PURPOSE: Although chimeric antigen receptor T therapy (CAR-T) cells are an established therapy for relapsed/refractory multiple myeloma (RRMM), there are no established models predicting outcome to identify patients who may benefit the most from CAR-T. PATIENTS AND METHODS: This is an international retrospective observational study including patients with RRMM infused with currently available commercial or academically produced anti–B-cell maturation antigen (BCMA) CAR-T. We describe characteristics and outcomes in Europe (n = 136) and the United States (n = 133). Independent predictors of relapse/progression built a simple prediction model (Myeloma CAR-T Relapse [MyCARe] model) in the training cohort (Europe), which was externally validated (US cohort) and tested within patient- and treatment-specific subgroups. RESULTS: The overall response rate was 87% and comparable between both cohorts, and complete responses were seen in 48% (Europe) and 49% (the United States). The median time to relapse was 5 months, and early relapse <5 months from infusion showed poor survival across cohorts, with the 12-month overall survival of 30% (Europe) and 14% (the United States). The presence of extramedullary disease or plasma cell leukemia, lenalidomide-refractoriness, high-risk cytogenetics, and increased ferritin at the time of lymphodepletion were independent predictors of early relapse or progression. Each factor received one point, forming the three-tiered MyCARe model: scores 0-1 (low risk), scores 2-3 (intermediate risk), and a score of 4 (high risk). The MyCARe model was significantly associated with distinct 5-month incidence of relapse/progression ( P < .001): 7% for low-risk, 27% for intermediate-risk, and 53% for high-risk groups. The model was validated in the US cohort and maintained prognostic utility for response, survival, and outcomes across subgroups. CONCLUSION: Outcomes of patients with RRMM after CAR-T are comparable between Europe and the United States. The MyCARe model may facilitate optimal timing of CAR-T cells in patient-specific subgroups.

Purpose: AL amyloidosis (AL) treatments are generally based on those employed for multiple myeloma. Anti–B-cell maturation antigen (BCMA) chimeric antigen receptor T (CART)-cell therapy, already approved for multiple myeloma, might be too toxic for patients with AL. Experimental Design: Here we describe the ex vivo applicability of a novel in-house, academic anti-BCMA CAR construct on AL primary cells, as well as the safety and efficacy in 4 patients with relapsed/refractory (RR) primary AL, treated in a phase I clinical trial (NCT04720313). Results: Three had MAYO stage IIIa cardiac involvement at enrollment. The treatment proved relatively safe, with a short and manageable grade 3 cytokine release syndrome evident in 2 patients and no neurotoxicity in any. Cardiac decompensations, observed in 2 patients, were also short and manageable. The overall hematologic response and complete response rates were observed in all patients with an organ response evident in all four. Within a median follow-up period of 5.2 (2.5–9.5) months, all 4 patients maintained their responses. Conclusions: BCMA-CART cells provide a first proof-of-concept that this therapy is safe enough and highly efficacious for the treatment of patients with advanced, RR AL.

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy shows remarkable efficacy in patients with relapsed and/or refractory (R/R) multiple myeloma (MM). HBI0101, a novel second generation optimized anti- BCMA CAR T-cell therapy, was developed in an academic setting. We conducted a phase I dose-escalation study of HBI0101 (cohort 1: 150x106 CAR T cells, n=6; cohort 2: 450x106 CAR T cells, n=7; cohort 3: 800x106 CAR T cells, n=7) in 20 heavily pre-treated R/R MM patients. Grade 1-2 cytokine release syndrome (CRS) was reported in 18 patients (90%). Neither grade 3-4 CRS nor neurotoxicity of any grade were observed. No dose-limiting toxicities were observed in any cohort. The overall response rate (ORR), (stringent) complete response (CR/sCR), and very good partial response rates were 75%, 50%, and 25%, respectively. Response rates were dose-dependent with 85% ORR, 71% CR, and 57% minimal residual disease negativity in the high-dose cohort 3. Across all cohorts, the median overall survival (OS) was 308 days (range 25-466+), with an estimated OS of 55% as of June 27th (data cut-off). The median progression-free survival was 160 days, with 6 subjects remaining progression free at the time of data cut-off. Our findings demonstrate the manageable safety profile and efficacy of HBI0101. These encouraging data support the decentralization of CAR T production in an academic setting, ensuring sufficient CAR T supply to satisfy the increasing local demand. Clinicaltrials.gov NCT04720313.

PURPOSE: The use of anti–B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CART) therapy for AL amyloidosis (AL) is limited owing to patient frailty. HBI0101 anti-BCMA CART was the first proof of concept for its applicability to AL. This report addresses the AL patient cohort treated to date within the phase Ia/Ib clinical trial (ClinicalTrials.gov identifier: NCT04720313 ). METHODS: After lymphodepletion, most AL patients were infused with 800 × 10 ⁶ CARTs. RESULTS: Sixteen patients were treated, with a median of four previous lines of therapy (range, 3-10), 14/16 were triple class refractory, and 6/16 were refractory to belantamab. Most patients (13/16) had cardiac involvement, including five with MAYO stage IIIa/IIIb at study entry. Cytokine release syndrome was frequent (14/16) but mostly low grade (grade 3: 3/16, no grade 4/5). No neurologic toxicity or treatment-related deaths were observed. There were five grade 3 AL-related organ deteriorations resolved quickly with supportive care. The overall hematologic response rate was 15/16 (94%) and complete response (CR) was 12/16 (75%). Minimal residual disease negativity was achieved in 9/14 evaluable patients. Most patients (8/13 evaluable) achieved an objective organ response. Seven patients died during long-term follow-up, three while in CR/very good partial response, and the median overall survival was 10.1 months (95% CI, 5.8 to not reached). CONCLUSION: This largest clinical trial of AL patients treated with anti-BCMA CART demonstrates acceptable and manageable toxicity in a highly frail and resistant population with remarkable efficacy, leading to fast organ responses. Among patients with baseline advanced cardiac disease, deaths in the first year were frequent, suggesting that this effective therapy should be considered earlier in the course of therapy. Anti-BCMA CART may become a powerful tool for improving organ function and survival in patients with AL.

MiR-103 inhibits proliferation and sensitizes hemopoietic tumor cells for glucocorticoid-induced apoptosis miR-103 inhibits proliferation and sensitizes hemopoietic tumor cells for glucocorticoid-induced apoptosis

Summary: Background: Chimeric antigen receptor (CAR) T cells targeted to the CD19 B‐cell antigen form an approved treatment for patients with relapsed/refractory diffuse large B‐cell lymphoma (r/r DLBCL). However, since this therapy is administered after multiple lines of treatment and exposure to lymphotoxic agents, there is an urgent need to optimize this modality of treatment.Methods: To circumvent the difficulties of harvesting adequate and optimal T cells from DLBCL patients and improve CART therapy, we suggest an earlier lymphopheresis (i.e. at first relapse, before salvage treatment). We conducted a prospective study and evaluated the potential benefit of an earlier lymphopheresis (early group, n = 22) on the clinical outcome of CD19‐CART infused DLBCL patients, in comparison with standard lymphopheresis (i.e. at second relapse and beyond; standard group, n = 23).Results: An increased percentage of naïve T cells and increased in vitro T‐cell functionality were observed in the early group. Additionally, these cells exhibit a lower exhaustion profile than T cells collected in the standard group.Conclusion: While improved T‐cell phenotype and function in the lymphopheresis product did not translate into significantly improved clinical outcomes, a trend towards better overall survival (OS) and progression‐free survival (PFS) was observed. Early lymphopheresis maximizes the potential of salvage therapies, without compromising CAR T‐cell quality.