Chimeric antigen receptor-engineered (CAR)-T cell therapy remains limited by significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill-defined. Anakinra has emerged as a promising agent based on preclinical data, but its safety and efficacy in CAR-T therapy recipients are unknown. The primary objective of this study was to evaluate the safety of anakinra to treat refractory CRS and ICANS after CAR-T therapy. The secondary objective was to evaluate the impact of key treatment-, patient-, and disease-related variables on the time to CRS/ICANS resolution and treatment-related mortality (TRM). We retrospectively analyzed the outcomes of 43 patients with B cell or plasma cell malignancies treated with anakinra for refractory CRS or ICANS at 9 institutions in the United States and Spain between 2019 and 2022. Cause-specific Cox regression was used to account for competing risks. Multivariable cause-specific Cox regression was used to estimate the effect of anakinra dose on outcomes while minimizing treatment allocation bias by including age, CAR-T product, prelymphodepletion (pre-LD) ferritin, and performance status. Indications for anakinra treatment were grade ≥2 ICANS with worsening or lack of symptom improvement despite treatment with high-dose corticosteroids (n = 40) and grade ≥2 CRS with worsening symptoms despite treatment with tocilizumab (n = 3). Anakinra treatment was feasible and safe; discontinuation of therapy because of anakinra-related side effects was reported in only 3 patients (7%). The overall response rate (ORR) to CAR-T therapy was 77%. The cumulative incidence of TRM in the whole cohort was 7% (95% confidence interval [CI], 2% to 17%) at 28 days and 23% (95% CI, 11% to 38%) at 60 days after CAR-T infusion. The cumulative incidence of TRM at day 28 after initiation of anakinra therapy was 0% in the high-dose (>200 mg/day i.v.) recipient group and 47% (95% CI, 20% to 70%) in the low-dose (100 to 200 mg/day s.c. or i.v.) recipient group. The median cumulative incidence of CRS/ICANS resolution from the time of anakinra initiation was 7 days in the high-dose group and was not reached in the low-dose group, owing to the high TRM in this group. Univariate Cox modeling suggested a shorter time to CRS/ICANS resolution in the high-dose recipients (hazard ratio [HR], 2.19; 95% CI, .94 to 5.12; P = .069). In a multivariable Cox model for TRM including age, CAR-T product, pre-LD ferritin level, and pre-LD Karnofsky Performance Status (KPS), higher anakinra dose remained associated with lower TRM (HR, .41 per 1 mg/kg/day increase; 95% CI, .17 to .96; P = .039. The sole factor independently associated with time to CRS/ICANS resolution in a multivariable Cox model including age, CAR-T product, pre-LD ferritin and anakinra dose was higher pre-LD KPS (HR, 1.05 per 10% increase; 95% CI, 1.01 to 1.09; P = .02). Anakinra treatment for refractory CRS or ICANS was safe at doses up to 12 mg/kg/day i.v. We observed an ORR of 77% after CAR-T therapy despite anakinra treatment, suggesting a limited impact of anakinra on CAR-T efficacy. Higher anakinra dose may be associated with faster CRS/ICANS resolution and was independently associated with lower TRM. Prospective comparative studies are needed to confirm our findings.

BACKGROUND: Little is known about pathogen-specific humoral immunity after chimeric antigen receptor–modified T (CAR-T) cell therapy for B cell malignancies. METHODS: We conducted a prospective cross-sectional study of CD19-targeted or B cell maturation antigen–targeted (BCMA-targeted) CAR-T cell therapy recipients at least 6 months posttreatment and in remission. We measured pathogen-specific IgG against 12 vaccine-preventable infections and the number of viral and bacterial epitopes to which IgG was detected (“epitope hits”) using a serological profiling assay. The primary outcome was the proportion of participants with IgG levels above a threshold correlated with seroprotection for vaccine-preventable infections. RESULTS: We enrolled 65 children and adults a median of 20 months after CD19- ( n = 54) or BCMA- ( n = 11) CAR-T cell therapy. Among 30 adults without IgG replacement therapy (IGRT) in the prior 16 weeks, 27 (90%) had hypogammaglobulinemia. These individuals had seroprotection to a median of 67% (IQR, 59%–73%) of tested infections. Proportions of participants with seroprotection per pathogen were comparable to population-based studies, but most individuals lacked seroprotection to specific pathogens. Compared with CD19-CAR-T cell recipients, BCMA-CAR-T cell recipients were half as likely to have seroprotection (prevalence ratio, 0.47; 95% CI, 0.18–1.25) and had fewer pathogen-specific epitope hits (mean difference, –90 epitope hits; 95% CI, –157 to –22). CONCLUSION: Seroprotection for vaccine-preventable infections in adult CD19-CAR-T cell recipients was comparable to the general population. BCMA-CAR-T cell recipients had fewer pathogen-specific antibodies. Deficits in both groups support the need for vaccine and immunoglobulin replacement therapy studies. FUNDING: Swiss National Science Foundation (Early Postdoc Mobility grant P2BSP3_188162), NIH/National Cancer Institute (NIH/NCI) (U01CA247548 and P01CA018029), NIH/NCI Cancer Center Support Grants (P30CA0087-48 and P30CA015704-44), American Society for Transplantation and Cellular Therapy, and Juno Therapeutics/BMS.

Chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA-CARTx) are an emerging treatment for relapsed or refractory multiple myeloma (R/R MM). Characterize the epidemiology of infections, risk factors for infection, and pathogen-specific humoral immunity in patients receiving BCMA-CARTx for R/R MM. We performed a retrospective cohort study in 32 adults with R/R MM enrolled in two single-institution phase 1 clinical trials of BCMA-CARTx administered after lymphodepleting chemotherapy alone (n=22) or with (n=10) a gamma secretase inhibitor (GSI). We tested serum prior to and up to approximately 180 days after BCMA-CARTx for measles-specific IgG and for any viral-specific IgG using a systematic viral epitope scanning assay to describe the kinetics of total and pathogen-specific IgG levels pre- and post-BCMA-CARTx. We identified microbiologically documented infections to determine infection incidence and used Poisson regression to explore risk factors for infections within 180 days after BCMA-CARTx. Most individuals developed severe neutropenia, lymphopenia and hypogammaglobulinemia after BCMA-CARTx. Grade ≥3 cytokine release syndrome (CRS; Lee criteria) occurred in 16% of participants; corticosteroids and/or tocilizumab were administered to 50% of participants. Before BCMA-CARTx, 28/32 (88%) participants had an IgG <400 mg/dL and only 5/27 (19%) had seropositive measles antibody titers. After BCMA-CARTx, all participants had IgG <400 mg/dL and declining measles antibody titers; of the 5 individuals with baseline seropositive levels, 2 remained above the seroprotective threshold post-treatment. Participants with IgG MM (n=13) had significantly fewer antibodies to a panel of viral antigens compared to participants with non-IgG MM (n=6), both prior to and after BCMA-CARTx. In the first 180 days after BCMA-CARTx, 17 (53%) participants developed 23 infections, in whom 13/23 (57%) infections were mild-to-moderate viral infections. Serious infections were more frequent in the first 28 days. Infections appeared to be more common in individuals with higher-grade CRS. Individuals with R/R MM have substantial deficits in humoral immunity. These data demonstrate the importance of plasma cells in maintaining long-lived pathogen-specific antibodies and suggest that BCMA-CARTx recipients should have ongoing surveillance for late-onset infections. Most infections were mild-moderate severity viral infections. The early infection incidence appears to be lower than reported after CD19-CARTx for B-cell neoplasms, which may be due to differences in patient/disease characteristics and regimen related toxicities.

Over the past decade, therapeutic options in multiple myeloma (MM) have changed dramatically. Given the unprecedented efficacy of novel agents, the role of hematopoietic cell transplantation (HCT) in MM remains under scrutiny. Rapid advances in myeloma immunotherapy including the recent approval of chimeric antigen receptor (CAR) T-cell therapy will impact the MM therapeutic landscape. The American Society for Transplantation and Cellular Therapy convened an expert panel to formulate clinical practice recommendations for role, timing, and sequencing of autologous (auto-HCT), allogeneic (allo-HCT) and CAR T-cell therapy for patients with newly diagnosed (NDMM) and relapsed/refractory MM (RRMM). The RAND-modified Delphi method was used to generate consensus statements. Twenty consensus statements were generated. The panel endorsed continued use of auto-HCT consolidation for patients with NDMM as a standard-of-care option, whereas in the front line allo-HCT and CAR-T were not recommended outside the setting of clinical trial. For patients not undergoing auto-HCT upfront, the panel recommended its use in first relapse. Lenalidomide as a single agent was recommended for maintenance especially for standard risk patients. In the RRMM setting, the panel recommended the use of CAR-T in patients with 4 or more prior lines of therapy. The panel encouraged allo-HCT in RRMM setting only in the context of clinical trial. The panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MM.

Teclistamab is an anti-CD3-/B-cell maturation antigen (BCMA) bispecific antibody approved for use in relapsed/refractory multiple myeloma. We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the US Multiple Myeloma Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell–associated neurotoxicity syndrome in 11% (2.2% grade ≥3), with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR or better in 45%. With 10.1 months of median follow-up, the estimated median progression-free survival (PFS) was 5.8 months and 12-month overall survival was 61%. Independent predictors of less than very good PR and shorter PFS included BCMA-directed chimeric antigen receptor T-cell therapy in the previous 9 months, high disease burden, lymphopenia, and elevated ferritin. Significance: T cell–engaging bispecific antibodies such as teclistamab represent an important new treatment modality for multiple myeloma and other blood cancers. This study evaluates the real-world safety and efficacy of teclistamab, including its activity in populations not represented in the initial phase I/II study, and identifies clinical variables associated with treatment response. See related commentary by Zweegman et al., p. 542

Circulating plasma cells (CPCs) have been detected in patients with multiple myeloma (MM) at various stages of disease and associated with worse outcomes. Little data exist regarding the impact of CPCs at the time of autologous peripheral blood stem cell (PBSC) collection on outcomes, and the impact of maintenance therapy after autologous stem cell transplantation (ASCT) on prognosis in patients with CPC-containing collections. All patients with MM who underwent first ASCT at Fred Hutchinson Cancer Research Center from 2012 to 2015 and had evaluation for CPCs at the time of PBSC collection were included in our analysis. Seven-color flow cytometry was used to detect the presence of CPCs. Kaplan-Meier estimates were used to generate overall survival (OS) and progression-free survival (PFS) rates from the time of ASCT. A multivariate analysis, including receipt of maintenance therapy post-ASCT, high-risk cytogenetics, and international staging system (ISS) stage, was included in a Cox proportional hazards regression model for associations with OS and PFS. We identified 227 patients with MM who underwent ASCT; of these, 144 (63.4%) patients had routine assessment of CPCs at the time of PBSC collection. One hundred seventeen (81.3%) patients did not have CPCs and 27 (18.8%) did have CPCs. The presence of CPCs was highly associated with poorer PFS (P = .031 by log-rank analysis), but did not affect OS. The median PFS for those patients without CPCs was 39.4 months (95% confidence interval [CI], 31.1 to not reached), while the median PFS for those patients with CPCs was 16.5 months (95% CI, 13.7 to not reached). A subgroup analysis of patients achieving very good partial response (VGPR) or better at time of collection, showed the median PFS for patients without CPCs was 38.3 months (95% CI, 29 to not reached), as compared with those patients with CPCs, where it was only 16.5 months (95% CI, 12 months to not reached; P = .02). There was no statistically significant difference in PFS or OS among those patients achieving partial response at the time of collection. In a Cox proportional hazards model, adjusting for post-ASCT maintenance therapy, high-risk cytogenetics, and ISS stage at time of initial diagnosis, there was a 43% higher risk of progression or death among the patients with CPCs (P = .04). The presence of CPCs at the time of autologous PBSC collection is a negative prognostic factor for risk of early relapse or death despite the advent of novel agents and maintenance strategies. The impact of CPCs was most significant among patients achieving a VGPR or better at time of collection. The presence of CPCs denotes a unique group of high-risk MM patients for whom alternative treatment strategies are needed to overcome resistance to current standard therapies.