Early sBCMA Kinetics as a Potential Indicator of Progression-Free Survival in Relapsed/Refractory Multiple Myeloma Patients Receiving CAR T-Cell Therapy

Objectives: The last 15 years have seen consistent increases in modeling efforts linking longitudinal tumor burden measurements to long-term efficacy endpoints across multiple modalities, Tumor types and applications. However, such applications have yet to be explored in the chimeric antigen receptor (CAR) T-cell space, a relatively new pharmacological modality. Herein, we leveraged longitudinal soluble B-cell maturation antigen (sBCMA) data, a surrogate for tumor burden in relapsed/refractory multiple myeloma (RRMM), to quantitatively establish the relationship between early changes in sBCMA and progression-free survival (PFS) in RRMM patients receiving CAR T-cell therapy, aiming to afford novel insights into the clinical development of these therapies. Methods: Data from 159 RRMM patients who were treated with orvacabtagene autoleucel (orva-cel, BCMA-targeted CAR T-cell therapy) in the EVOLVE study (ClinicalTrials.gov Identifier: NCT03430011) were used in the model development. The longitudinal sBCMA profile is well described by Stein regression-growth model1, comprised of an exponential regression and an exponential growth of sBCMA. The influence of early sBCMA kinetics (i.e., relative sBCMA reductions from baseline at weeks 2, 4, 6, 8, 10 and 12) and clinically-relevant baseline factors (i.e., lactate dehydrogenase [LDH], percentage of bone marrow plasma cells, albumin, aspartate transaminase, alanine transaminase, and baseline sBCMA) on PFS were quantitatively assessed using the Weibull model, a parametric time-to-event (TTE) model. Results: The longitudinal sBCMA profile was well described by the Stein regression-growth model, which provided estimates of the regression rate constant (0.11/day) and growth rate constant (0.00031/day) for a typical subject. Exploratory analysis indicated subjects with higher growth rate constants experienced shorter median PFS, suggesting the positive relationship between deeper and more sustained sBCMA clearance and longer PFS. To enhance early prediction of PFS, sBCMA reductions from baseline at weeks 2, 4, 6, 8, 10 and 12 were calculated using the kinetic model and included as covariates in a parametric TTE analysis, along with other clinically-relevant factors. The survival model provided an adequate fit to the PFS data, with sBCMA reduction from baseline at 6 weeks post infusion showing the most significant positive correlation with PFS. Additionally, baseline LDH was negatively correlated with PFS. Conclusion: We herein showed that early sBCMA kinetics may serve as a promising indicator of PFS in RRMM patients receiving CAR T-cell treatments. This modeling effort provides novel insights into the development of CAR T-cell therapies, including supporting clinical study design, enabling early efficacy readout and informing critical decision-making.*We extend our gratitude to Matthew Putnins for his contributions to the initial model analysisCitations: [1] Wilfred D. Stein, James L. Gulley, et al; Tumor Regression and Growth Rates Determined in Five Intramural NCI Prostate Cancer Trials: The Growth Rate Constant as an Indicator of Therapeutic Efficacy. Clin Cancer Res 15 February 2011; 17 (4): 907–917. https://doi.org/10.1158/1078-0432.CCR-10-1762