Associations of T-cell fitness prior to B-cell maturation antigen (BCMA)–targeted chimeric antigen receptor T-cell (CART) and bispecific T-cell engager (BiTE) therapies and efficacy/toxicity in relapsed/refractory multiple myeloma (RRMM).
Authors: Poy Theprungsirikul, Mansen Yu, Kerri Rall, Martin Matthews, Natalia Neparidze, Terri L. Parker, Sabrina Browning, Tara Anderson, Erica Stevens, Francine M. Foss, Lohith Gowda, Manoj Pillai, Iris Isufi, Stuart Seropian, Sayeef Mirza, Noffar Bar
Journal: Journal of Clinical Oncology (2024)

7549 Background: While CART and BiTE have led to unprecedented responses in RRMM, some patients (pts) do not respond or have short-lived responses. Currently no predictive markers exist to identify these pts. This study explored pretreatment T-cell fitness and efficacy/toxicity in RRMM using a novel single-cell secretome analysis. We hypothesized that pretreatment Polyfunctional Strength Index (PSI) may predict efficacy to BCMA-directed T-cell therapies. Methods: We included 14 RRMM pts treated with idecabtagene vicleucel or teclistamab at Yale Cancer Center with ≥6 mos post-treatment follow-up. Peripheral blood prior to treatment was frozen and then PBMC’s thawed for analysis. PSI, a metric for T-cell fitness combining polyfunctional T-cells % with the intensity of secreted cytokines, was obtained using the IsoPlexis’ Single-Cell Secretome Platform. The overall PSI was an average of CD4+ and CD8+ PSIs. Response was assessed by the International Myeloma Working Group criteria and response duration was defined as time from response to disease progression. Responder (R) was defined as ≥very good partial response for ≥6 mos. Non-responder (NR) was defined as stable or progressive disease ≤3 mos. Cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS) were graded using the American Society for Transplantation &amp; Cellular Therapy system. Statistics were performed with Mann-Whitney U test using GraphPad PRISM v.9. Results: There were 7 pts in R group (2 BiTE &amp; 5 CART) and 7 pts in NR group (3 BiTE &amp; 4 CART). Median follow-up time was 13.5 mos(range, 7-27). Median age at treatment was 64 yrs in R and 63 yrs in NR. Extramedullary disease (EM) was present in 14.3%(n=1) in R and 71.4%(n=5) in NR. High-risk cytogenetics, defined as del17p, t(4;14), t(14;16), t(14;20), 1q gain/amplification and del1p, were seen in 42.9%(n=3) in R and 85.7%(n=6) in NR. Median prior lines of therapy was 6(range, 4-9) in R and 8(range, 4-10) in NR. CRS/ICANS occurred 85.7%(n=6) in R and 28.6%(n=2) in NR. Overall PSI was 184 in R and 91 in NR(p=0.1649). CD4+ PSI was 160 in R and 75 in NR(p=0.1649). CD8+ PSI was 207 in R and 108 in NR(p=0.1981). Overall PSI was 143 in CRS/ICANS and 130 in no CRS/ICANS(p=0.7546). Conclusions: Overall PSI, CD4+ PSI and CD8+ PSI were 1.9-2.1 times higher in R compared to NR and overall PSI was slightly higher in CRS/ICANS compared to no CRS/ICANS though the difference was not statistically significant. One limitation was a small sample size and thus testing PSI in a larger cohort might yield statistically significant results. The NR group had more high-risk cytogenetics and higher EM. One confounder could be that measuring peripheral T-cell fitness may not be sufficient to predict response in EM where spatial determinants of T-cell influx play a role.