Introduction: A Paradigm Shift in Early Relapse Management
The management of multiple myeloma (MM) has been revolutionized over the last decade by the introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies. However, the emergence of lenalidomide-refractory disease early in the treatment course represents a significant clinical hurdle. For patients who fail lenalidomide-based regimens in the first to third line of therapy, subsequent outcomes have historically been suboptimal with conventional triplet or quadruplet combinations. The CARTITUDE-4 trial was designed to address this unmet need by evaluating ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy, against the current standard of care (SoC).
Highlighting the CARTITUDE-4 Update
The updated analysis of the CARTITUDE-4 trial provides a definitive look at the long-term efficacy and, most importantly, the overall survival (OS) benefit of cilta-cel. Key highlights include:
1. A 45% reduction in the risk of death (HR 0.55) compared to standard-of-care regimens.
2. Superior progression-free survival (PFS) with the median not yet reached in the cilta-cel arm at 33.6 months.
3. Consistent safety profiles with manageable, though significant, hematologic toxicities.
Background: The Challenge of Lenalidomide Resistance
Lenalidomide is a cornerstone of frontline MM therapy. Unfortunately, its widespread use as maintenance therapy means that most patients are already refractory to it by the time they experience their first relapse. Once a patient becomes lenalidomide-refractory, the duration of response to subsequent lines of therapy typically diminishes. While combinations like pomalidomide-bortezomib-dexamethasone (PVd) or daratumumab-pomalidomide-dexamethasone (DPd) are effective, they require continuous administration and eventually lead to disease progression. Cilta-cel offers a ‘one-and-done’ treatment approach with the potential for deep, durable molecular remissions.
Study Design and Methodology
CARTITUDE-4 is an open-label, multicentre, randomised, phase 3 trial conducted across 81 sites globally. The study enrolled 419 adults with lenalidomide-refractory MM who had received one to three prior lines of therapy. Patients were required to have prior exposure to both a PI and an IMiD.
Interventions and Stratification
Participants were randomly assigned (1:1) to receive either:
1. Cilta-cel: Following apheresis and bridging therapy (physician’s choice of PVd or DPd), patients underwent lymphodepletion followed by a single infusion of cilta-cel (target dose 0.75 × 10^6 CAR-positive viable T cells per kg).
2. Standard of Care (SoC): Physician’s choice of PVd or DPd, administered until disease progression.
Stratification factors included the choice of SoC regimen, International Staging System (ISS) stage, and the number of previous treatment lines. The primary endpoint was PFS, while overall survival served as a critical secondary endpoint in this interim analysis.
Key Findings: Unprecedented Survival and Efficacy
At a median follow-up of 33.6 months, the results favor cilta-cel across all primary and key secondary metrics.
Progression-Free Survival (PFS)
The median PFS for the cilta-cel group was not reached (95% CI 34.5 months–not evaluable). In stark contrast, the SoC group reached a median PFS of only 11.8 months (9-7–14.0). This translates to a hazard ratio (HR) of 0.29 (95% CI 0.22–0.39), representing a 71% reduction in the risk of disease progression or death. The durability of the response in the cilta-cel arm suggests that a significant proportion of patients may achieve long-term disease control.
Overall Survival (OS)
The most striking finding of this updated analysis is the statistically significant improvement in OS. Median OS was not reached in either arm; however, the cilta-cel group demonstrated a clear survival advantage with an HR of 0.55 (95% CI 0.39–0.79; p=0.0009). This is one of the first instances where a CAR-T therapy has demonstrated a clear OS benefit over active standard-of-care comparators in an early-line setting for multiple myeloma.
Response Rates and Depth
While specific overall response rates (ORR) were previously reported, the updated data reinforces the depth of response achieved with cilta-cel. A higher proportion of patients in the cilta-cel arm achieved complete response (CR) or better and minimal residual disease (MRD) negativity compared to those receiving SoC.
Safety and Tolerability Profile
The safety profile of cilta-cel in this earlier-line population remains consistent with previous reports, though the intensity of treatment-emergent adverse events (TEAEs) remains a consideration for clinicians.
Hematologic Toxicities
Grade 3 or 4 TEAEs were common in both groups. Grade 4 neutropenia occurred in 73% of the cilta-cel group compared to 54% in the SoC group. Anaemia was the most common Grade 3 event in the cilta-cel arm (35%). These cytopenias are generally manageable with supportive care but require vigilant monitoring in the post-infusion period.
Infections and Mortality
Serious TEAEs occurred in 47% of patients in both groups. Deaths due to treatment-related adverse events were rare but present: six deaths (3%) in the cilta-cel group and five (2%) in the SoC group. Notably, the majority of treatment-related deaths in both arms were due to infections, highlighting the immunosuppressive nature of both CAR-T therapy and intensive triplet regimens.
Expert Commentary: Clinical Implications
The CARTITUDE-4 results are transformative. Achieving a hazard ratio of 0.55 for overall survival in a population that has already failed lenalidomide is a landmark achievement. In previous years, the debate surrounding CAR-T therapy in myeloma focused on whether these therapies should be reserved for the ‘end-of-the-road’ late-line settings. The data now strongly suggests that moving cilta-cel into the second or third line provides a significant survival advantage that may not be recaptured if the therapy is delayed.
Mechanistic Insights
The success of cilta-cel is attributed to its dual-epitope binding design, which targets two distinct regions of the BCMA protein. This high-affinity binding likely contributes to the high rates of MRD negativity. Furthermore, administering CAR-T cells earlier in the disease course—when a patient’s T-cell repertoire is less exhausted by multiple prior lines of cytotoxic chemotherapy—may enhance the expansion and persistence of the CAR-T product.
Study Limitations
Despite the positive results, the open-label nature of the trial is a potential limitation, although the objective nature of endpoints like OS and PFS minimizes bias. Additionally, the complexity and cost of CAR-T cell manufacturing and the requirement for specialized treatment centers remain barriers to global access.
Conclusion: A New Standard for Early Relapse
The updated analysis of CARTITUDE-4 confirms that cilta-cel is superior to standard triplet regimens for lenalidomide-refractory multiple myeloma after the first relapse. With a significant improvement in overall survival and a 71% improvement in PFS, cilta-cel should be considered a preferred treatment option for eligible patients in this setting. These findings reinforce the importance of early intervention with highly effective cellular therapies to alter the natural history of the disease.
Funding and Clinical Trial Information
This study was funded by Johnson & Johnson and Legend Biotech USA. ClinicalTrials.gov Identifier: NCT04181827.
References
1. Einsele H, San-Miguel J, Dhakal B, et al. Cilta-cel in lenalidomide-refractory multiple myeloma (CARTITUDE-4): an updated analysis including overall survival from an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2026;27(2):254-268. doi:10.1016/S1470-2045(25)00653-9.
2. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N Engl J Med. 2023;389(4):335-347. (Original PFS report).
