Highlight
– Cilta-cel induces a median overall survival of over 5 years in heavily pretreated RRMM patients.
– One-third of patients remain progression-free for ≥5 years following a single cilta-cel infusion without maintenance therapy.
– All evaluated patients at one center showed deep and durable minimal residual disease negativity and PET-CT negativity at ≥5 years.
– Baseline immunological parameters including naïve T cell fraction and tumor burden trends correlate with long-term progression-free survival.
– The safety profile remains consistent and manageable, supporting cilta-cel’s potential as a curative approach in RRMM.
Study Background and Disease Burden
Multiple myeloma (MM) is a malignant plasma cell disorder characterized by recurrent relapses despite advances in therapy including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Relapsed/refractory multiple myeloma (RRMM) presents significant treatment challenges and a poor prognosis, especially among heavily pretreated patients who have exhausted standard options. Median survival in this population remains limited, underscoring the urgent need for novel, effective therapies that can achieve deep, durable remissions and improve long-term outcomes. Chimeric antigen receptor T-cell (CAR-T) therapies targeting B-cell maturation antigen (BCMA) have emerged as promising options, with ciltacabtagene autoleucel (cilta-cel) demonstrating striking early clinical efficacy. However, long-term follow-up data to firmly establish the durability of remission, survival benefit, and safety are crucial to delineate cilta-cel’s curative potential in RRMM.
Study Design
CARTITUDE-1 was a multicenter, single-arm clinical trial evaluating the efficacy and safety of cilta-cel in adult patients with RRMM who had received a median of six prior lines of therapy. A total of 97 patients received a single infusion of cilta-cel, a genetically engineered autologous CAR-T cell product targeting BCMA. Key endpoints included overall survival (OS), progression-free survival (PFS), minimal residual disease (MRD) status assessed by next-generation sequencing with a sensitivity threshold of at least 10-5, and imaging assessments via positron emission tomography-computed tomography (PET-CT). Median follow-up duration was 61.3 months—representing the longest follow-up reported to date for CAR-T therapy in RRMM. The study also explored baseline clinical and immunological biomarkers to identify predictors of long-term remission and survival. Safety was monitored throughout, focusing on known CAR-T associated adverse events such as cytokine release syndrome and neurotoxicity.
Key Findings
The median overall survival among the 97 treated patients was 60.7 months (95% confidence interval [CI], 41.9 to not estimable), representing a substantial extension compared with historical data in heavily pretreated RRMM. Remarkably, 32 patients (approximately one-third) remained alive and progression-free at five years or longer following a single cilta-cel infusion without any maintenance therapy, signifying unprecedented durability of response.
Twelve patients treated at a single center underwent comprehensive longitudinal MRD assessment and PET-CT imaging at 5 years or beyond. All these patients (100%) were MRD-negative at the 10-5 threshold and PET-CT-negative, confirming eradication of detectable myeloma at both molecular and imaging levels. This depth of sustained remission strongly supports the potential curative effect of cilta-cel in this population.
Baseline characteristics of patients with ≥5-year progression-free survival were generally comparable to those who relapsed before 5 years, including the prevalence of high-risk cytogenetics and extramedullary disease, indicating that cilta-cel may overcome some adverse risk features. However, trends associated with durable remission included lower baseline tumor burden, higher fractions of naïve T cells in the infused CAR-T product, elevated T cell-to-neutrophil ratios in peripheral blood, and higher baseline hemoglobin and platelet counts. Furthermore, patients with higher effector-to-target cell ratios in the drug product were more likely to achieve long-term progression-free status, suggesting the importance of immune competence and CAR-T product composition in sustained efficacy.
The safety profile of cilta-cel remained consistent with previous reports from CARTITUDE-1, with no new or unexpected adverse events observed during extended follow-up. Cytokine release syndrome and neurotoxicity episodes were manageable with standard interventions. No late-onset toxicities or secondary malignancies related to therapy were identified, reinforcing the treatment’s safety over the long term.
Expert Commentary
CARTITUDE-1 provides landmark data that may redefine therapeutic expectations for heavily pretreated RRMM patients. Achieving a median OS exceeding five years and sustained MRD negativity at five years post-treatment is unprecedented within this refractory population historically characterized by poor prognosis and limited survival. The findings imply that cilta-cel does not simply control disease but may eradicate malignant clones, thus fulfilling criteria of a functional cure.
Importantly, the correlation between immune biomarkers and long-term outcomes suggests avenues for optimizing CAR-T product manufacturing and patient selection to enhance efficacy. Strategies that augment naïve T cell fractions in the infusion product or optimize patient baseline immune status may further improve durable remission rates.
Nevertheless, as a single-arm study without a comparator, CARTITUDE-1 results require contextualization within broader clinical evidence, and confirmatory studies or real-world datasets will further cement cilta-cel’s role. Potential limitations include the selected patient population and the need to monitor longer-term effects beyond five years. Integration with other modalities such as consolidation or maintenance therapies warrants investigation to optimize outcomes.
Conclusion
Ciltacabtagene autoleucel represents a paradigm shift in the management of relapsed/refractory multiple myeloma, demonstrating remarkable long-term remission and survival benefits. CARTITUDE-1’s 5-year data provide the first compelling evidence supporting cilta-cel’s curative potential in RRMM patients refractory to multiple prior therapies. The durable molecular and imaging remission, coupled with a consistent safety profile, supports broader therapeutic adoption and ongoing research to expand access and refine treatment algorithms. This breakthrough offers renewed hope for improving survival and quality of life in this challenging oncologic setting.
References
Jagannath S, Martin TG, Lin Y, Cohen AD, Raje N, Htut M, Deol A, Agha M, Berdeja JG, Lesokhin AM, Liegel JJ, Rossi A, Lieberman-Cribbin A, Usmani SZ, Dhakal B, Parekh S, Li H, Wang F, Montes de Oca R, Plaks V, Sun H, Banerjee A, Schecter JM, Lendvai N, Madduri D, Lengil T, Zhu J, Koneru M, Akram M, Patel N, Costa Filho O, Jakubowiak AJ, Voorhees PM. Long-Term (≥5-Year) Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma. J Clin Oncol. 2025 Sep;43(25):2766-2771. doi: 10.1200/JCO-25-00760. Epub 2025 Jun 3. PMID: 40459151; PMCID: PMC12393059.
