Background: The intravenous (IV) formulation of daratumumab (DARA), a human CD38-targeted monoclonal antibody, is approved in many countries for use as monotherapy in relapsed/refractory multiple myeloma (RRMM) and in combination with standard-of-care regimens in RRMM or newly diagnosed MM. A subcutaneous (SC) formulation of DARA is under investigation in several ongoing studies. In the phase 3 COLUMBA study, DARA SC was shown to be non-inferior to DARA IV, demonstrating similar efficacy and pharmacokinetics, with a significantly decreased rate of infusion-related reactions and reduced administration time. The phase 2 LYNX (MMY2065) study will evaluate the efficacy and safety of retreatment with DARA. Methods: In this ongoing, multicenter, open-label, randomized phase 2 study, ~230 patients (pts) with prior exposure to DARA will be randomized 1:1 to receive carfilzomib and dexamethasone (Kd) ± DARA. Pts must have received 1 to 2 prior lines of therapy (at least one of which included DARA IV), with DARA-based therapy completed ≥3 months prior to randomization. Eligible pts have achieved a partial response or better (IMWG criteria) to DARA-based therapy, with a duration of response of ≥4 months. Pts must not have discontinued DARA due to a related adverse event or received prior treatment with carfilzomib. Pts will receive 20 mg/m² carfilzomib IV on Day 1 of Cycle 1, escalated to 70 mg/m² on Days 8 and 15; carfilzomib 70 mg/m² will be administered on Days 1, 8, and 15 of each 28-day cycle thereafter. Dexamethasone 40 mg will be administered (IV or PO) QW for Cycles 1-9 and then on Days 1, 8 and 15 from Cycle 10 onwards. Pts in the D-Kd group will also receive DARA SC (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; Halozyme]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter. The primary endpoint is the rate of pts achieving a very good partial response or better. Secondary endpoints include overall response rate, rate of pts achieving complete response or better, progression-free survival, overall survival, overall minimal residual disease-negativity rate, time to next treatment, pharmacokinetics, and safety. Clinical trial information: NCT03871829.