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-2 (NCT04133636) is a phase II, multi-cohort clinical trial designed to assess the efficacy and safety of the anti-BCMA CAR-T cell therapy, Ciltacabtagene Autoleucel (cilta-cel), in patients with multiple myeloma. This update reports on the efficacy and safety data from Cohort A (patients who received 1-3 prior lines of therapy and are lenalidomide-refractory) and Cohort B (early relapse: relapse within 12 months after ASCT or initial myeloma therapy), with a median follow-up time of approximately 29 months for both cohorts.
Study Methods
Patients in Cohort A and Cohort B had not previously received CAR-T or targeted BCMA therapy. All enrolled patients received a single infusion of cilta-cel (target dose: 0.75×10^6/kg) 5-7 days after lymphodepletion therapy. The primary endpoint was the measurable residual disease (MRD) negativity rate (threshold of 10^-5, based on NGS or flow cytometry).
Study Results
As of April 2023, 20 patients in Cohort A were treated with cilta-cel, 35% of whom had high-risk cytogenetics; on average, patients had received 2 lines of prior therapy; 95% were refractory to their last treatment; 40% were triple-refractory; 85% had previously undergone ASCT, with a median follow-up of 29.9 months. In Cohort B, 19 patients received cilta-cel treatment, 16% of whom had high-risk cytogenetics, 79% were refractory to their last treatment, 16% were triple-refractory, and 79% had previously undergone ASCT, with a median follow-up of 27.9 months.
Results showed that all 17 evaluable patients in Cohort A achieved MRD negativity, while in Cohort B, 14 out of 15 evaluable patients (93%) achieved MRD negativity. The overall response rate (ORR) for patients in Cohort A and Cohort B was 95% (≥CR 90%) and 100% (≥CR 90%), respectively. The median progression-free survival (mPFS) has not yet been reached for either group, with 2-year PFS rates of 75% (Cohort A) and 73% (Cohort B), and 2-year overall survival rates (OS) of 75% (Cohort A) and 84% (Cohort B), respectively.
In terms of safety, Cohort A experienced hematological adverse events (TEAEs) primarily consisting of leukopenia (60% occurrence, with one case of grade 3-4), lymphopenia (80% occurrence, with two cases of grade 3-4), and thrombocytopenia (80% occurrence, with one case of grade 3-4). Cohort B’s hematological AEs remained consistent with previous reports, with no new AEs observed. Additionally, no new CAR-T-related neurological toxic events or second primary malignancies (SPM) were observed in Cohort A; however, Cohort B reported one new neurological toxicity event, grade 2 sensory loss (which subsequently resolved), and one new SPM (choroidal melanoma). In Cohort A, a new death (total of five) occurred on day 666, due to disease progression; in Cohort B, a new death (total of four) occurred on day 749, due to cardiac arrest (not related to treatment).
Study Conclusion
With longer follow-up data, this study demonstrates that cilta-cel provides good efficacy, achieving deep and sustained remission in patients with multiple myeloma who have received 1-3 prior lines of treatment and are lenalidomide-refractory or have early relapse. Aside from one CAR-T-related neurological event in Cohort B, no new safety issues related to CAR-T treatment were observed.
Expert Commentary
Based on the favorable safety profile of cilta-cel previously observed in patients treated with four or more therapies, the CARTITUDE-2 study updated efficacy and safety data for Cohort A (patients who received 1-3 prior lines of therapy and are lenalidomide-refractory) and Cohort B (early relapse: within 12 months after ASCT or initial myeloma treatment). MRD negativity was achieved in 100% of evaluable patients in Cohort A and 93% in Cohort B. The overall response rates (ORR) for Cohorts A and B were 95% (≥CR 90%) and 100% (≥CR 90%), respectively. The median progression-free survival (mPFS) has not yet been reached for either group, with 2-year PFS rates of 75% (Cohort A) and 73% (Cohort B), and 2-year overall survival rates (OS) of 75% (Cohort A) and 84% (Cohort B). Regarding safety, the main hematological adverse events in Cohort A included leukopenia (60%, one case grade 3-4), lymphopenia (80%, two cases grade 3-4), and thrombocytopenia (80%, one case grade 3-4). No new AEs were reported in Cohort B. Other adverse events were manageable. Based on the efficacy and safety data from this study, there is significant support for advancing the line of therapy for cilta-cel treatment.
