Divergence between regulatory approvals and guideline recommendations in multiple myeloma: Helping solve physician’s dilemmas with a real-time updated evidence library.

e23047 Background: Despite the large number of trials and emergence of new therapies/combinations in multiple myeloma (MM), guidelines highlight uncertainties in ranking all treatment options and providing therapy sequencing recommendations. Physicians must exercise their best judgement and rely on package inserts and individual trial data for treatment decisions. For therapies for which regulatory assessment is delayed or not pursued, there is additional uncertainty around the availability and quality of the data informing off-label use. We aimed to understand the alignment between guideline recommendations and regulatory endorsement in multiple myeloma and assess whether creation of a living evidence library could help address these gaps. Methods: We conducted a REal-time AI-assisted Living systematic review (REAL-SLR) in MM, compliant with PRISMA and Cochrane guidelines. Clinical trials reporting on efficacy and/or safety of treatments for MM were identified in PubMed and international conference proceedings and included based on predefined criteria. Critical clinical data on efficacy (survival and response), safety and quality of life was extracted in the REAL-SLR. Results: The daily-updated REAL-SLR included 712 critical path studies in MM (301-newly diagnosed; 413-relapsed/refractory) as of January 19, 2026. Evidence was stratified according to disease stage, prior treatment exposure/refractoriness, risk/cytogenetic profile, transplant eligibility, treatment pathway, and intervention class, and mapped against regulatory documents and international guidelines. Among 266 studies reporting on treatments recommended in US guidelines, only 153 (58%) involved FDA-approved regimens/combinations. In contrast, among 144 studies supporting therapies recommended by the European Hematology Association, majority (85%) aligned with European Medicines Agency approvals. Similar REAL-SLRs conducted in non-small cell lung cancer, breast cancer, and prostate cancer, reveal a better overlap between US guidelines and FDA endorsement compared to MM (83%, 75%, and 90%, respectively). Trials stratification and daily maintenance of REAL-SLR allowed real-time identification of supporting evidence for therapies investigated, recommended, or discussed outside regulatory labeling, with almost half of the REAL SLR studies published just in the past 2 years and 5 new drug approvals in 2025 in MM. Conclusions: There is a pronounced guideline-regulatory divergence despite substantial growth and diversification of evidence in the past years across newly diagnosed and relapsed/refractory MM. Continuously maintained REAL-SLR that reflects disease and treatment pathways can complement guidelines and regulatory documentation, providing a living data support tool to make informed decisions for patient treatment.