Abstract Background: The HRQoL of patients with RRMM is highly impacted by their disease and is typically only maintained with conventional treatments before deteriorating. We conducted an SLR and meta-analyzed temporal trends in HRQoL to contextualize findings from emerging immunotherapies for 4L+ RRMM such as chimeric antigen receptor T-cell (CAR T) therapies and bispecific antibodies (BsAb). Methods: MEDLINE, EMBASE, CENTRAL and the grey literature were systematically searched (Jan 2012 to Mar 2024) for studies of patients with 4L+ RRMM where HRQoL was measured according to either the EORTC QLQ-C30 or QLQ-MY20. Changes from baseline were described, by treatment category (CAR T, BsAb, and Other), using fixed-effect meta-analyses over one year of follow-up. Estimates were compared to minimally important differences (MIDs) to determine clinical meaningfulness. Results: We included 14 studies with QLQ-C30 (n=14) or QLQ-MY20 (n=11) outcomes at timepoints of interest (Table). In patients treated with CAR T, sustained clinically meaningful improvements were observed from 3 months onwards on the Physical functioning and Pain domains and from 4 months onwards on Global health status and the Social functioning, Fatigue, and Future perspective domains. Treatment with a BsAb tended to maintain baseline HRQoL over time, with some meaningful improvements in Emotional functioning, Physical functioning, Fatigue, and Pain. Meaningful deteriorations were seldom observed on any domain. Conclusions: This evidence base is evolving, and some findings are limited by few studies and small sample sizes. Nevertheless, our study demonstrated earlier and sustained improvement in key HRQoL domains among patients with 4L+ RRMM who receive CAR T. These findings are similar to the results of CAR T in other hematological settings and reflect improved general well-being post-CAR T. Citation Format: Ken Hasegawa, Xavier P. Leleu, Taha Itani, Monique Giordana, Enrique Granados, Rebecca J. Chan, Ana Kostic, Jie Ting, Sean P. Harrigan, Michael J. Zoratti, Rahul Banerjee. Temporal trends in health-related quality of life (HRQoL) outcomes in fourth line or higher treatment for relapsed/refractory multiple myeloma (RRMM): A systematic literature review (SLR) and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4991.