BACKGROUND: Although anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CART) therapy showed unprecedented efficacy in relapsed/refractory (R/R) multiple myeloma (MM) and is recommended as a standard of care, its availability remains limited by capacity constraints and high costs. HBI0101 is a novel second-generation optimized anti-BCMA CART developed in an academic setting. We previously reported high efficacy and manageable toxicity with HBI0101 in a frailer and higher-risk population compared to registrational trials with commercial products, and were the first to test anti-BCMA CART in patients with AL amyloidosis. This study (NCT04720313) completed accrual in February 2025, and here we present its summary analysis in MM.

METHODS: Patients had R/R MM with ≥3 prior lines of therapy, including a proteasome inhibitor, immunomodulatory agent and anti-CD38 antibody. Inclusion criteria were relatively permissive compared to other CART clinical trials, including thresholds of 30×10⁹/l platelets, creatinine clearance of 20ml/min and ECOG performance status of 2. Following the first 13 patients who received 150×10⁶ cells (n=6) and 450×10⁶ cells (n=7), all subsequent 117 patients received 800×10⁶ cells, which was found to be the recommended dose for the 1b phase.

RESULTS: Focusing on the 117/130 (90%) of patients receiving the target dose, patients had a median of 4 prior lines of therapy (range: 3-13), most (98/117, 83.8%) were triple refractory, 41/117 (35%) were penta-refractory and 23/117 (19.7%) had received prior anti-BCMA therapy. Extramedullary disease (EMD) was evident in 25/117 (19.7%); 42/117 (35.9%) had high-risk cytogenetics (t(4;14)/t(14;16)/del17p), and 73/117 (62.4%) when including 1q-gain. Sixty-five patients (55.6%) would not have met the inclusion criteria for the registrational trials of both approved anti-BCMA CART. The manufacturing success rate was 117/117 (100%), with 108/117 (92%) receiving the target dose ±20%.

The overall response rate was 107/115 evaluable patients (93%) and the complete response (CR)/stringent CR rate was 82/115 (71%). The minimal residual disease negativity rate (10⁻⁵ by flow cytometry) was 88/115 (77%). At data cutoff, with a median follow-up of 24.1 months (95% CI: 20.4-26.3), the median progression-free survival (PFS) was 14.6 months (95% CI: 11.2-20.9) and the median overall survival was 39.7 months (95% CI: 25.9-not reached (NR)).

Toxicities were overall manageable, with grade 3-4 cytopenias common (anemia 56%, thrombocytopenia 45.5%, neutropenia 97.4%). Cytokine release syndrome (CRS) occurred in 111/117 (94.9%), including 17 patients with grade 3 CRS (15.3%), only one case with grade 4 CRS and no grade 5 cases. Immune effector cell-associated neurotoxicity syndrome (ICANS) was rare (5/117, 4.3%) and mild (all of grade 1-2), and there were 3 cases of delayed neurotoxicity. Three deaths were possibly or partially attributed to CART.

In July 2023, we transitioned from a fresh to a frozen product formulation. PFS with the frozen product was numerically improved, with a median of 19.5 months (95% CI: 12.1-NR) compared to 12.1 months (95% CI: 8.5-18.6), however, it was not statistically significant at this point, with a much shorter follow-up for the frozen product cohort. In a multivariable analysis, the most significant factors associated with worse PFS were extramedullary disease (hazard ratio (HR) 3.8, 95% CI: 1.9-7.4, p<0.0001) and prior anti-BCMA therapy (HR 3.3, 95% CI: 1.5-7.2, p=0.002). Incompatibility with the inclusion criteria of at least one of the registrational trials of commercial CART (KarMMa, CARTITUDE 1) was also associated with worse PFS.

CONCLUSION: HBI0101 anti-BCMA CART results demonstrate high efficacy and safety in a more difficult-to-treat population as compared with the registrational studies with commercial products. These data not only support further utilization of HBI0101 CART therapy, but also demonstrate the feasibility of CART production in an academic setting, ensuring a sufficient CART supply in light of the increasing demand. This study completed enrollment in February 2025, and was immediately followed by a phase 2 study, including R/R MM and AL amyloidosis patients at earlier stages.

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2025
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