Editor's Note: From April 14 to 17, 2024, the 50th European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting was grandly held in Glasgow, UK, a city renowned for its historical significance. This year marks the 50th anniversary of EBMT, and the event gathered leading figures in the field of hematopoietic stem cell transplantation and over 6,000 hematology experts from around the world. The attendees reviewed the remarkable achievements in the fields of hematology and bone marrow transplantation over the past 50 years and explored forward-looking patient management strategies. At the conference, chimeric antigen receptor T-cell (CAR-T) therapy, a highlight of this meeting, showcased a series of breakthroughs in the treatment of multiple myeloma and lymphoma, attracting significant attention. This issue features a special invitation to Professor Jun Ma from the Harbin Institute of Hematological Oncology to provide an insightful interpretation of five major research studies in the field of CAR-T cell therapy. Here, we present a compilation of these insights for our readers.

Study Background

CARTITUDE-4 (NCT04181827) is a phase III randomized clinical trial comparing the efficacy of the BCMA-targeted CAR-T cell therapy ciltacabtagene autoleucel (cilta-cel) to standard of care (SOC) therapies—pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd)—in patients with lenalidomide-refractory multiple myeloma. The study authors reported on the efficacy and safety of cilta-cel treatment.

Study Methods

Patients who had received 1-3 prior lines of therapy, including proteasome inhibitors and immunomodulatory drugs, were included. After leukapheresis, bridging therapy (DPd [28-day cycles] or PVd [21-day cycles]), and lymphodepletion, patients received a single infusion of cilta-cel (target dose, 0.75×10^6 cells/kg). Treatment responses and disease progression were assessed using IMWG criteria; measurable residual disease (MRD) negativity (threshold of 10^-5) was evaluated using next-generation sequencing from day 56 post-infusion; time-to-event endpoints were analyzed using the Kaplan-Meier method.

Study Results

As of November 1, 2022, out of 208 patients randomly assigned to the cilta-cel group, 176 received cilta-cel treatment. The median age was 61 years, 34% had received first-line treatment, 6% were ISS III stage, 60% had high-risk cytogenetics, 17% had extramedullary plasmacytomas, and 13% had a high tumor burden; 11% were triple-class refractory. The median follow-up time from randomization was 16 months.

Results showed that the median progression-free survival (PFS) was not reached, with a 12-month PFS rate from infusion of 85% and a 12-month overall survival (OS) rate of 92%. Among the 176 treated patients, 175 achieved an objective response (ORR: 99%), including 86% achieving complete response (CR). The median time to first response was 2.1 months, with responses deepening over time.

The median duration of response was not reached. Of the treatment group, 72% (88% of the 144 evaluable patients for MRD) achieved MRD negativity at any time point. Among the 144 MRD-evaluable patients, 111 (77%) achieved both MRD negativity and ≥CR. Patients who achieved sustained MRD negativity and/or ≥CR had improved PFS compared to those who remained MRD positive and/or did not reach CR (HR=0.36; 95%CI: 0.15-0.88; P=0.0196); their 12-month PFS rates were 89% and 71%, respectively.

Safety Profile

The most common CAR-T cell-related toxicity was cytokine release syndrome (CRS) (76% at any grade; 1% grade 3). Overall CAR-T cell neurotoxicity rate was 21% (3/4 grade at 3%). Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 5% of patients (no grade 3/4). Other neurotoxicities occurred in 17% of patients (3/4 grade at 2%); these included 9% of patients experiencing cranial nerve palsies (CNP) (1% grade 3), 3% with peripheral neuropathy (1% grade 3/4), and one patient with a grade 1 motor/neurocognitive treatment-related adverse event (MNT). As of the clinical cut-off, all cases of CRS and ICANS had resolved; except for two cases of CNP and peripheral neuropathy, and one case of MNT had not resolved.

Study Conclusion

This analysis demonstrated the potent effect of cilta-cel in patients with multiple myeloma who are lenalidomide-refractory after receiving 1-3 lines of therapy. Compared to a similar real-world population reported by Lecat et al. in Front Oncol 2021, which showed a 12-month PFS rate of less than 50%, the 12-month PFS rate for cilta-cel treatment was 85%, indicating a more favorable outcome.

Expert Commentary

This phase III CARTITUDE-4 study analyzed the efficacy and safety of cilta-cel compared to standard treatments in patients with multiple myeloma who had received 1-3 prior lines of treatment. With a median follow-up of 16 months, the median PFS was not reached, with a 12-month PFS rate of 85% and an OS rate of 92%. The study treatment achieved a 99% ORR, including 86% reaching ≥CR. The median time to first response was 2.1 months, with responses deepening over time, and the median duration of response was not reached. The most common CAR-T cell-related toxicity was CRS (76% at any grade; 1% grade 3). Overall CAR-T cell neurotoxicity rate was 21% (3% grade 3/4). ICANS occurred in 5% of patients (no grade 3/4). Safety was manageable. The data from the CARTITUDE-4 study provides a new treatment option for patients with first relapse.