Idecabtagene vicleucel for relapsed and refractory multiple myeloma: post hoc 18-month follow-up of a phase 1 trial

Abstract

Idecabtagene vicleucel (ide-cel) is a B-cell-maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy. We performed a post hoc analysis of a single-arm phase 1 multicenter study in relapsed/refractory multiple myeloma (CRB-401) (n = 62; median follow-up, 18.1 months). The primary endpoint was safety outcomes, and secondary endpoints included overall response rate (ORR), complete response (CR) and very good partial response (VGPR). The study met its primary endpoint with low rates of grade 3/grade 4 cytokine release syndrome (6.5%) and neurotoxicity (1.6%). ORR was 75.8%; 64.5% achieved VGPR or better and 38.7% achieved CR or stringent CR. Among exploratory endpoints, median duration of response, progression-free survival (PFS) and overall survival were 10.3, 8.8 and 34.2 months, respectively, and ide-cel expansion in blood and bone marrow correlated with clinical efficacy and postinfusion reduction of soluble BCMA. Patients with PFS ≥ 18 months had more naive and less exhausted T cells in apheresis material and improved functional T cell phenotype in the drug product compared with those with less durable responses. These results confirm ide-cel safety, tolerability and efficacy and describe T cell qualities that correlate with durable response. Clinicaltrials.gov identifier : NCT02658929 .

Fig. 1. Efficacy outcomes in all dose groups.

Efficacy outcomes include the following: a–e, Best overall response by dose (a), DOR by dose (b), DOR by best overall response (c), PFS by dose (d) and OS by dose (e).

Fig. 2. sBCMA dynamics and cellular kinetics associated with DOR.

Box and whisker plots are provided, whereby the center horizontal line denotes the median, and the box denotes the IQR (25th–75th percentiles). The upper whisker extends to the maximum value, but no further than 1.5× IQR above the 75th percentile, and the lower whisker extends to the minimum value, but no lower than 1.5× IQR below the 25th percentile. Data beyond 1.5× IQR from the 25th or 75th percentiles, respectively, are plotted individually as outlying points. a, sBCMA nadir by DOR: >18 months, n = 8 patients; 12–18 months, n = 10 patients; 6–12 months, n = 16 patients; <6 months, n = 13 patients; NR, n = 15 patients. b, Duration of deep pharmacodynamic (greater sBCMA reduction) response by DOR: >18 months, n = 8 patients; 12–18 months, n = 10 patients; 6–12 months, n = 16 patients; <6 months, n = 13 patients; NR, n = 15 patients. c, Concentrations, measured by qPCR, of ide-cel in the PB CD3⁺ cell matrix on day 14 postinfusion by DOR (P = 0.00003 versus nonresponders, two-sided Wilcoxon rank-sum test; P value is not corrected for multiple hypothesis testing): >18 months, n = 3; 12–18 months, n = 7; 6–12 months, n = 7; <6 months, n = 9; NR, n = 8. d, Concentrations, measured by qPCR, of ide-cel in bone marrow aspirate (whole bone marrow matrix) on day 14 postinfusion by DOR (P = 0.001 versus nonresponders, two-sided Wilcoxon rank-sum test; P value is not corrected for multiple hypothesis testing): >18 months, n = 3; 12–18 months, n = 7; 6–12 months, n = 7; <6 months, n = 9; NR, n = 8. e, Ratio of bone marrow aspirate (whole bone marrow matrix) to PB CD3⁺ cell matrix concentrations of ide-cel on day 14 postinfusion by DOR. DOR was binned as 0–6, 6–12, 12–18 and ≥18 months. Duration of deep pharmacodynamic response was defined by the last visit at which sBCMA levels were less than the median nadir (4692 ng l⁻¹): >18 months, n = 3; 12–18 months, n = 7; 6–12 months, n = 7; <6 months, n = 9; NR, n = 8. BM, bone marrow; IQR, interquartile range; NR, nonresponder.

Fig. 3. Correlates of long-term responders.

Logistic regression analyses of starting material PBMC and final DP correlates from long-term responders (patients with PFS ≥ 18 months; n = 13) and non-long-term responders (n = 46) and time of recent exposure to selected prior antimyeloma drug classes as a potential correlate of the PBMC and DP variables enriched in long-term responders. Three patients were censored from the total treated population (n = 62) due to study discontinuation before progression (n = 1), start of subsequent antimyeloma therapy before progression (n = 1) and ongoing response with a <18-month progression-free interval (n = 1). Note that the y-axis labels corresponding to the staining patterns defined for each type of cell are shown in the table of median values below the plots. Box plots show nominal P value of the long-term response coefficient from a nonparametric linear regression where rank (Y) ~ long-term response + dose and Y is the rank order value of the PBMC or DP attribute of interest. P values are not corrected for multiple hypothesis testing.