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Abstract Introduction: Despite therapeutic advances in relapsed/refractory multiple myeloma (RRMM), optimal sequencing remains a clinical challenge. On April 5, 2024, ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, received Food and Drug administration (FDA) approval for patients with lenalidomide-refractory MM after ≥1 prior line of therapy (LOT), based on the phase III CARTITUDE-4 trial which demonstrated significant survival benefits over standard-of-care (SOC) regimens. Previously, we queried oncologists on initial CARTITUDE-4 data from ASCO 2023 and revealed that oncologist adoption was largely driven by CAR T center availability. At ASH 2024, updated CARTITUDE-4 results (median follow-up: 33.6 months) demonstrated cilta-cel's ability to induce deep and sustained minimal residual disease (MRD) negativity. Our current study assessed U.S. hematologist/oncologists' (H/O) treatment practices and further explored factors influencing clinical decision-making in response to these updated data. Methods:During a live meeting in February 2025, U.S.-based H/O who represented all major US regions were surveyed regarding their RRMM treatment practices and perceptions on updated CARTITUDE-4 data. Respondents who did not treat hematologic malignancies were excluded and not all participants responded to every question. Survey responses were collected before and after reviewing trial data and summarized using descriptive statistics. Results: Among 67 participating H/O, 61% were dual certified in hematology, 51% practiced in community settings, and the median (range) time in practice was 15 years (3-48). Prior to reviewing CARTITUDE-4 data, 36% of respondents reported referring 1–25% of their patients with RRMM for CAR T therapy in the second line (2L) setting in the past 3 months, while 34% had not referred any patients. The most frequently cited barriers to 2L CAR T use were the availability of other effective therapies [e.g. SOC or bispecific antibodies (BsAbs) on clinical trials] (43%) and availability of CAR T therapy (33%). For bridging therapy before receiving CAR T therapy, 42% of respondents preferred the regimen recommended by the CAR T center, while 15% favored a combination of BsAbs and immunomodulatory drugs (IMiDs). Before reviewing trial data, 63% of respondents preferred CAR T therapy as the next treatment for a hypothetical 66-year-old male with RRMM (1–3 prior LOT, including proteasome inhibitors + IMiD, ECOG PS of 1), assuming FDA approval. After reviewing the CARTITUDE-4 trial data, 88% of respondents preferred CAR T therapy for the same hypothetical patient—an increase of 25 percentage points (p = 0.002). The most clinically meaningful MRD findings cited from the trial included significantly increased MRD-negativity rates (49%) and deeper MRD responses (49%) with cilta-cel. Additional MRD results of clinical relevance, included MRD benefits across all prespecified subgroups (40%), more patients achieved sustained MRD negativity (25%), and rapidly achieved MRD negativity with cilta-cel (21%). Key clinical factors influencing CAR T consideration included aggressiveness of disease progression (42%), cytogenetic disease risk (34%), patient fitness (32%), and treatment history (31%). In our previous study, 58% of oncologists identified the availability of CAR T cell centers as the primary factor in therapy selection. We further explored these findings and discovered that access-related delays were also important, with 47% of respondents reporting somewhat frequent delays and 19% reporting very frequent delays due to limited CAR T center capacity. Conclusions: Updated CARTITUDE-4 efficacy data significantly reinforced U.S. H/O' preference for cilta-cel as a 2L treatment in lenalidomide-refractory MM, with MRD-negativity and depth of response identified as the most clinically impactful outcomes. These findings underscore the importance of MRD as a clinical endpoint and highlight how pivotal trial data can shape treatment paradigms and accelerate the integration of novel therapies into earlier lines of care. While enthusiasm for cilta-cel is high, real-world adoption remains constrained by access limitations, logistical barriers, and patient-specific considerations.