P34 lighthouse (op-108): melflufen plus daratumumab (dara) and dexamethasone (dex) versus dara in relapsed/refractory multiple myeloma (rrmm) refractory to an immunomodulatory drug (imid) and a proteasome inhibitor (pi) or had received ≥3 prior lines of therapy including an imid and a pi

Background: Patients (pts) with RRMM often develop resistance to standard therapies. Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages peptidases and esterases to rapidly release alkylating agents into tumor cells. Melflufen+dex was approved in Europe for the treatment of pts with ≥3 prior lines of therapy (LoTs) and triple-class refractory RRMM (time to progression [TTP] >36 mo if pt had a prior autologous stem cell transplant [ASCT]). Approval was based on results from the phase 2 HORIZON study supported by the phase 3 OCEAN study (Richardson PG, et al. J Clin Oncol. 2021;39(7):757-767; Schjesvold FH, et al. Lancet Haematol. 2022;9(2):e98-e110). Melflufen+dex+dara showed clinical activity and manageable safety in the phase 1/2 ANCHOR study (Ocio EM, et al. ASH 2020, abstract 417), and was further assessed in the phase 3 LIGHTHOUSE study (NCT04649060). Methods: Pts had RRMM and were refractory to an IMiD and a PI or had received ≥3 prior LoTs including an IMiD and a PI. Prior anti-CD38 monoclonal antibody therapy was allowed, but no pts had received it. Pts were randomized (1:1) to 28-day (D) cycles (C) of intravenous melflufen (30 mg on D1 of each C) + oral dex (40 mg weekly; 20 mg if aged ≥75 y) + subcutaneous dara (1800 mg on D1, 8, 15, and 22 in C1-2, D1 and 15 in C3-6, and D1 in C7+) or dara monotherapy (regimen as in the melflufen arm) until disease progression or unacceptable toxicity. Pts with confirmed disease progression in the dara arm could cross over to the melflufen arm. Primary endpoint was progression-free survival (PFS); key secondary endpoints were overall response rate (ORR) and safety. A partial clinical hold issued by the FDA for all melflufen studies led to premature study closure on 23 Feb 2022 (data cutoff date). Results: From 21 Dec 2020 to 7 Jul 2021, 54 of 240 planned pts were randomized (melflufen arm, n=27; dara arm, n=27); 2 pts crossed over to the melflufen arm. In the melflufen vs dara arm, median (range) age was 65 y (43-80) vs 68 y (50-83), 11 (41%) vs 13 (48%) had no prior ASCT, and 3 (11%) vs 2 (7%) had a TTP >36 mo after a prior ASCT, respectively. Median PFS was not reached (NR) in the melflufen arm vs 4.9 mo in the dara arm (hazard ratio [HR], 0.18 [95% CI, 0.05-0.65]; P=0.0032; Figure). ORR (95% CI) was 59.3% (38.8-77.6) in the melflufen arm vs 29.6% (13.8-50.2) in the dara arm (P=0.0300). OS was immature, with 2 events in the melflufen arm vs 4 events in the dara arm (HR, 0.47 [95% CI, 0.09-2.57]; P=0.3721). Among pts with no prior ASCT or with a TTP >36 mo after a prior ASCT (melflufen arm, n=14; dara arm, n=15), median PFS was NR in the melflufen arm (1 event) vs 3.9 mo in the dara arm (11 events; HR, 0.06 [95% CI, 0.01-0.49]; P=0.0005), ORR was 64.3% vs 13.3% (P=0.0055), and 1 vs 4 OS events occurred (P=0.0369), respectively. In the melflufen vs dara arm, the most common grade ≥3 treatment-emergent adverse events were neutropenia (50% vs 12%), thrombocytopenia (50% vs 8%), and anemia (32% vs 19%); those leading to discontinuation occurred in 2 pts (9%) and 4 pts (15%), respectively. Conclusion: Melflufen+dex+dara demonstrated superior PFS and ORR vs dara in the overall population and in pts with no prior ASCT or with a TTP >36 mo after a prior ASCT, which resembles the population with confirmed benefit from OCEAN. The safety profile of melflufen as a triplet regimen was consistent with that reported in ANCHOR and previous reports of melflufen+dex.