The Phase 2 iMMagine-1 registrational trial evaluated anitocabtagene autoleucel (anito-cel), an anti-BCMA CAR-T therapy featuring a novel D-domain binder with unique attributes including small size, simple structure, and fast off-rate designed to enhance transduction efficiency and reduce tonic signaling risks. Among 117 heavily pretreated patients with relapsed/refractory multiple myeloma (median 5 prior lines, 86% triple-class refractory, 40% penta-drug refractory) followed for a median 12.6 months, the investigator-assessed overall response rate reached 97% with 68% complete response/stringent complete response rate and median time to first response of only 1 month. Remarkably, 93% of evaluable patients (70/75) achieved MRD negativity at sensitivity of 1 in 100,000, with 78% achieving ultra-sensitive MRD negativity at 1 in 1,000,000, both occurring at median 1 month post-infusion. The progression-free survival rates at 12 and 18 months were 79% and 66% respectively, with overall survival rates of 95% and 90%, while median PFS and OS have not been reached. Most notably, the safety profile showed no delayed neurotoxicity including zero cases of Parkinsonism, cranial nerve palsies, or Guillain-Barré syndrome across both Phase 1 and Phase 2 studies, no immune effector cell-associated enterocolitis, mild cytokine release syndrome (85% Grade 1 or less, 97% resolved within 10 days), minimal ICANS (8% any grade, only 1% Grade 3), and manageable cytopenias, establishing anito-cel as potentially best-in-class for safety among BCMA-targeted CAR-T therapies.

Key Points:

• Exceptional Response Rates: 97% overall response rate (114/117) with 68% complete response/stringent complete response (79/117), achieved rapidly at median 1 month from infusion (range 0.9-13.4 months)
• Universal Deep MRD Negativity: Among 75 evaluable patients, 93% achieved MRD negativity at 1 in 100,000 sensitivity and 78% at ultra-sensitive 1 in 1,000,000 sensitivity, both at median 1 month, representing among the highest and fastest MRD negativity rates reported for CAR-T therapy
• Durable Disease Control: 12-month and 18-month PFS rates of 79% and 66% with median PFS not reached; 12-month and 18-month OS rates of 95% and 90% with median OS not reached after 12.6 months median follow-up
• Zero Delayed Neurotoxicity: Across both Phase 1 (38.1 months median follow-up) and Phase 2 studies, no cases of Parkinsonism, cranial nerve palsies, Guillain-Barré syndrome, or any non-ICANS neurotoxicity observed, distinguishing anito-cel from other BCMA CAR-T products
• Minimal ICANS: Only 8% experienced any grade ICANS (4 Grade 1, 4 Grade 2, 1 Grade 3), dramatically lower than typical 10-20% rates seen with other BCMA CAR-T therapies
• Mild, Transient CRS: 85% experienced Grade 1 or less CRS (including 15% with no CRS), 97% had CRS resolution within 10 days of infusion, median onset day 4 with median duration 2 days; only one Grade 5 CRS event
• Manageable Blood Counts and Infections: Grade 3/4 cytopenias included neutropenia (66%), anemia (24%), and thrombocytopenia (24%); Grade 3/4 infections occurred in only 9% of patients
• No IEC-Associated Complications: Zero cases of immune effector cell-associated enterocolitis or secondary T-cell origin malignancies reported across both trials
• Heavily Pretreated Population: Median 5 prior lines (range 3-8) with 51% receiving only 3 prior lines, 100% refractory to last line, 86% triple-class refractory, 40% penta-drug refractory, 38% high-risk cytogenetics, 15% extramedullary disease
• Outpatient Feasibility: 9% of patients (10/117) received outpatient infusion, demonstrating favorable safety profile allows for non-hospital-based administration

Conclusion:
The iMMagine-1 Phase 2 trial establishes anitocabtagene autoleucel as potentially the safest and most effective BCMA-targeted CAR-T therapy for relapsed/refractory multiple myeloma, with the novel D-domain binder technology delivering on its design promise of enhanced efficacy without increased toxicity. The unprecedented combination of 97% response rate, 68% complete response rate, 93% MRD negativity at ultra-sensitive levels achieved within one month, and complete absence of delayed neurotoxicity including zero Parkinsonism cases across both Phase 1 and Phase 2 studies represents a meaningful advance over existing CAR-T options where delayed neurotoxicity affects 10-12% of patients. The remarkably low ICANS rate of 8% (compared to typical 15-25% with other products), predominantly mild CRS that resolves within days, absence of immune effector cell-associated enterocolitis, and feasibility of outpatient administration in selected patients suggest that anito-cel's unique molecular design—featuring fast off-rate kinetics and resistance to tonic signaling—translates into tangible clinical benefits of reduced on-target/off-tumor toxicity while maintaining superior anti-myeloma activity. With durable disease control demonstrated by 79% and 66% progression-free survival at 12 and 18 months in this heavily pretreated population (median 5 prior lines, 86% triple-class refractory), median PFS of 30.2 months in the Phase 1 cohort, and continued absence of safety signals with extended follow-up, these results support anito-cel's registrational potential and suggest it may become a preferred option for patients and physicians seeking to maximize efficacy while minimizing the risk of debilitating delayed neurological complications that can significantly impact quality of life.

Authors:
Krina Patel, Binod Dhakal, Gurbakhash Kaur, Richard Maziarz, Natalie Callander, Adam Sperling, Carolina Schinke, Andrzej Jakubowiak, Noa Biran, Douglas Sborov, Cindy Varga, Larry Anderson, Abhinav Deol, Abraham Kanate, Mehmet Kocoglu, Melhem Solh, Kamalika Banerjee, Krishna Rana, Ana Kostic, Enrique Granados, Carolyn Jackson, Christopher Heery, Ciara Louise Freeman, Tim Welliver, and Matthew Frigault. 

Presented at ASH 2025 (Abstract #256).