BCMA targeted CAR T / Fred Hutchinson Cancer Center - LARVOL DELTA

Immune effector cell-associated enterocolitis (IEC-EC) across CAR-T products in myeloma and lymphoma: A real world pharmacovigilance analysis (ASH 2025) - "Introduction: IEC-EC has emerged as a unique toxicity of BCMA-targeted CAR-T therapy in multiple myeloma (MM)patients (pts), most commonly with ciltacabtagene autoleucel (cilta-cel) (G...Reports were distributed as follows: axicabtagene ciloleucel (axi-cel, 57.6%,n=7828), cilta-cel (19.5%, n=2647), brexucabtagene autoleucel (brexu-cel, 11.9%, n=1615), idecabtagenevicleucel (ide-cel, 6.9%, n=933), and lisocabtagene maraleucel (liso-cel, 4.7%, n=641)...Compared with checkpoint inhibitors, cilta-cel-associated IEC-EC rates (1.02%) exceeded those for the PD-1 agents nivolumab (0.23%), pembrolizumab(0.13%) and the CTLA-4 inhibitor ipilimumab (0.46%)... Our PV analysis reveals distinct GI SAE profiles among CAR-T therapies, with cilta-cel demonstrating aparticularly high signal for IEC-EC (ROR: 126.35, p<0.001). However, 3 cases occurred with axi-cel as well.The reported colitis rates well exceeded those observed with established checkpoint inhibitors,suggesting unique..."

Adverse events • Clinical • Real-world • Real-world evidence • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Immunology • Lymphoma • Multiple Myeloma

The real-world safety and efficacy of BCMA-directed chimeric antigen receptor T-cell therapy in systemic AL amyloidosis (ASH 2025) - "While daratumumab has transformed the management ofnewly diagnosed disease, many daratumumab-treated patients will not clear amyloidogenic serum freelight chains or will relapse...Therate of CRS was 56% for ide-cel (G1: 33%, G2: 22%) and 67% for cilta-cel (G1: 50%, G2: 8%, G3: 8%)...We demonstrate that commercial BCMA-targeted CAR T-cell therapy induces deep and rapidhematological responses in a cohort of heavily pretreated patients with AL amyloidosis. Although allpatients exhibited overlapping features with concurrent multiple myeloma (≥10% plasma cells atdiagnosis), CAR T-cell therapy was feasible to administer, with modest rates of CRS and only isolatedcases of severe CRS or ICANS. Nearly all patients achieved a deep hematological response, whichappeared to translate into meaningful organ improvement among those who were evaluable."

CAR T-Cell Therapy • Clinical • Real-world • Real-world evidence • Amyloidosis • CNS Disorders • Hematological Malignancies • Infectious Disease • Inflammation • Multiple Myeloma • Renal Disease

CAR T-cell therapy and bispecific antibodies in the management of multiple myeloma. (PubMed, Hematology Am Soc Hematol Educ Program) - "At present, two B-cell maturation antigen (BCMA)-targeted CAR T-cell therapies, idecabtagene vicleucel and ciltacabtagene autoleucel, are approved for standard use in the United States. There are currently 4 commercially approved bispecific antibodies: teclistamab, elranatamab, and linvoseltamab, which target BCMA, as well as talquetamab, which targets the GPRC5D antigen on the surface of plasma cells. In this review, we explore (a) the advantages and challenges of integrating CAR T-cell therapy earlier in the RRMM treatment course; (b) the safety and efficacy of bispecific antibodies and their evolving role in the current RRMM treatment paradigm; (c) practical considerations for both modalities, focusing on patient selection and supportive care strategies; and (d) recommendations for sequencing of T-cell redirecting therapies to maximize long-term outcomes."

Journal • Review • Hematological Malignancies • Multiple Myeloma • Oncology

Talquetamab Bridging: Paving the Way to B-Cell Maturation Antigen (BCMA) CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma (RRMM) (ASH 2024) - "Introduction : Anti-BCMA CAR-T therapies like idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have revolutionized RRMM treatment...Conclusions : Talquetamab is an excellent bridging option before BCMA-targeted CAR-T therapy, showing high response rates even with short-term use and enabling most pts to receive CAR-T...These findings underscore the effectiveness of a short course of talq bridging to maintain disease control and improve outcomes post CAR-T. Updated data with longer follow-up will be presented at the meeting."

CAR T-Cell Therapy • CNS Disorders • Hematological Malignancies • Inflammation • Multiple Myeloma • Oncology

The Role of Trogocytosis in BCMA CAR T Cell Therapy with Gamma-Secretase Inhbition (IMS 2025) - P1 | "We investigated the effects of GSI on trogocytosis kinetics and its consequences in vitro, and in concert with clinical data from two Phase I trials of BCMA-targeted CAR T therapy. Human T cells transduced with BCMA-directed 4-1BB/CD3ζ CAR (EGFRt⁺), were expanded and sorted. MM cell lines (H929, MM.1R, MOLP8) and BCMA-mCherry⁺ K562 cells were co-cultured with CAR T cells (E:T 1:1) for 10 min–24h ± GSI [crenigacestat] (0.1 μM, 24h).BCMA density and trogocytosis were evaluated by flow cytometric (FC) analysis.Latrunculin A (1 μM) was used to inhibit trogocytosis.BCMA-acquiring CAR T cells (Trogo⁺) were sorted after 6h co-culture and re-plated with naí¯ve CAR T cells for 24h to assess fratricide.Patient samples from two Phase I trials—FCARH143 (NCT03338972) and FCARH143+GSI (NCT03502577) were analyzed for trogocytosis, CAR T persistence (qPCR) and clinical response. GSI significantly increased BCMA density, enhanced CAR T cell cytotoxicity, but also..."

CAR T-Cell Therapy • IO biomarker • Hematological Malignancies • Multiple Myeloma • CD4 • CD8 • HAVCR2 • LAG3 • PD-1

Impact of Gamma-Secretase Inhibition on Outcomes Following BCMA CAR-T Therapy in Multiple Myeloma: A Comparison of Two Phase 1 Trials. (PubMed, Transplant Cell Ther) - "Co-administration of a GSI with BCMA CAR-T therapy was associated with improved survival in BCMA-naïve RRMM patients, particularly those with low baseline tumor BCMA levels. These findings suggest GSI modulation of BCMA surface expression may enhance CAR-T efficacy in select patients and support further prospective investigation."

IO biomarker • Journal • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology

Extramedullary disease is associated with severe toxicities following B-cell maturation antigen CAR T-cell therapy in multiple myeloma. (PubMed, Haematologica) - "Extramedullary disease (EMD) in multiple myeloma (MM) is associated with poor outcomes following B-cell maturation antigen (BCMA)-targeted CAR-T therapy, yet its impact on treatment-related toxicity remains unclear...We conducted a retrospective cohort study of all patients with MM who received ide-cel (n=32) or cilta-cel (n=76) as standard-of-care therapy at our institution from August 2021 to October 2024...Among 108 patients, 26 (24%) had EMD. Patients with EMD experienced higher rates of grade (G)1+ (38% vs. 17%, p=0.022) and G3+ ICANS (19% vs. 1.2%, p=0.003), as well as G1+ (96% vs. 78%, p=0.041) and G3+ eICAHT (31% vs. 0%, p."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology

A phase 1 trial of fully human BCMA CAR-T therapy for relapsed/refractory multiple myeloma with 5-year follow-up. (PubMed, Blood) - P1 | "FCARH143, an autologous BCMA-targeted CAR-T therapy which incorporates a fully human BCMA-specific scFv and 4-1BB costimulatory domain, was evaluated in a phase 1 trial (NCT03338972) for relapsed/refractory multiple myeloma (RRMM). FCARH143 demonstrated potent anti-myeloma activity with a 100% response rate and manageable toxicity, independent of disease burden or cytogenetic risk. Further evaluation in high-risk RRMM is warranted."

Journal • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology

Active Extramedullary Disease Predicts ICANS and Early ICAHT after CAR-T Therapy in Multiple Myeloma (TCT-ASTCT-CIBMTR 2025) - "Introduction: BCMA-targeted CAR-T therapy has revolutionized treatment for multiple myeloma (MM), showing remarkable efficacy in clinical trials... Our analysis included 96 pts treated with idecabtagene vicleucel (n=32, 33%) and ciltacabtagene autoleucel (n=64, 67%) as standard of care at our institution between Aug 2021 and Aug 2024... While EMD is recognized for its association with poor long-term outcomes, our study is the first to link EMD with increased short-term toxicity and systemic inflammation following CAR-T therapy. These findings emphasize the need for careful pt selection when considering CAR-T therapy for MM pts with active EMD, and suggest that earlier intervention, when the EMD burden is lower, may be beneficial. Further research is needed to explore whether targeted EMD therapies, such as radiation, can reduce the risks associated with CAR-T treatment."

IO biomarker • Hematological Malignancies • Hemophagocytic lymphohistiocytosis • Inflammation • Multiple Myeloma • Oncology • IL6

Autoimmune Outcomes in Patients with Concurrent Autoimmune Disease Receiving CD19- or BCMA-Targeted CAR T-Cell Therapy for Lymphoma or Multiple Myeloma (TCT-ASTCT-CIBMTR 2025) - "Products included axicabtagene ciloleucel, brexucabtagene autoleucel, ciltacabtagene autoleucel, idecabtagene vicleucel, lisocabtagene maraleucel, and tisagenlecleucel. In our center’s experience, half of patients on active treatment for AID prior to CAR-T experienced improvement in AID symptoms and/or cessation or decrease in intensity of AID-directed therapy. Worsening of AID, a feared complication with CAR-T, is fortunately uncommon. CAR-T may be a potential treatment option for patients with severe AID."

CAR T-Cell Therapy • Clinical • Hematological Malignancies • Immunology • Lymphoma • Multiple Myeloma • Oncology

Distinct Patterns of Pathogen-Specific and Non-Specific Immune Reconstitution after CD19/20- Versus BCMA-Targeted CAR-T Cell Therapy (TCT-ASTCT-CIBMTR 2025) - "Conclusion In this cohort of CARTx recipients, participants receiving BCMA-CARTx had greater immune deficits than CD19/20-CARTx recipients before and up to 1 year after CARTx, though they showed recovery of humoral immunity from pre- to 1-year post-CARTx. Pathogen-specific deficits were common in both groups, underscoring the need for re-vaccination."

CAR T-Cell Therapy • Infectious Disease • Oncology

NCI-2018-00514: BCMA-Specific CAR T-Cells Combined With a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma (clinicaltrials.gov) - P1 | N=19 | Terminated | Sponsor: Fred Hutchinson Cancer Center | Active, not recruiting ➔ Terminated; Closed per SRC Low Accrual Policy

CAR T-Cell Therapy • Combination therapy • IO biomarker • Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

NCI-2018-00514: BCMA-Specific CAR T-Cells Combined With a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma (clinicaltrials.gov) - P1 | N=19 | Active, not recruiting | Sponsor: Fred Hutchinson Cancer Center | Suspended ➔ Active, not recruiting

CAR T-Cell Therapy • Combination therapy • Enrollment closed • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

CMV Reactivation and CMV-Specific Cell-Mediated Immunity after Chimeric Antigen Receptor T-Cell Therapy. (PubMed, Clin Infect Dis) - "CMV testing could be considered between 2-6 weeks in high-risk CARTx-recipients."

CAR T-Cell Therapy • Journal • Cytomegalovirus Infection • Hematological Disorders • Infectious Disease • Oncology • CD20 • IFNG

NCI-2018-00514: BCMA-Specific CAR T-Cells Combined With a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma (clinicaltrials.gov) - P1 | N=18 | Suspended | Sponsor: Fred Hutchinson Cancer Center | Trial completion date: Sep 2025 ➔ Sep 2026 | Trial primary completion date: Sep 2024 ➔ Sep 2025

CAR T-Cell Therapy • Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

CMV and HHV-6 after Chimeric Antigen Receptor (CAR)-T-Cell Immunotherapy for B-Cell Malignancies: A Prospective Study (TCT-ASTCT-CIBMTR 2023) - "Pre-CARTx variables that may be associated with increased risk include multiple myeloma treated with BCMA-targeted CARTx, prior HCT, and more lines of antitumor treatments. Enrollment is ongoing to increase sample size and allow for adjusted analyses."

Clinical • CNS Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Oncology • Transplantation

Anti-HLA antibodies in recipients of CD19 versus BCMA-targeted CAR T-cell therapy. (PubMed, Am J Transplant) - "These data implicate CD19 long-lived plasma cells as an important source for anti-HLA antibodies, a model supported by infrequent HLA sensitization in BCMA-CARTx subjects receiving previous plasma cell-targeted therapies. Thus, plasma cell-targeted therapies may be more effective against HLA antibodies, thereby enabling improved access to organ transplantation and rejection management."

CAR T-Cell Therapy • Journal • Hematological Disorders • Hematological Malignancies • Immune Modulation • Immunology • Inflammation • Oncology • Solid Organ Transplantation • Transplantation • CD19

Safety and Efficacy of Fully Human BCMA CAR T Cells in Combination with a Gamma Secretase Inhibitor to Increase BCMA Surface Expression in Patients with Relapsed or Refractory Multiple Myeloma (ASH 2021) - "We have completed accrual to a phase 1 first-in-human trial of escalating doses of BCMA targeted CAR T cells in combination with a GSI (JSMD194) for patients with relapsed or refractory multiple myeloma, and herein report results on the 18 patients accrued to this trial. From June 2018 to March 2021, 18 patients underwent leukapheresis, run-in with JSMD194, and treatment with BCMA CAR T cells. The median age was 65 years, and patients had received a median of 10 prior lines of therapy (range, 4-19). 67% of patients were refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, 72% had high-risk cytogenetic features, and 28% had extramedullary disease."

CAR T-Cell Therapy • Clinical • Combination therapy • IO biomarker • Hematological Malignancies • Inflammation • Multiple Myeloma • Oncology • CD4 • CD8 • SDC1

NCI-2018-00514: BCMA-Specific CAR T-Cells Combined With a Gamma Secretase Inhibitor (JSMD194) to Treat Relapsed or Persistent Multiple Myeloma (clinicaltrials.gov) - P1 | N=18 | Suspended | Sponsor: Fred Hutchinson Cancer Center | Trial completion date: Apr 2022 ➔ Sep 2025 | Trial primary completion date: Apr 2022 ➔ Sep 2024

CAR T-Cell Therapy • Combination therapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

Stromal cell derived IL6 inhibits the extrinsic apoptotic pathway in multiple myeloma cell lines (AACR 2022) - "Clinical trials have shown that BCMA targeted CAR-T therapy induces MM remission in most patients with heavily pretreated relapsed refractory MM; however, the duration of the response has been disappointing...This suggests that soluble factors in the BMM can convert cells from type I to type II (mitochondrial-dependent) death receptor signaling and that inhibiting BMM signals such as IL6 may enhance FASL-induced cell death in MM. However, the data also demonstrate that the role of FAS in CAR-T killing is cell context dependent."

IO biomarker • Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • FAS • FASLG • GZMB • IL6