CAR-T Cell Multiple Myeloma,CAR T-Cell Therapy Shows Promising Efficacy in Treating Multiple Myeloma Patients Who Failed Initial Treatment

CAR-T Cell Multiple Myeloma,CAR T-Cell Therapy Shows Promising Efficacy in Treating Multiple Myeloma Patients Who Failed Initial Treatment

According to the data from Cohort B of the phase 2 CARTITUDE-2 trial presented at the 2022 EHA Annual Meeting, the CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel; Carvykti) demonstrated a very high response rate in patients with early relapsed or primary refractory multiple myeloma.

In February 2022, the U.S. Food and Drug Administration (FDA) approved cilta-cel for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody, based on the results from the CARTITUDE-1 trial.

CARTITUDE-2 (NCT04133636) aimed to further evaluate the use of cilta-cel in multiple myeloma patient populations. The primary endpoint of CARTITUDE-2 was minimal residual disease (MRD) negativity at 10-5 assessed by next-generation sequencing or next-generation flow. Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to response, and safety. As per the editor’s understanding, previously reported data from Cohort A showed an ORR of 95% in patients who had received two prior lines of therapy, with 79% achieving a complete response (CR) or better, and 90% achieving a very good partial response (VGPR) or better.

Cohort B enrolled multiple myeloma patients who experienced early relapse after initial treatment with a PI and an IMiD. According to the International Myeloma Working Group criteria, patients were required to have progressive disease within 12 months after autologous stem cell transplant (ASCT) or from the start of anti-myeloma treatment for those who did not receive ASCT.

After screening, patients underwent bridging therapy as needed prior to cilta-cel infusion. Five days before cilta-cel infusion, patients received cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2 for 3 days. On study day 1, patients received cilta-cel infusion at a target dose of 0.75 x 106 CAR-positive viable T cells/kg. Post-infusion evaluations were conducted from Day 1 to Day 100, and post-treatment evaluations from Day 101 until the end of the cohort.

In Cohort B, the median age was 58 years (range, 44-67). Most patients were male (73.7%), white (73.7%), had bone marrow plasma cells <60% (78.9%), had no extramedullary plasmacytoma (84.2%), and had no high-risk cytogenetics (84.2%). The median time from initial diagnosis was 1.15 years (range, 0.5-1.9), with a median of 1 prior line of therapy (range, 1-1), and 78.9% of patients had previously received ASCT. Notably, 21.1% of patients had triple-class exposure.

Furthermore, 15.8% of patients were triple-class refractory, 78.9% were refractory to their last line of therapy, 78.9% were lenalidomide (Revlimid) refractory, 31.6% were bortezomib (Velcade) refractory, 15.8% were daratumumab (Darzalex) refractory, and 10.5% were pomalidomide refractory.

At a median follow-up of 13.4 months (range, 5.2-21.7), cilta-cel induced an ORR of 100% (95% CI, 82.4%-100%) in 19 patients; 90% of patients achieved a CR or better, and 95% had a VGPR or better. The partial response rate with CAR T-cell therapy was 5%, and the stringent CR rate was 63%. Notably, 93.3% (95% CI, 68.1%-99.8%) of the 15 patients with evaluable minimal residual disease (MRD) values achieved MRD negativity with treatment.

Additional data showed that the median DOR was not reached with CAR T-cell therapy. The median time to first response was 1.0 month (range, 0.9-9.7), and the median time to best response was 5.1 months (range, 0.9-11.8). The 12-month progression-free survival rate with CAR T-cell therapy was 89.5% (95% CI, 64.1%-97.3%).

Peak CAR T-cell expansion occurred on Day 13 (range, 9-210), with a median CAR T-cell persistence of 77 days (range, 41-222). Levels of IL-6 and IFN-γ increased after cilta-cel infusion, peaked between Days 7 and 14, and returned to baseline levels within 2 to 3 months. Notably, the occurrence of cytokine release syndrome (CRS) was associated with peak elevations in IL-6 and IFN-γ.

CRS was reported in 84% of patients, with one patient experiencing Grade 3/4 CRS. The median time to CRS onset was 8 days (range, 5-11), and the median duration was 3.5 days (range, 1-7). Additionally, 63% of patients received tocilizumab (Actemra), and 21% were given corticosteroids for CRS. This toxicity resolved in all patients.

Neurotoxicity was reported in 26% of patients, with 3 out of 5 patients having resolved events. One patient experienced Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) with an onset of Day 11 and a duration of 4 days. Another patient developed Grade 3 motor and neurocognitive movement and neurocognitive treatment-emergent adverse events (MNTs)/parkinsonism on Day 38. Notably, this patient had at least 2 risk factors for MNTs/parkinsonism, and they showed improvement at the time of data cutoff, achieving a CR.

Regarding other safety data, any-grade hematological adverse events (AEs) included neutropenia (95%), anemia (58%), thrombocytopenia (58%), lymphopenia (32%), and leukopenia (26%). Grade 3 or 4 hematological AEs included neutropenia (90%), anemia (47%), thrombocytopenia (26%), lymphopenia (32%), and leukopenia (26%). Notably, the rates of Grade 3/4 cytopenias not improving to Grade 2 or lower by Day 60 were: thrombocytopenia 16%, lymphopenia 11%, and neutropenia 11%.

In summary, these results are consistent with the responses observed in the phase 1b/2 CARTITUDE-1 trial and Cohort A of CARTITUDE-2, and researchers continue to explore the efficacy and safety of cilta-cel in high-risk, treatment-failed multiple myeloma patients. Further positive trial results are anticipated to benefit more patients. For more information on the latest treatment approaches for hematological malignancies, feel free to inquire via email or online consultation.