Background: Daratumumab (dara), carfilzomib (K), pomalidomide (P), and dexamethasone (d) are established in relapsed multiple myeloma (MM) with activity in 3-drug combinations including: dara Kd; dara Pd; and KPd. The paradigm in relapsed/refractory disease is moving towards more intensive and well-tolerated combinations to achieve deeper and more durable responses while ensuring tolerability. Quadruplet regimens are now becoming standard in newly diagnosed MM, and we explored a 4-drug regimen in relapsed disease. Preliminary results of a phase 2 study of dara KPd with a twice/week schedule of K showed an ORR of 86% in pts with a median of 1 prior line (Jasielec et al., ASH 2020). Here we report an ongoing study of dara with weekly KPd (dara wKPd) to improve the accessibility of this regimen. Methods: This phase 2 study (NCT04176718) will enroll up to 43 pts with relapsed/refractory MM who have received at least 1 prior therapy, including both lenalidomide and a proteasome inhibitor. Prior therapy with dara, K, or P was permitted except for K and P given together as last line of therapy. Dara wKPd was given on a 28-day schedule. Dara was given according to the dara Pd schedule. An initial cohort received dara 16 mg/kg iv (with first dose split over two days); the trial was amended to dara 1800 mg sc. K 56 mg/m² iv was given weekly on days 1, 8, 15; for C1D1, dose was 20 mg/m². P 4 mg was given po on days 1-21. Dex 40 mg was given weekly with the dose split over two days. Treatment was until progression or unacceptable toxicity. The primary endpoints are overall response and the safety profile of dara wKPd. Secondary endpoints include PFS. Results: At time of data cutoff, 24 pts were enrolled; median age was 65 (range 42-73), and median number of prior regimens was 2 (range 1-3). All pts were refractory to their last line of therapy and had prior lenalidomide and bortezomib. Additional prior therapies included: pomalidomide (54%), carfilzomib (13%), ixazomib (46%), cyclophosphamide (4%), auto SCT (29%). High risk FISH was present (out of 24 pts): del 17p (13%); t(14;16) (8%); gain of 1q (46%). Median follow up was 8.4 months. 2 pts came off study due to neutropenia leading to delay in treatment. Grade 3-4 hematologic AEs included neutropenia (46%) and thrombocytopenia (25%). There was 1 episode of febrile neutropenia. Common non hematologic AEs (all; grade 3-4) included fatigue (42%; 0%); dyspnea (38%; 4%); increase in ALT/AST (29%; 8%); insomnia (21%; 0%); neuropathy (17%; 0%). 22 pts were evaluable for response, with an overall response rate of 95% (PR 23%, VPGR 68%, CR 5%). Median PFS at 12 months was 86.2% (95% CI, 70%-100%). Conclusions: Dara wKPd shows some of the highest response rates (95%) reported to date in relapsed/refractory MM. This likely reflects the incorporation of 4 active drugs in 1 regimen and builds on the efficacy of dara-based triplet regimens, with manageable toxicity and convenience of weekly K. Clinical trial information: NCT04176718.