEAEs) were thrombocytopenia and neutropenia; thrombocytopenia was the most common TEAE leading to treatment discontinuation. In the daratumumab arm, patients receiving melflufen 30 mg remained on treatment longer than those receiving the 40-mg dose. In the daratumumab arm, ORR was 73% and median progression-free survival (PFS) was 12.9 months. Notably, in the bortezomib arm, ORR was 78% and median PFS was 14.7 months. Considering the totality of the data, melflufen 30 mg was established as the recommended dose for use with dexamethasone and daratumumab or bortezomib for future studies in RRMM.

The Role of Autologous Stem Cell Transplantation in the Treatment of Newly Diagnosed Multiple Myeloma: Is It Time to Rethink the Paradigm in the Era of Targeted Therapy?

“…This notwithstanding, melflufen is a novel targeted cytotoxic drug-peptide conjugate that delivers the alkylator warhead directly to plasma cells and may thereby retain melphalan's cytotoxic activity, including against "stemness", while potentially resulting in less toxicity and an improved therapeutic index [70,71]. Moreover, current data support the use of this novel, first-in-class, peptide-drug conjugate in the management of relapsed and refractory MM in additional combination approaches, such as those recently reported in the AN-CHOR study [72] and LIGHTHOUSE trial [73], with promising results seen using either bortezomib or daratumumab in combination with melflufen and dexamethasone.…”