This CARTITUDE-4 subgroup analysis evaluated long-term progression-free survival outcomes with ciltacabtagene autoleucel (cilta-cel) in patients with standard-risk cytogenetics among those with lenalidomide-refractory multiple myeloma after 1-3 prior lines of therapy. With 33.6 months median follow-up in the intent-to-treat population, patients with standard-risk disease achieved a remarkable 30-month PFS rate of 71.0% (95% CI: 58.8-80.2) with cilta-cel versus 43.2% (31.3-54.5) with standard-of-care triplet therapy, while the as-treated population (59 patients who received cilta-cel infusion, excluding those who progressed during bridging) demonstrated even more impressive outcomes with an 80.5% 30-month PFS rate (95% CI: 67.2-88.8). Notably, this represented superior outcomes compared to the heavily pretreated CARTITUDE-1 population where standard-risk patients achieved 59.9% 30-month PFS, supporting earlier use of cilta-cel in the treatment course. Among the as-treated standard-risk population, only 8 progression events occurred within the first year and 4 beyond one year, while all 26 patients (100%) who achieved MRD-negative complete response at 12 months remained progression-free at 30 months. The findings demonstrate that 80% of standard-risk patients remained progression-free and off treatment at 2.5 years, with this rate reaching 100% among those achieving 12-month MRD-negative CR, establishing the profound and durable benefit of a single cilta-cel infusion in this population and supporting its use as early as second-line therapy.

Key Points:

• Superior PFS in Standard-Risk Disease: Intent-to-treat analysis showed 30-month PFS of 71.0% versus 43.2% for standard-of-care in standard-risk patients; as-treated population achieved 80.5% 30-month PFS rate, demonstrating exceptional durability
• Earlier Line Therapy Benefits: Standard-risk patients in CARTITUDE-4 (1-3 prior lines) achieved 80.5% 30-month PFS versus 59.9% in heavily pretreated CARTITUDE-1 patients (3+ prior lines), supporting cilta-cel use as early as second line
• MRD-Negative CR Predicts Cure-Like Outcomes: All 26 patients (100%) who achieved MRD-negative complete response at 12 months by next-generation sequencing (sensitivity 1 in 100,000) remained progression-free at 30 months, suggesting potential functional cure in this subgroup
• Low Late Progression Rate: Among 59 as-treated standard-risk patients, only 8 PFS events occurred within first year and merely 4 events beyond one year, indicating that patients who remain progression-free past 12 months have excellent long-term outcomes
• Treatment-Free Remission: 80% of standard-risk patients remained progression-free and off treatment at 2.5 years, demonstrating durable benefit from single infusion without need for continuous therapy
  Standard-Risk Definition: Excluded patients with del(17p), t(14;16), t(4;14), or gain/amplification of 1q (105 patients excluded), as well as those with unknown cytogenetics (12 patients), focusing on truly favorable-risk biology
• As-Treated Population Analysis: 176 of 208 randomized patients received cilta-cel infusion; 32 patients progressed or died during bridging therapy, highlighting importance of effective disease control during manufacturing period
• High Dose Intensity Maintained: Patients received bridging therapy with either pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone, followed by lymphodepletion and single cilta-cel infusion
• MRD Evaluation Challenges: Of 59 standard-risk as-treated patients, 14 were not evaluable for MRD due to calibration failure (12 patients), sample unavailability (1), or indeterminate results (1), emphasizing need for robust MRD testing protocols

Conclusion:
The CARTITUDE-4 standard-risk subgroup analysis provides compelling evidence that ciltacabtagene autoleucel delivers exceptional, potentially curative outcomes in patients with favorable cytogenetics when used earlier in the treatment course, fundamentally challenging traditional approaches that reserve CAR-T therapy for heavily pretreated disease. The remarkable finding that 80.5% of as-treated standard-risk patients remained progression-free at 30 months, with 80% both progression-free and off treatment, represents outcomes unprecedented in relapsed/refractory myeloma and approaches cure-like durability seen primarily in upfront autologous transplant for newly diagnosed disease. Most strikingly, the 100% progression-free rate at 30 months among all 26 patients achieving MRD-negative complete response at 12 months suggests that deep, early response to cilta-cel may identify a subset of standard-risk patients for whom a single infusion provides functional cure, eliminating the need for continuous therapy and fundamentally altering the disease trajectory. The superior outcomes compared to CARTITUDE-1 (80.5% vs 59.9% 30-month PFS in standard-risk patients) provide definitive evidence that earlier intervention with cilta-cel yields better results, likely reflecting lower tumor burden, less treatment-resistant clones, and better patient fitness at earlier lines of therapy. The low rate of late progression events (only 4 beyond one year among 59 patients) suggests that most relapses occur early, and patients maintaining remission through the first year have exceptional prospects for durable disease control, potentially identifying a window for treatment de-escalation or discontinuation strategies in future trials. These findings have immediate clinical implications for treatment sequencing decisions in standard-risk relapsed myeloma, where the traditional approach of exhausting multiple lines of conventional therapy before considering CAR-T may deprive patients of their best chance for long-term remission, particularly given that 32 of 208 randomized patients (15%) progressed or died during bridging before receiving cilta-cel, underscoring the risk of delaying definitive therapy. For standard-risk patients experiencing first relapse with lenalidomide-refractory disease, these data support strong consideration of cilta-cel as a preferred second-line option rather than sequential conventional triplets, with the potential to achieve treatment-free remission in 80% and possible functional cure in the subset achieving early MRD-negative complete response.

Authors:
Luciano Costa, Albert Oriol, Dominik Dytfeld, Salomon Manier, Peter Voorhees, Yi Lin, Myo Htut, Wilfried Roeloffzen, Phoebe Joy Ho, Urvi Shah, Man Zhao, Quanlin Li, Agnes Balogh, Katherine Li, Ana Slaughter, Nina Benachour, Carolina Lonardi, Arnab Ghosh, Huabin Sun, Nikoletta Lendvai, Tamar Lengil, Nitin Patel, Mythili Koneru, Erika Florendo, Octavio Costa, Vrinda Mahajan, Paula Rodriguez-Otero, Christopher Strouse, Keith Stewart, and Surbhi Sidana.

Presented at ASH 2025 (Abstract #94)