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 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 (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 triplet regimens, the most common grade ≥3 treatment-emergent adverse events were thrombocytopenia and neutropenia; thrombocytopenia was the most common treatment-emergent adverse event 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, the overall response rate was 73% and median progression-free survival was 12.9 months. Notably, in the bortezomib arm, the overall response rate was 78% and median progression-free survival 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 relapsed/refractory MM.

4th Department of Medicine Hematology Charles University Hospital Hradec Králové Czech Republic

Dana Farber Cancer Institute Harvard Medical School Boston MA

Department of Hematology Centre Hospitalier Lyon Sud University Claude Bernard Lyon 1 Pierre Bénite

Department of Hematology Oncology Division of Blood and Marrow Transplant and Cellular Therapy OhioHealth Columbus OH USA and OhioHealth Columbus OH

Department of Hematooncology University Hospital Ostrava Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Drug Development Department Gustave Roussy Université Paris Saclay Villejuif

Fakultní nemocnice Brno Brno Czech Republic

Hôpital Morvan Brest

Hospital Clinico Universitario de Salamanca IBSAL CIC Salamanca

Hospital Universitario Marqués de Valdecilla Universidad de Cantabria Santander

Institut Català d'Oncologia and Josep Carreras Research Institute Hospital Germans Trias i Pujol Badalona

Oncopeptides AB Stockholm

Všeobecná fakultní nemocnice Prague Czech Republic

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