B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). However, data on cellular (CAR) T cell dynamics and the association with response, resistance or the occurrence of cytokine release syndrome (CRS) are limited. Therefore, we performed a comprehensive flow cytometry analysis of 27 RRMM patients treated with Idecabtagene vicleucel (Ide-cel) to assess the expansion capacity, persistence and effects on bystander cells of BCMA-targeting CAR T cells. Additionally, we addressed side effects, like cytokine release syndrome (CRS) and cytopenia. Our results show that in vivo expansion of CD8⁺ CAR T cells is correlated to response, however persistence is not essential for durable remission in RRMM patients. In addition, our data provide evidence, that an increased fraction of CD8⁺ T cells at day of leukapheresis in combination with successful lymphodepletion positively influence the outcome. We show that patients at risk for higher-grade CRS can be identified already prior to lymphodepletion. Our extensive characterization contributes to a better understanding of the dynamics and effects of BCMA-targeting CAR T cells, in order to predict the response of individual patients as well as side effects, which can be counteracted at an early stage or even prevented.

Establishing a strategy for sequencing of T cell–redirecting therapies for relapsed/refractory multiple myeloma (RRMM) is a pressing clinical need. We longitudinally tracked the clinical and immunologic impact of bispecific T cell–engaging antibodies (BsAb) as bridging therapy (BT) to subsequent B-cell maturation antigen–directed chimeric antigen receptor T (CAR-T) cell therapies in 52 patients with RRMM. BsAbs were a potent and safe option for BT, achieving the highest overall response rate (100%) to BT compared with chemotherapy, anti-CD38, or anti-SLAMF7 antibody–based regimens (46%). We observed early CD4+CAR+ and delayed CD8+CAR+ T-cell expansion in patients receiving BsAbs as BT. In vitro cytotoxicity of CAR-T cells was comparable among BT options. Single-cell analyses revealed increased clonality in the CD4+ and CD8+ T-cell compartments in patients with previous exposure to BsAbs at leukapheresis and on day 30 after CAR-T cell infusion. This study demonstrates the feasibility and efficacy of BT with BsAbs for CAR-T cell therapy in RRMM. Significance: CAR-T cell therapy and BsAbs have revolutionized treatment of triple-class refractory multiple myeloma; however, optimal sequencing is unknown. We demonstrate that BT with BsAb before B-cell maturation antigen–directed CAR-T cell therapy is safe and effective, which might have implications for other hematologic malignancies as well. See related commentary by Bal and Costa, p. 10

For most patients with acute myeloid leukemia (AML), an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of cure. Recently, the European LeukemiaNet (ELN) published updated recommendations on the diagnosis and risk classification in AML based on genetic factors at diagnosis as well as a dynamic adjustment (reclassification) according to the measurable residual disease (MRD) status for the favorable and intermediate risk groups. Validation of the ELN2022 risk classification has not been reported. We retrospectively analyzed 522 AML patients who received an HSCT at a median age of 59 (range 16–76) years. For patients with adequate material available and in remission prior to HSCT (n = 229), the MRD status was evaluated. Median follow-up after HSCT was 3.0 years. ELN2022 risk at diagnosis was in 22% favorable, in 26% intermediate, and in 52% adverse. ELN2022 risk at diagnosis is associated with the cumulative incidence of relapse/progression (CIR), event-free survival (EFS), and overall survival (OS) in the whole patient cohort, as well as the subgroup of patients transplanted in first remission. However, the risk stratification based on the ELN2022 classification did not significantly improve outcome prognostication in comparison to the ELN2017 classification. In our study, the newly added group of patients with myelodysplasia-related gene mutations did not have adverse outcomes. Re-classifying these patients into the intermediate risk group and adjusting the grouping for all AML patients by MRD at HSCT, led to a refined and improved risk stratification, which should be validated in independent studies.

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49–8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9–8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1–7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.