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What have we learned from all randomized controlled trials with new agents added on to standard of care for the treatment of patients with systemic lupus erythematosus (SLE)? While positive studies have revealed clinical response rates of 40–60% a substantial proportion (40–60%) of patients still do not achieve an adequate response when these agents are introduced as a late addition to their treatment regimen. This persistent unmet need has spurred a critical shift towards the concept of combined, multitarget therapy at induction. This strategy aims to address the inherent heterogeneity of SLE pathogenesis by simultaneously modulating multiple dysregulated pathways from the outset.While multitarget approaches are sometimes achieved with a single therapeutic agent, they more commonly involve the strategic combination of two or more agents. Emerging ‘double-hit’ single therapies include telitacicept (an anti-BAFF and anti-APRIL agent), ianalumab (which both enhances antibody-dependent cellular cytotoxicity-mediated B-cell depletion and blocks BAFF:BAFF-R signaling), and a novel BCMA-CD19 CAR-T cell therapy that targets both BCMA and CD19.1–3 Newer single hit therapies, which could be used in conjunction with standard of care, are the JAK inhibitors. These agents include upadacitinib a classic JAK 1 inhibitor, deucravacitinib a TYK2 inhibitor and baricitinib a JAK1/2 inhibitor.4–6 These small molecule drugs have the advantage of being oral agents. Both these approaches offer multitarget approaches more appropriate for the heterogenous pathogenic mechanisms’ characteristic of SLE.Learning Objectives At the end of this presentation participants will be able to:Explain the limitations of traditional add-on therapeutic strategies in SLE, specifically recognizing the suboptimal response rates (40–60%) observed in randomized controlled trials, when newer agents are added to failed standard of careExplain the evolving paradigm in SLE treatment, emphasizing the rationale for earlier, multitargeted therapeutic approaches, whether through single ‘double-hit’ agents or combination regimensIdentify and describe specific examples of emerging ‘double-hit’ single therapies for SLE, including telitacicept, ianalumab, and BCMA-CD19 CAR-T cell therapyDiscuss the role of newer oral small molecule kinase inhibitors, such as upadacitinib and deucravacitinib, as potential additions to standard of care in SLE, considering their mechanisms and current developmental statusReferences Agmon-Levin N, Ignatenko S, Gordienko A, et al. OP0089 phase 2 safety and efficacy of subcutaneous (s.C.) dose ianalumab (vay736; anti-baffr mab) administered every 4 weeks up to 48 weeks in patients with systemic lupus erythematosus (sle). Ann Rheum Dis. 2024;83(Suppl 1):140. doi: 10.1136/annrheumdis-2024-eular.634Jin HZ, Li YJ, Wang X, et al. Efficacy and safety of telitacicept in patients with systemic lupus erythematosus: A multicentre, retrospective, real-world study. Lupus Sci Med. 2023;10(2). doi: 10.1136/lupus-2023-001074Wang W, He S, Zhang W, et al. BCMA-CD19 compound CAR T cells for systemic lupus erythematosus: a phase 1 open-label clinical trial. Ann Rheum Dis. 2024. doi: 10.1136/ard-2024-225785Merrill JT, Tanaka Y, D’Cruz D, et al. Efficacy and safety of upadacitinib or elsubrutinib alone or in combination for patients with systemic lupus erythematosus: a phase 2 randomized controlled trial. Arthritis Rheumatol. 2024;76(10):1518–29. doi: 10.1002/art.42926Morand E, Pike M, Merrill JT, et al. Deucravacitinib, a tyrosine kinase 2 inhibitor, in systemic lupus erythematosus: a phase II, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2023;75(2):242–52. doi: 10.1002/art.42391Shah HH, Ashfaque F, Hadi Z, et al. Baricitinib in the treatment of systemic lupus erythematosus: a systematic review of randomized controlled trials. Ann Med Surg (Lond). 2024;86(8):4738–44. doi: 10.1097/ms9.0000000000002298