Background: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen + dex showed clinical efficacy and was well tolerated in pts with heavily pretreated RRMM (HORIZON; Richardson et al. J Clin Oncol. 2020 Dec 9 [Epub]). The ongoing phase 1/2 ANCHOR study (OP-104) established the optimal dose for melflufen + dex and dara, showing meaningful clinical activity and manageable safety at both melflufen doses tested in pts with RRMM (Ocio et al. ASH 2020. Oral 417). The aim of this study (OP-108; NCT04649060) is to evaluate the efficacy and safety of melflufen + dex and dara vs dara in pts with RRMM previously treated with an IMiD and a proteasome inhibitor (PI), similar to the indication for dara monotherapy. Methods: Pt enrollment has begun (N = 240 planned). Pts must be ≥ 18 y, double refractory to (or intolerant of) an IMiD and a PI or had ≥ 3 prior lines of therapy (LoTs) including an IMiD and a PI, have measurable disease, and Eastern Cooperative Oncology Group performance status ≤ 2. Pts with primary refractory disease and refractoriness to an anti-CD38 antibody are excluded. Pts will be randomized 1:1 to open-label melflufen + dex and dara (Arm A) or single-agent dara (Arm B) until progressive disease [PD] or unacceptable toxicity, stratified by prior LoT number. Pts in Arm B with PD can opt to receive Arm A triplet therapy. Arm A: melflufen 30 mg intravenously on d 1 of each 28-d cycle; dex 40 mg/wk orally (20 mg if aged ≥ 75 y); dara 1800 mg subcutaneously on d 1, 8, 15, and 22 of cycle 1 and 2, d 1 and 15 of cycles 3-6, and d 1 of cycles 7+. Arm B: dara at the same dosage as Arm A. Primary objective: superiority (P value from the 2-sided statistical test < 0.05; upper limit of the 2-sided 95% CI for the hazard ratio < 1) of progression-free survival (PFS) in pts treated with triplet therapy vs dara. An estimated sample of 240 pts with 160 expected events (PD or death) and 15% assumed dropout rate would provide 90% power at a 2-sided log rank test at 5% significance level to detect a hazard ratio for death of 0.6. Key secondary endpoints: overall response rate (ORR; ≥ partial response [PR]), duration of response, and safety. Response will be assessed by a blinded independent review committee based on International Myeloma Working Group criteria. Other secondary endpoints: clinical benefit rate (≥ minimal response), time to response, time to progression, time to next treatment, and overall survival. Exploratory endpoints include: minimal residual disease in pts achieving ≥ very good PR, PFS following next line of treatment (PFS-2), pt-reported outcomes, pharmacokinetics, translational biomarkers, response rate in pts with extramedullary disease, and efficacy (including ORR) in Arm B pts who receive Arm A triplet therapy after PD. Clinical trial information: NCT04649060