Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with ≥3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received ≥3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade ≥3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies.

<sup>st< sup> Department of Medicine Department of Hematology 1st Faculty of Medicine Charles University and General Hospital Prague Prague Czech Republic

<sup>th< sup> Department of Medicine Hematology Charles University Hospital and Faculty of Medicine Hradec Kralove Czech Republic

City Clinical Hospital No 4 of Dnipro City Council Dnipro Ukraine

Clinic of Hematology Clinical Center of Serbia Faculty of Medicine University of Belgrade Belgrade

Dana Farber Cancer Institute Boston MA

Department of Clinical Oncology Medical Faculty Medical University of Plovdiv Plovdic Bulgaria

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

Department of Internal Medicine Hematology and Oncology University Hospital Brno Babak Myeloma Group Faculty of Medicine Masaryk University Brno Czech Republic

Hospital Clínico Universitario de Salamanca IBSAL CIC Salamanca

Oncopeptides AB Stockholm

Oslo Myeloma Center Department of Hematology Oslo University Hospital and KG Jebsen Center for B Cell Malignancies University of Oslo Oslo

Plasma Cell Dyscrasias Center Department of Hematology Jagiellonian University Faculty of Medicine Krakow

University Clinical Centre Department of Hematology and Transplantology Gdansk

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NCT04649060