Background: Outcomes have historically been poor for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Despite an increase in approved R/R DLBCL treatment options, clinical outcomes of these therapies remain less certain. Novel treatments for R/R DLBCL patients include chimeric antigen receptor T-cell (CAR T) therapy, polatuzumab vedotin plus bendamustine and rituximab (pola-BR), tafasitamab plus lenalidomide (tafa-len), loncastuximab (lonca), and selinexor. The objective of this study was to examine real-world outcomes of these novel therapies. Methods: US patient data from the COTA electronic health records database (2010–2021) were used for this retrospective study. Patients had a diagnosis of DLBCL after 1/1/2010, with ≥1 prior line of systemic antineoplastic therapy (including an anti-CD20 antibody), and treatment with any of these novel therapies. Patients receiving variations of pola-BR or tafa-len regimens were included. Outcomes included overall response rate (ORR), complete response (CR) rate, median progression-free survival (mPFS), and median overall survival (mOS). Outcomes were also analyzed for those treated with any novel therapy following prior CAR T exposure. Results: A total of 175 R/R DLBCL patients were included (median age 63 y, 60.6% male, median of 2 prior therapies); 29.1% had an international prognostic index score ≥3, 61.7% had stage III/IV disease, and 65.7% had primary refractory disease. A total of 73, 69, and 27 patients were treated with CAR T, pola-BR, and tafa-len regimens, respectively. Only 6 patients were treated with lonca and no patients received selinexor. Among 169 patients treated in the 2L+ setting with tafa-len, pola-BR, and CAR T, the CR rate was 11.1%, 18.8%, and 52.1%, respectively (Table). A total of 112 patients were treated in the 3L+ setting with CR rate of 10.0%, 13.5%, and 41.8%, for tafa-len, pola-BR, and CAR T, respectively. Outcomes in the 18% of patients treated with any novel agent following CAR T exposure were ORR of 19.1%, CR of 4.8%, and mPFS and mOS of 1.4 mo and 2.3 mo, respectively. Conclusions: Outcomes of pola-BR and tafa-len regimens in the 2L+ and 3L+ R/R DLBCL setting remain suboptimal, with worse outcomes as patients advance through lines of therapy. Outcomes are particularly poor when these agents are used following CAR T therapy.