Randomized Phase 2 Study of Subcutaneous Daratumumab Plus Carfilzomib/Dexamethasone Versus Carfilzomib/Dexamethasone Alone in Patients with Multiple Myeloma Who Have Been Previously Treated with Intravenous Daratumumab to Evaluate Retreatment (LYNX)

Background: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. The intravenous (IV) formulation of daratumumab 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 and patients with NDMM who are transplant ineligible. A subcutaneous (SC) formulation of daratumumab is currently under investigation in several ongoing studies. In the phase 3 COLUMBA study, daratumumab SC was shown to be non-inferior to daratumumab IV, demonstrating similar efficacy and pharmacokinetics, with a significantly decreased rate of infusion-related reactions and reduced administration time. The randomized phase 2 LYNX (MMY2065) study will evaluate the efficacy and safety of retreatment with subcutaneous daratumumab in patients with RRMM who were previously exposed to daratumumab IV therapy.

Study Design and Methods: In this ongoing, multicenter, open-label, randomized phase 2 study, approximately 230 patients with prior exposure to daratumumab will be randomized 1:1 to receive daratumumab plus carfilzomib and dexamethasone (D-Kd) or carfilzomib and dexamethasone (Kd) alone. Patients must have received 1 to 2 prior lines of therapy (at least one of which included daratumumab IV) with the daratumumab-based therapy completed ≥3 months prior to randomization. Eligible patients must have achieved a partial response or better (as defined by International Myeloma Working Group [IMWG] criteria) to daratumumab-based therapy, with a duration of response of ≥4 months. Patients must not have discontinued daratumumab due to a daratumumab-related adverse event or received prior treatment with carfilzomib. All patients 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. Patients in the D-Kd group will also receive daratumumab SC (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE^® drug delivery technology, Halozyme, Inc.]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter. The primary endpoint is the rate of patients achieving a very good partial response or better. Secondary endpoints include overall response rate, rate of patients achieving complete response or better, progression-free survival, overall survival, overall MRD-negativity rate, time to next treatment, pharmacokinetics, and safety. The ClinicalTrials.gov identifier is NCT03871829.