Background: DARA, a human IgG1κ monoclonal antibody that targets CD38, induces deep and durable responses in patients with RRMM. In a phase 1b RRMM study, a SC co-formulation of DARA with recombinant human hyaluronidase (rHuPH20; DARA SC) was found to be well tolerated with low infusion-related reaction (IRR) rates. Moreover, response rates were similar to those observed historically with DARA IV. The phase 3 COLUMBA study will compare the efficacy, pharmacokinetics, and IRRs of DARA SC versus DARA IV in patients with RRMM. Methods: This is an ongoing phase 3, randomized, open-label, multicenter, non-inferiority study of DARA SC (1,800 mg DARA in combination with rHuPH20 [2,000 U/mL] administered by manual push [15 mL] over 3-5 minutes at alternating left/right abdominal sites) versus DARA IV (16 mg/kg IV infusion) weekly for Cycles 1-2 (28-day cycles), every 2 weeks for Cycles 3-6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. Pre- and/or post-infusion medications include paracetamol, diphenhydramine, methylprednisolone, and an optional leukotriene inhibitor. Eligible patients (≥18 years) with RRMM must have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI; ≥2 cycles or 2 months of treatment) and an immunomodulatory drug (IMiD; ≥2 cycles or 2 months of treatment), or must be double refractory to both a PI and an IMiD. The co-primary endpoints are overall response rate and maximum C_trough concentration of DARA on Cycle 3 Day 1. Secondary endpoints include IRR rates, progression-free survival, ≥very good partial response and ≥complete response rates, time to next therapy, overall survival, time to response, and duration of response. Approximately 480 patients will be enrolled and randomly assigned (1:1) to the 2 treatment groups. Randomization will be stratified by body weight at baseline (≤65 kg, 66 kg to 85 kg, > 85 kg), number of prior lines of therapy (≤4 prior lines versus > 4 prior lines), and type of myeloma (IgG versus non-IgG). Clinical trial information: NCT03277105