Abstract CT103: Ciltacabtagene autoleucel in high-risk smoldering myeloma: Results from the CAR-PRISM trial

Background: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy, is approved for patients with relapsed/refractory multiple myeloma after 1 line of therapy. In the CAR-PRISM trial, we hypothesized that early use of cilta-cel in patients with high-risk smoldering myeloma (HR-SMM) would yield even higher efficacy with the potential for cure. Here, we report the initial safety and efficacy results from the complete study cohort. Methods: In this single-center, phase 2 study, patients received a single infusion of cilta-cel at target doses of 0.3, 0.5, or >0.5×106 CAR+ T cells/kg following lymphodepleting chemotherapy. No induction or bridging therapy was administered. High-risk SMM was defined by the 20/2/20 model or bone marrow plasma cells >10% with additional adverse features. Patients with >40% infiltration were excluded. Primary endpoint was the incidence of dose-limiting toxicities (DLTs) and treatment-emergent adverse events (AEs); key secondary endpoints included overall response rate and minimal residual disease (MRD) negativity. Results: As of December 31, 2025, 20 patients (median age, 58 years; 6 women) received cilta-cel. No pre-specified DLTs were observed during the dose-escalation phase. The most common AEs were transient hematologic toxicities (neutropenia grade 4: 11/20, grade 3: 7/20; median duration 3 days). Cytokine release syndrome occurred in all patients (grade 1: 17/20, grade 2: 3/20). Non-ICANS neurologic toxicities (NINTs) occurred in seven patients, predominantly at the >0.5×106 dose level; five events were low grade and included facial palsy, tremor or paresthesia. Among two patients with movement and neurocognitive treatment-emergent AEs (MNTs); one patient’s work-up demonstrated CAR-T persistence and testing suggestive of a pre-existing synucleinopathy characterized by phosphorylated α-synuclein on skin biopsy and abnormal dopamine transporter imaging, whereas the other experienced grade 1 symptoms. Patients with NINTs showed significantly different longitudinal profiles, with higher absolute lymphocyte count (ALC, p<0.0001) and altered CD4:CD8 ratio (p=0.007), prompting dose reduction to 0.3×106 CAR+ T cells/kg and ALC-guided pre-emptive dexamethasone. At a median follow-up of 12 months, all patients achieved MRD negativity at 10-6 by 2 months, which is sustained. Of note, all six patients with follow-up beyond 18 months continue to have a sustained MRD negative status. For the 16 patients with ≥6 months of follow-up, the best overall response rate was 100% complete response. No progression or death events were observed. Conclusions: In this first study of CAR T-cell therapy in a precursor malignancy, cilta-cel induced rapid, deep, and sustained MRD-negative responses in all patients with HR-SMM in the absence of induction therapy. Biomarker-guided mitigation strategies may further optimize neurologic safety. Citation Format: Omar Nadeem, David Cordas dos Santos, Sarah Nikiforow, Kevin DeBraganca, Anna Bosch-Vilaseca, Elizabeth O'Donnell, Adam Sperling, Yuxin Liu, Frances Arters, Marjorie Marto, Amy Bergeron, Colin O'Donnell, Brendan Kineavy, Emilie Swenson, Kristin McHugh, Quentin Berry, Hope Wei, Emily Durlacher, Elizabeth Grimm, Rocio Montes de Oca, Denise De wiest, Robert Redd, Lorenzo Trippa, Caleb McIntire, Eric Smith, Kenneth Anderson, Nikhil Munshi, Deepu Madduri, Craig Tendler, Jordan Schecter, Mark Wildgust, Jerome Ritz, Irene Ghobrial. Ciltacabtagene autoleucel in high-risk smoldering myeloma: Results from the CAR-PRISM trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT103.