†These authors contributed equally.
Ide-cel, an anti-BCMA CAR T cell therapy, has demonstrated promising efficacy in the phase I CRB-401 trial in relapsed/refractory multiple myeloma (MM) (objective response rate, 85%; median progression-free survival [PFS], 11.8 months [95% CI: 6.2, 17.8]), but a subset of patients failed to respond and the duration of response varied across patients (Raje et al, N Engl J Med. 2019). A systematic examination of patient, product, and post-infusion correlates of overall and long-term response could offer biological insight into heterogeneous efficacy as well as provide biomarkers to guide post-CAR T disease management and future CAR T manufacturing and patient enrollment efforts. Soluble BCMA was of particular interest due to its expression on malignant and healthy plasma cells and its role as a composite measure of disease burden in MM.
We performed a retrospective analysis of 33 patients from the phase I CRB-401 study of ide-cel. The concentrations of ten immune-related factors in the blood (GMCSF, IFN-γ, IL-10, IL-1b, IL-2, IL-6, IL-8, MCP-1, TNF-α) and soluble BCMA were measured by ELISA before and after infusion with ide-cel along with 290 ide-cel CAR T-cell drug product attributes measured by flow cytometry and immunoassays. The absolute concentrations and fold-changes from baseline were assessed for correlation with overall and long-term response using univariate and multivariate (random forests) approaches.
Several CAR T-cell drug product covariates nominally associated with longer PFS included reduced senescence phenotype in CD4 CAR T-cells and increased IL-2 and TNF-α production (P < 0.05). Pre-infusion levels of soluble BCMA correlated with serum monoclonal protein (M-protein) levels in 20 of 33 patients for whom M-protein levels were measurable (ρ = .49; P = 0.03) and with concentrations of the involved free light chain (ρ = .59; P = 0.005) in 23 of 33 patients with measurable levels. Our investigation of soluble BCMA levels in patients achieving a partial response (PR) or better confirmed significant decreases in soluble BCMA levels relative to nonresponders (NR) as early as seven days post-infusion (median reduction of 50% for ≥ PR vs. median increase of 27% for NR, P = 0.02). The fold-change in soluble BCMA 1 month after infusion stratified patients who achieved a PR or better from those who did not (P = 0.0001). Notably, patients who maintained a response to ide-cel for ≥ 18 months (M18 R) experienced a greater depth of clearance of soluble BCMA at month 2 (median concentration of 1835 ng/L for M18 R vs. 6299 ng/L for M18 NR, P = 0.002). The induction of IL-6 and TNF-α in blood on days 1-9 post-infusion was also higher in patients with a PR or better in response to ide-cel (e.g. IL-6 median fold change increase at day 2 of 2.9 for ≥ PR vs. 0.7 for NR, P = 0.001), consistent with an active inflammatory response and higher levels of CAR T expansion.
These data from CRB-401 identify candidate drug product attributes and soluble factors that correlate with response to ide-cel and potentially MM-directed cellular therapies in general. These data suggest that changes in soluble BCMA may be a robust biomarker of both early and durable responses to ide-cel and the depth of clearance of soluble BCMA at 2 months post-infusion may identify patients at risk of progression before standard markers of myeloma progression have emerged. Further molecular characterization of drug product attributes, including CyTOF and RNA sequencing, is ongoing to identify additional biomarkers associated with clinical outcomes following ide-cel treatment. These data will help inform future strategies to improve the efficacy of ide-cel and validation in a larger cohort is ongoing.
Thompson:Celgene Corporation: Employment, Equity Ownership. Jiang:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Campbell:Celgene Corporation: Employment, Equity Ownership. Fuller:Celgene Corporation: Employment, Equity Ownership. Kaiser:Celgene Corporation: Employment. Mashadi-Hossein:Celgene Corporation: Employment, Equity Ownership. Rytlewski:Adaptive Biotechnologies: Equity Ownership; Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Martin:Celgene Corporation: Employment, Equity Ownership. Finney:bluebird bio Inc.: Employment. Kleinsteuber:bluebird bio Inc.: Employment, Equity Ownership. Alonzo:bluebird bio Inc.: Employment, Equity Ownership. Pandya:bluebird bio Inc.: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees. Raje:Merck: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy; Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy. Munshi:Celgene: Consultancy; Oncopep: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Adaptive: Consultancy. Hause:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership.
ide-cel /bb2121 is an investigational agent and not yet approved in the US
Asterisk with author names denotes non-ASH members.