Kaiser, Shari M.

Background: Anti-BCMA CAR T cells are a new standard of care for the treatment of RRMM patients. Hence, it is paramount to identify determinants of response and resistance for individualized approaches. There is emerging data about the importance of depth of response in prolonged progression-free survival (PFS) and of genetic antigen escape in treatment resistance. By contrast, there is limited understanding of how patient' outcomes are shaped by immune fitness prior aphaeresis, and virtually no data about CAR T and endogenous profiles post infusion. Aim: Characterize immune dynamics and investigate its prognostic value in RRMM patients treated with CAR T cells. Methods: Immune profiling was performed using multidimensional and computational flow cytometry in 285 bone marrow aspirates from 120 RRMM patients enrolled in the KarMMa phase 2 trial. In total, 170 immune clusters were identified and systematically quantified in a pileup analysis of samples collected before and at months 1, 3, 6 and 12 after CAR T infusion. Immune scores were developed using cox regression with 10-fold cross-validation. Results: At baseline (n = 63), there were significant associations between the bone marrow immune composition and the number of prior lines of treatment, prior autologous transplant and staging. Namely, there were higher proportions of ICOS, PD1, TIGIT and TIM3 positive cells within the CD4+ and CD8+ T cell compartments from heavily pretreated patients and those with R-ISS 3. A baseline immune score defined by the percentages of GrzmB+HLADR+ cytotoxic NK cells, TIGIT+ Tregs, CD4+CD127+ICOS+ and CD4+CD25+CD127+TIGIT+, CD8+TIGIT+, CD8+GrzmB+HLADR+ and CD8+CD27+CD95+CD45RAloCD197lo T cells was associated with PFS. Patients with low vs high risk immune score at baseline had median PFS of 25 vs 6 months, respectively (p < .001). Interestingly, there were no significant associations between the baseline risk score and treatment or staging, suggesting potential complementarity of immune profiling with other prognostic factors. At month 1 after infusion (n = 55), the presence of >1% vs <1% CAR T cells was associated with longer PFS (medians of 20 vs 8 months, p = .002). In addition to the magnitude of CAR T persistence, it was interesting to observe increased percentages of CD8+ CAR T cells in patients with <5 prior lines of therapy, of CD4+HLADR+ and CD8+TEMRA CAR T cells in patients with R-ISS 1/2, as well as of PD1+TIM3+ CD4+ and CD8+ CAR T cells in patients with R-ISS 3. Moreover, the phenotype of CAR T cells was associated with PFS. Patients with low vs high risk immune score (ie, based on the percentages of CD4+CD57+, CD8+CD27-EM, CD8+PD1+TIM3+ and CD4+CD8+ CAR T cells) had median PFS not reached vs 11 months, respectively (p < .0001). Similarly to the above, there were no significant associations between the CAR T immune risk score and treatment or staging, suggesting potential complementarity of CAR T quantification and phenotyping post-infusion with other patient' characteristics. Next, we investigated endogenous T cell dynamics in 51 RRMM patients with paired samples prior and after CAR T infusion. There were significant differences in the frequencies of 30 immune clusters, including CD27+ naïve and EM CD4+ and CD8+ T cells, ICOS+ and TIGIT+ Tregs, CD4+ and CD8+ T cells, as well as of CD25+CD127+ CD4+ and CD8+ T cells. Furthermore, an immune risk score defined at the latest available time point (n = 95) was associated with PFS (p < .0001). Patients with lower levels of GrzmB+ cytotoxic NK cells and of immunoregulatory HLADR- NK cells, as well as of CD4+CD27+CD95+CM, CD4+HLADR+, CD8+PD1+ and CD8+CD27-CD95+EM T cells showed a high risk score and a median PFS of 6 vs 20 months in patients with low risk immune score. Conclusions: This is one of the largest dynamic studies of immune profiling in a clinical trial investigating anti-BCMA CAR T cells in RRMM. Our results uncovered that patient' immune status is shaped by prior treatment and staging, and that the distribution of different NK, Treg, CD4+ and CD8+ T cells prior aphaeresis is associated with PFS. Furthermore, the phenotype of CAR T cells at month 1 after infusion may be as prognostic as its percentage. We also showed how treatment with CAR T cells modulates the bone marrow immune composition and how it may contribute to immune escape vs surveillance. Altogether, this study supports immune profiling for improved understanding of response and resistance to CAR T cells in RRMM.

7529 Background: iAEs, such as cytokine release syndrome (CRS) and macrophage activation syndrome (MAS), can occur after infusion of chimeric antigen receptor T cell therapies such as ide-cel, but are typically low-grade and manageable with tocilizumab and corticosteroids. Although high-grade iAEs are rare with ide-cel, identification of patients at increased risk may improve management and remains an unmet need. Three composite biomarkers (multivariate models) of iAE risk were previously developed in a discovery cohort from the KarMMa and KarMMa-2 studies of ide-cel in RRMM (Mashadi-Hossein A, et al. J Clin Oncol 2023;41(16_suppl):e20005). Here, we validate these 3 prototype models for risk of developing high-grade iAEs after ide-cel infusion. Methods: Two models used pretreatment patient and routine clinical laboratory parameters; the third model also included change in 6 exploratory cytokines from baseline to 1 day following ide-cel infusion. To validate, each model was retrospectively applied to KarMMa-3 (NCT03651128) data in a blinded fashion, and sensitivity and specificity to identify grade ≥3 CRS and any-grade MAS were determined. Model performance thresholds used for sensitivity and specificity were 90% and 50%, respectively. Performance for identifying grade 2 CRS was also analyzed post hoc. Results: The first and simplest model comprised a manual algorithm with 7 features; it identified patients with grade ≥3 CRS or MAS with 85% sensitivity and 60% specificity. The second model comprised 19 routinely measured pretreatment features; it identified grade ≥3 CRS with 91% sensitivity and 59% specificity, and any-grade MAS with 60% sensitivity and 88% specificity. The third and most complex model comprised 7 pretreatment clinical features and 6 exploratory cytokines; it identified grade ≥3 CRS with 100% sensitivity and 51% specificity, and any-grade MAS with 100% sensitivity and 81% specificity. None of the models identified grade ≥2 CRS with passable sensitivity or specificity. Clustering analyses across all features showed that only a subset of grade 2 CRS cases was within the previously identified high-risk iAE cluster while the remaining grade 2 CRS cases were spread across other clusters. Conclusions: Two of the 3 composite biomarkers met validation criteria for grade ≥3 CRS risk. Criteria were not met for grade 2 CRS, suggesting these models are specific to higher-grade events and that grade 2 CRS represents a more heterogeneous group of patients. While high-grade iAEs are rare with ide-cel, these models may further optimize the robust benefit–risk profile that ide-cel has demonstrated by helping identify, prior to or shortly after infusion, patients most at risk for severe events. Clinical trial information: NCT03651128 .

Abstract The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus <CR. Persistent MRD in the 10−6 logarithmic range and reappearance of normal plasma cells in MRD-negative patients were associated with inferior PFS. This study unveils different prognostic implications of serological and MRD response dynamics after ide-cel and suggests the potential value of studying the reappearance of normal plasma cells as a surrogate of loss of CAR T-cell functionality. Significance: This is one of the first studies evaluating the impact of CR and MRD dynamics after CAR T therapy in relapsed/refractory multiple myeloma. These data help interpret the prognostic significance of serological and MRD responses at early and late time points after CAR T-cell infusion. See related commentary by Landgren and Kazandjian, p. 346 . This article is featured in Selected Articles from This Issue, p. 337