Clinical evaluation and determinants of response to HBI0101 (BCMA CART) therapy in relapsed/refractory multiple myeloma

Abstract

HBI0101 is an academic chimeric antigen receptor T-cell (CART)-targeted to B-cell maturation antigen (BCMA) for the treatment of relapsed and refractory multiple myeloma (R/RMM) and light chain amyloidosis. Herein, we present the phase 1b/2 results of 50 heavily pretreated patients with R/RMM dosed with 800 × 106 CART cells. Inclusion criteria were relatively permissive (i.e., performance status and baseline organ function) and consequently, approximately half of the enrolled patients would have been ineligible for pivotal clinical trials. The median time elapsed from patient enrollment until CART delivery was 25 days (range, 14-65). HBI0101-related toxicities included grade 1 to 3 cytokine release syndrome, grade 3 to 4 hematologic toxicities, and grade 1 to 2 immune effector cell-associated neurotoxicity syndrome. Responses were achieved in 90% of the patients, 56% achieved stringent and complete response, and 70% reached a minimal residual disease negativity. Within a median follow-up of 12.3 months, the median progression-free survival (PFS) was 11.0 months (95% confidence interval [CI], 6.2-14.6), and the overall survival was not reached (95% CI, 13.3 to not reached). Multivariable analysis on patient/disease and CART-related characteristics revealed that high-risk cytogenetic, extramedullary disease, and increased number of effector-memory T cells in CART products were independently associated with inferior PFS. In conclusion, comprehensive analyses of the parameters affecting the response to CART therapy are essential for improving patients' outcome. This trial was registered at www.ClinicalTrials.gov as #NCT04720313.

Graphical abstract

Figure 1.

Response to HBI0101 therapy. Best ORR (A), PFS (B), DOR in HBI0101 responders (C), and OS (D) were estimated in the first consecutive 50 patients dosed with 800 × 10⁶ CAR⁺ cells. sCR/CR (dark/light blue); VGPR (dark/light green); PR (dark/light yellow); MRD positive, light colors; MRD negative, dark colors. DOR, duration of response.

Figure 2.

HBI0101 trial permissive inclusion criteria affect patient survival. (A) Major eligibility criteria discriminating HBI0101 trial from the KarMMa/CARTITUDE-1 at study entrance. ORR (B), PFS (C), and OS (D) of patients receiving HBI0101 infusion according to their eligibility to KarMMa/CARTITUDE-1 trial (blue line, eligible, n = 23; red line, noneligible, n = 27; green line, HBI0101 cohort, n = 50). In panel 2B, the percentages for CR, VGPR, and PR do not add up to the percentage atop the bar graph due to rounding. PCL, plasma cell leukemia; PLT, platelet.

Figure 3.

Response to HBI0101 therapy by RF groups. ORR (A,D,G), PFS (B,E,H), and OS (C,F,I) were estimated in patients receiving HBI0101 infusion, according to HR cytogenetics (A-C; n = 12), EMD presentation (D-F; n = 16), and the number of CAR⁺ T_EMs in CART FP above the median (>5.7 × 10⁸ CAR⁺ T_EMs) (G-I; n = 23). In panel 3G, the percentages for CR, VGPR, and PR do not add up to the percentage atop the bar graph due to rounding. Pink lines indicate patient group with RF, and blue lines indicate patient group without RF.

Figure 4.

Effect of RFs accumulation on HBI0101 outcome and impact of treatment lines on RFs acquisition. (A-C) Best ORR (A), PFS (B), and OS (C) were estimated in patients receiving HBI0101 infusion, according to their acquisition of RFs, with RF = 0 defined as no RF (red lines); RF = 1 defined as 1 RF (that is, RF HR cytogenetic or extramedullary presentation or the absolute number of CAR⁺ T_EMs detected in HBI0101 FP; blue lines), RF = 2/3, defined as acquisition of 2 or 3 RFs of the formers (green lines). (D-F) Effect of the number of treatment lines endured by patients with myeloma on the acquisition of HR cytogenetic (D), EMD (E), and on the number of CAR⁺ T_EMs in the FP (F). In panel 4A, the percentages for CR, VGPR, and PR do not add up to the percentage atop the bar graph due to rounding.

Figure 5.

Determinants of durable response to HBI0101 therapy in patients with infused MM. Numerous variables related to patient characteristics, disease, and CART features (ie, SM, FP, and CART in peripheral blood) were analyzed to determine the potential predictors of PFS in response to HBI0101 therapy. Bold faceted and underlined parameters in red were identified as strong independent determinants of PFS. HR cytogenetic, EMD presentation, and the absolute numbers of CAR⁺ T_EMs (defined as CD3⁺CAR⁺CD45RA⁻CCR7⁻) in HBI0101 CART FP were identified as predictors of inferior PFS. This illustration was generated with BioRender.com.