<h3>Background</h3> Despite recent advances, new therapies are needed to deepen and extend remissions in early-line relapsed/refractory multiple myeloma (RRMM). Iberdomide (IBER) is a novel, potent oral cereblon E3 ligase modulator (CELMoD®) compound with enhanced tumoricidal and immune-stimulatory effects when compared with IMiD® agents. Preclinically, IBER overcomes IMiD resistance and has synergy with dexamethasone (DEX), daratumumab (DARA), and bortezomib (BORT). In a phase 1/2 trial in patients (pts) with RRMM, IberDd showed efficacy with favorable tolerability, and pharmacodynamic data demonstrated increased NK and T cell proliferation (Lonial S, et al. HemaSphere 2021; 5(S2):49). The EXCALIBER trial was initiated to compare efficacy and safety of IberDd with that of DVd, a globally approved regimen, in pts with early-line RRMM. <h3>Methods</h3> In this multicenter, open-label, phase 3 study ≈742 pts will be randomized 1:1 to receive IberDd or DVd. Pts will be stratified within each cohort by number of prior lines of therapy (1 vs 2), age (≤70 years vs >70 years), and ISS staging at study entry (I–II vs III). Key eligibility criteria include age (≥18 years), measurable disease treated with 1–2 prior lines of antimyeloma therapy where a partial response or better to ≥1 prior therapy was achieved, and disease progression during or after the last regimen. Prior treatment with anti-CD38 monoclonal antibodies and/or BORT is permitted under stringent conditions. Treatment in the IberDd arm will consist of 28-day (D) cycles (C) with 1.6 mg IBER on D1–21; 1,800 mg subcutaneous (SC) DARA on D1, 8, 15, and 22 of C1–2, D1 and 15 of C3–6, and D1 of ≥C7; and 40 mg oral DEX (20 mg if ≥75 years) on D1, 8, 15, and 22. Treatment in the DVd arm will consist of 21-D cycles for C1–8 and 28-D cycles for ≥C9; 1,800 mg SC DARA on D1, 8, and 15 for C1–3, D1 for C4–8, and D1 for ≥C9; 1.3 mg/m2 SC BORT on D1, 4, 8, and 11 for C1–8; and 20 mg oral DEX (10 mg if ≥75 years) on D1, 2, 4, 5, 8, 9, 11, and 12 for C1–8. Treatment will continue until confirmed progressive disease, unacceptable toxicity, or consent withdrawal. Primary efficacy endpoint is PFS, calculated as the time from randomization to progressive disease, or death. Assuming a decrease in the PFS risk by 25% (HR=0.75) with IberDd, under exponential distribution assumption of PFS (one-sided α=0.025) and adjusted for the 2 interim analyses, 441 PFS events will have 85% power to detect an improvement in treatment effect. Secondary efficacy endpoints include OS, duration of response, time to progression, overall response rate, measurable residual disease, and quality of life. Safety evaluations include treatment-emergent adverse events, laboratory parameters, and vital signs. Two interim analyses are planned for PFS, when ≈134 (30%) and ≈334 (75%) events have been accumulated, to examine futility and superiority, respectively. Enrollment is expected to begin in Q3, 2021. NCT number is pending.