Cilta-cel Induces Strong Response in Chinese Patients With Relapsed/Refractory Multiple Myeloma

Ciltacabtagene autoleucel (cilta-cel; Carvykti) produced early, deep, and durable responses in patients with relapsed/refractory multiple myeloma (RRMM) treated at 8 sites in China.¹ Investigators said the results from the pivotal phase 2 CARTIFAN-1 trial (NCT03758417) were nearly identical to those observed in US patients in the CARTITUDE-1 trial (NCT03548207).

In CARTIFAN-1, the BCMA-targeting chimeric antigen receptor (CAR) T-cell therapy induced an overall response rate (ORR) of 89.6% (95% CI, 77.3%-96.5%). The median time to first response was 0.95 months (95% CI, 0.9-5.2).

At a median follow-up of 18.0 months (range, 0.2-28.0), 77.1% (95% CI, 62.7%-88.0%) of patients achieved a complete response (CR) or better. The median time to CR or better was 3.32 months (range, 0.9-15.1).

Six patients had progressive disease, 4 due to new extramedullary plasmacytoma development and/or lytic bone lesions.

Data from the 1b/2 CARTITUDE-1 trial presented at the 2022 ASCO Annual Meeting showed that cilta-cel induced an ORR of 97.9% (95% CI, 92.7%-99.7%) among 97 evaluable US patients, including a stringent CR rate of 82.5% (95% CI, 73.4%-89.4%). Moreover, 94.8% of patients experienced a very good partial response or better.²

Previous data from CARTITUDE-1 showed that at a median follow-up of 21.7 months, patients achieved an ORR of 98.0%, with a stringent CR rate of 82.5%.³ The FDA approved cilta-cel in February 2022 for the treatment of adults with RRMM following 4 or more prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody.⁴

CARTIFAN-1 is an ongoing, open-label, confirmatory study evaluating the efficacy and safety of cilta-cel in Chinese patients with RRMM (N = 48). Investigators sought to assess the agent in Chinese patients, a population that is racially and ethnically distinct from the US-based CARTITUDE-1 study population. Notably, cilta-cel was evaluated in the context of Chinese medical practice and standard of care.

Eligible patients were diagnosed with myeloma per International Myeloma Working Group criteria and received 3 or more prior lines of therapy, including a PI and an IMiD. Unlike CARTITUDE-1, patients were not required to have received an anti-CD38 antibody because China had not approved such an agent when enrollment began. Patients were excluded if they had previous CAR T-cell therapy or BCMA-targeted therapy, or were positive for hepatitis B virus (HBV).

Patients received a single infusion of cilta-cel at a target dose 0.75 × 106 CAR T cells/kg. The median dose was 0.67 × 106 (range, 0.42-0.84 × 106) CAR T cells/kg.

Patients who initially benefited from the treatment could receive another dose in the event of disease progression at investigator discretion. Investigators measured MRD negativity (10−5 threshold) using flow cytometry on bone marrow aspirate.

The median number of previous lines of therapy was 4 (range, 3-9) and 31.3% of patients were triple-class exposed. In the study population, 85.4% of patients were PI-refractory, 91.7% were IMiD-refractory, 79.2% were both PI- and IMiD-refractory, 27.1% were daratumumab (Darzalex)-refractory, 18.8% were triple-class refractory, and 97.9% were refractory to their last line of therapy. Seventeen (35.4%) patients had previously undergone autologous stem cell transplantation (ASCT).

ORR was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), and incidence and severity of adverse events (AEs).

The median patient age was 61.0 years (range, 30-72) at baseline. The median time from diagnosis to cilta-cel infusion was 3.7 years (range, 1.4-10.2). All patients had evaluable bone marrow biopsy or aspirate samples; 20.8% had 30% to 60% of plasma cells, and 16.7% had 60% or more plasma cells. Twenty-one patients (43.8%) had a high-risk cytogenetic profile, 22.9% had t(4,14), 20.8% had del17p, and 0% had t(14;16), and 5 patients (10.4%) had extramedullary plasmacytomas.

Thirty-eight patients remained on study at the July 19, 2021, data cutoff.

Of 40 patients with evaluable samples, 39 (97.5%; 95% CI, 86.8%-99.9%) achieved MRD negativity. Thirty-five of these patients also had CR or better.

Median duration of response (DOR) was not reached. Of 43 responders, 67.2% had a DOR of 18 months or more. Thirty-three patients were still in response at the data cutoff, including 1 patient who received a cilta-cel dose below the target range and maintained stringent CR for 28 months.

The median PFS was not reached. The PFS rate was 77.0% (95% CI, 62.3%-86.5%) at 12 months and 66.8% (95% CI, 49.4%-79.4%) at 18 months. The median overall survival (OS) was not reached, and the 18-month OS rate was 78.7% (95% CI, 64.0%-88.0%).

Forty-seven patients experienced cytokine release syndrome (CRS), including 17 with grade 3/4 CRS. The median onset time was 7 days (range, 2-10) with a median duration of 5 days (range, 2-32). Forty-six (95.8%) patients received supportive measures to treat CRS, and 90.4% of cases resolved by data cutoff.

Five cases of CRS had not resolved by death. Five patients experienced second wave CRS and 3 patients experienced hemophagocytic lymphohistiocytosis.

Ten patients died following cilta-cel infusion, 2 within the first 30 days (before first disease evaluation) and the remainder within 60 days (n = 4) or within 100 days (n = 4). Investigators determined that 8 of the deaths were treatment related.

Forty-one (85.4%) patients experienced infections, 28 (37.5%) of whom experienced grade 3/4 infections. The most common infections were pneumonia (35.4%), upper respiratory tract infection (33.3%), and herpes zoster (18.8%). Five (10.4%) patients had HBV reactivation, and 3 (6.3%) additional patients had new HBV infections.

All patients experienced treatment-emergent AEs (TEAEs) and 40 (83.3%) experienced grade 3/4 TEAEs. The most common grade 3/4 hematologic TEAEs were neutropenia (97.9%), leukopenia (93.8%), lymphopenia (91.7%), thrombocytopenia (54.2%), and anemia (52.1%).

The most common nonhematologic grade 3/4 TEAEs were pneumonia (31.3%), hypokalemia (22.9%), increased aspartate aminotransferase (20.8%), increased gamma-glutamyl transferase (16.7%), and increased alanine aminotransferase (10.4%).

Investigators recorded a single fatal TEAE, a case of pneumonia.

References

1. Mi JQ, Zhao W, Jing H, Fu W, et al. Phase II, open-label study of ciltacabtagene autoleucel, an anti–B-cell maturation antigen chimeric antigen receptor-t-cell therapy, in Chinese patients with relapsed/refractory multiple myeloma (CARTIFAN-1). J Clin Oncol. Published online October 21, 2022. doi:10.1200/JCO.22.00690
2. Usmani SZ, Martin TG, Berdeja JG, et al. Phase 1b/2 study of ciltacabtagene autoleucel, a BCMA-directed CAR-T cell therapy, in patients with relapsed/refractory multiple myeloma (CARTITUDE-1): two years post LPI. J Clin Oncol. 2022;40(suppl 16):8028. doi:10.1200/JCO.2022.40.16_suppl.8028
3. Martin T, Usmani SZ, Berdeja JG, et al. Updated results from CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell Maturation Antigen-directed Chimeric Antigen Receptor T-cell therapy, in patients with relapsed/refractory multiple myeloma. Blood. 2021;138(suppl 1):549. doi:10.1182/blood-2021-146060
4. US FDA approves Carvykti (ciltacabtagene autoleucel), Janssen’s first cell therapy, a BCMA-directed CAR-T immunotherapy for the treatment of patients with relapsed or refractory multiple myeloma. News release. Janssen. February 28, 2022. Accessed October 27, 2022. https://bit.ly/35yWwjv