orvacabtagene autoleucel (JCARH125) / BMS - LARVOL DELTA

NOVEL SIGNATURE OF BASELINE INFLAMMATION IDENTIFIES PATIENTS AT HIGH RISK OF RELAPSE AFTER BCMA CAR-T IN MULTIPLE MYELOMA (EBMT 2025) - " This is a single center retrospective study of 180 patients with RRMM treated with BMCA-directed CAR-T (Orvacabtagene autoleucel n=32, 18%; Idecabtagene vicleucel n=50, 28%; Ciltacabtagene autoleucel n=98, 54%; Table 1). Our findings demonstrate that systemic inflammation, characterized by a unique immune signature identified through a machine learning approach, adversely impacts outcomes in BCMA-directed CAR-T-treated patients. This blood-based signature represents a readily accessible biomarker for risk stratification and can be incorporated as an exploratory endpoint in prospective clinical trials using BCMA-directed CARTs."

Clinical • IO biomarker • Hematological Malignancies • Inflammation • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • IL6

NOVEL SIGNATURE OF BASELINE INFLAMMATION IDENTIFIES PATIENTS AT HIGH RISK OF RELAPSE AFTER BCMA CAR-T IN MULTIPLE MYELOMA (EBMT 2025) - " This is a single center retrospective study of 180 patients with RRMM treated with BMCA-directed CAR-T (Orvacabtagene autoleucel n=32, 18%; Idecabtagene vicleucel n=50, 28%; Ciltacabtagene autoleucel n=98, 54%; Table 1). Our findings demonstrate that systemic inflammation, characterized by a unique immune signature identified through a machine learning approach, adversely impacts outcomes in BCMA-directed CAR-T-treated patients. This blood-based signature represents a readily accessible biomarker for risk stratification and can be incorporated as an exploratory endpoint in prospective clinical trials using BCMA-directed CARTs."

Clinical • IO biomarker • Hematological Malignancies • Inflammation • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • IL6

Population Pharmacokinetics of Orvacabtagene Autoleucel, an Autologous BCMA-Directed Chimeric Antigen Receptor T-cell Product, in Patients with Relapsed/Refractory Multiple Myeloma (Clin Cancer Res) - P1/2 | N=165 | EVOLVE (NCT03430011) | Sponsor: Juno Therapeutics | "The population PK analysis included 159 patients from the EVOLVE study....Our modified model incorporating a cell number–dependent expansion rate outperformed traditional models by (i) more accurately capturing the cellular expansion phase and (ii) yielding a Tmax that closely matches observed values. Additionally, dose level, percentage of plasma cells in bone marrow, and treatment-induced antitherapeutic antibody were identified as statistically significant covariates and associated with orva-cel expansion and/or persistence."

P1/2 data • PK/PD data • Multiple Myeloma

Phase 1 clinical trial of B-Cell Maturation Antigen (BCMA) NEX-T® Chimeric Antigen Receptor (CAR) T cell therapy CC-98633/BMS-986354 in participants with triple-class exposed multiple myeloma. (PubMed, Leukemia) - "Median progression-free survival was 12.3 months (95% CI 11.3-16). Compared to orvacabtagene autoleucel (same CAR construct, conventional manufacturing), BMS-986354 had higher proportion of T central memory cells, were less differentiated and had enhanced potency and proliferative capacity, supporting the use of NEX-T® in future CAR T development."

Journal • P1 data • Hematological Malignancies • Infectious Disease • Inflammation • Multiple Myeloma • Oncology

Impact of Daratumumab Refractoriness on Clinical Outcomes Following CAR T-Cell Therapy for Relapsed/Refractory Multiple Myeloma (TCT-ASTCT-CIBMTR 2025) - "Methods : Our analysis included RRMM patients treated with ide-cel, cilta-cel, or orvacabtagene autoleucel (orva-cel) from April 2018 to November 2023. Most patients treated with BCMA-directed CAR T for RRMM in this study were dara refractory. Despite more lines of prior therapy and aggressive disease biology, the DR group showed comparable efficacy to the DN group. Expanded data with further efficacy and safety analyses will be presented at the meeting."

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

Population Pharmacokinetics of Orvacabtagene Autoleucel, an Autologous BCMA-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Multiple Myeloma. (PubMed, Clin Cancer Res) - P1/2 | "Orva-cel PK were adequately described by the modified piecewise model incorporating a cell number-dependent expansion phase, which aligns closely with T cell biology."

Journal • PK/PD data • Hematological Malignancies • Multiple Myeloma • Oncology

Impact of Daratumumab Refractoriness on Clinical Outcomes Following CAR T-Cell Therapy for Relapsed/Refractory Multiple Myeloma (ASH 2024) - "Therefore, we conducted a single-center retrospective cohort study comparing the clinical outcomes of RRMM patients who received BCMA-directed CAR T-cell therapy based on their dara refractoriness status.Methods : Our analysis included all patients with RRMM who received ide-cel, cilta-cel, or orvacabtagene autoleucel (orva-cel) between April 2018 and November 2023. Despite more prior lines of therapy and higher rates of EMD, high tumor burden, prior BCMA-directed therapy, and prior T-cell-redirecting therapy; the DR group showed comparable efficacy outcomes to DN group. Longer follow up with more patients, as well as details of efficacy and safety outcomes with univariate and multivariate analysis will be presented at the meeting."

CAR T-Cell Therapy • Clinical • Clinical data • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • TP53

Impact of Daratumumab Refractoriness on Clinical Outcomes Following CAR T-cell Therapy for Relapsed/Refractory Multiple Myeloma (IMW 2024) - " Our analysis included all pts with RRMM who received ide-cel, cilta-cel, or orvacabtagene autoleucel (orva-cel) between April 2018 and November 2023. A majority of pts treated with BCMA-directed CAR T for RRMM in this single-center experience were dara refractory. Despite more prior LOT, higher rates of EMD, and higher rates of prior BCMA-directed therapy, the DR group showed similar efficacy outcomes to DN group. Longer follow up with more patients, as well as details of efficacy and safety outcomes with univariate and multivariate analysis will be presented at the meeting."

CAR T-Cell Therapy • Clinical • Clinical data • IO biomarker • Hematological Malignancies • Inflammation • Multiple Myeloma • Oncology • TP53

Expansion and persistence of anti-BCMA CAR T cells correlates with durability of responses in multiple myeloma patients (AACR 2024) - "Previous studies have shown that specific cell states in the apheresis and infusion products are associated with long-term efficacy of anti-BCMA CAR therapy in MM and the relationship between durability of response and CAR T cell persistence remains unclear. We analyzed serial bone marrow and PBMC samples from 20 MM patients who received BCMA CAR T therapy, including cilta-cel, ide-cel, and JCARH125. Our data demonstrate that distinct anti-BCMA CAR T cell treatments lead to very different cellular outcomes: Cilta-cel CAR T cell treatment leads to greater expansion and persistence compared to other anti-BCMA CAR T cells. Cilta-cel CAR T cells also shift from the initial effector state to a memory phenotype. These results provide insights into features of more efficacious anti-BCMA CAR T cells that can help guide the future development of more durable treatments for MM."

CAR T-Cell Therapy • Clinical • Hematological Malignancies • Multiple Myeloma • Oncology • CD4 • CD8

EVOLVE: Study Evaluating the Safety and Efficacy of JCARH125 in Subjects With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=169 | Completed | Sponsor: Juno Therapeutics, a Subsidiary of Celgene | Active, not recruiting ➔ Completed

Trial completion • Hematological Malignancies • Multiple Myeloma • Oncology

Real-World Efficacy of CAR T-Cell Therapies: A HealthTree Cure Hub's Study of Multiple Myeloma Patients (IMW 2023) - "We assessed the effectiveness of CAR T-cell therapies (Abecma [ide-cel], Carvykti [cilta-cel], orva-cel, and other) by using Kaplan-Meier probability to examine event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). Our evaluation of real-world data suggests CAR T-cell therapy is a promising treatment strategy for RRMM regardless of therapy. The findings underscore the advantages of utilizing RWD through digital platforms such as HealthTree Cure Hub. This methodology offers a powerful tool to continually assess the impact of emerging therapeutics within the multiple myeloma patient population."

CAR T-Cell Therapy • Clinical • Real-world • Real-world effectiveness • Real-world evidence • Hematological Malignancies • Multiple Myeloma • Oncology

Results from the First Phase 1 Clinical Study of the B-Cell Maturation Antigen (BCMA) Nex T Chimeric Antigen Receptor (CAR) T Cell Therapy CC-98633/BMS-986354 in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM) (ASH 2022) - P1 | "Pts received a single BMS-986354 infusion 2–7 days after lymphodepleting chemotherapy (3 days fludarabine [30 mg/m2] and cyclophosphamide [300 mg/m2])...Median onset was day 4 (range, 2–8), median duration was 4 days (range, 1–8), and common treatments included tocilizumab (n = 38), steroids (n = 25), and anakinra (n = 9)... BMS-986354, a NEX-T investigational BCMA-targeted CAR T-cell product, is a less differentiated, more potent cellular drug product than orva-cel and can be manufactured with a more rapid processing time. At low doses, BMS-986354 demonstrated a favorable safety profile and promising efficacy, including deep and durable responses in pts with heavily pretreated RRMM. The study continues to enroll patients in the dose-expansion phase."

Clinical • P1 data • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Neutropenia • Oncology • Thrombocytopenia • Transplantation • IFNG • IL2 • TNFA

[VIRTUAL] Relapsed/Refractory (R/R) MM (ASCO 2021) - "Results from the Phase III BOSTON trial evaluating selinexor in combination with bortezomib and dexamethasone; clinical implications Key efficacy and safety findings supporting the FDA approval of daratumumab in combination with carfilzomib and dexamethasone for patients with R/R MM (CANDOR and EQUULEUS trials) Mechanism of action of isatuximab; structural and pharmacologic similarities and differences between isatuximab and daratumumab and the implications, if any, for activity and tolerability Design, eligibility criteria and key efficacy and safety findings from the Phase III ICARIA-MM and IKEMA trials; FDA-approved indication for isatuximab and current and potential clinical role Mechanism of action of belantamab mafodotin and efficacy and safety results from the Phase II DREAMM-2 study evaluating that agent for R/R MM; preliminary findings from DREAMM-6 evaluating belantamab mafodotin in combination with bortezomib/dexamethasone FDA approval of belantamab mafodotin..."

IO biomarker • BCL2

[VIRTUAL] BCMA-Directed CAR T-Cells: Early Results and Future Directions (SOHO 2021) - "Other Constructs of Interest Orva-cel (orvacabtagene autoleucel) is an anti-BCMA CAR T product with a construct containing a fully human scFv, an optimized spacer, a 4-1BB co-stimulatory domain, and a CD3z activation domain...Bb21217 has an identical construct to ide-cel except for coculturing with the phosphoinositide 3 kinase inhibitor (PI3K) bb007 during ex vivo culture to enrich for T cells displaying a memory-like phenotype...The ORR was 94%.17 P-BCMA-101 is a novel construct using an anti-BCMA Centyrin™ fused to a 4-1BB costimulatory domain and CD3z signaling domain...Both ide-cel and cilta-cel are being evaluated in various patient populations, including early-relapse and newly diagnosed high-risk patients...The first results of an allogeneic BCMA-directed CAR-T was with ALLO-715. The initial results from the UNIVERSAL phase 1 study in RRMM are encouraging, with responses reported and more attenuated toxicity.26 Others, including CTX120, BCMAUCART, UCART CS1, and..."

CAR T-Cell Therapy • Hematological Malignancies • Multiple Myeloma • Oncology • CD19 • CD4 • CD8 • SDC1 • TNFA

BCMA CAR-T-Cell Therapy (ide-cel idecabtagen-vicleucel) in Relapsed and Refractory Multiple Myeloma (RRMM): Results of the Phase 1 Study Support the design of the Phase 3 study KarMMa-3 comparing ide-cel with triplicate combinations standard of care (DGHO 2019) - P1, P2, P3; "Eligible patients have received 2-4 prior regimens, including an IMiD, PI, and daratumumab and are refractory to last therapy... RRMM patients have poor outcomes despite increasing treatments options. The CRB-401 data in patients who received ≥3 prior therapies support investigating ide-cel in earlier treatment lines, as planned in KarMMa-3."

CAR T-Cell Therapy • P1 data • P3 data

[VIRTUAL] Orvacabtagene Autoleucel (orva-cel; JCARH125): A Fully Human BCMA-Targeted Second-Generation CAR T Cell Product Characterized By a Predominant Central Memory Phenotype with High in Vitro and In Vivo Proliferative Potential and Sustained In Vivo Persistence (ASH 2020) - P1/2 | "Conclusions : The orva-cel manufacturing process results in drug products characterized by highly pure T cells, with high frequencies of early memory and polyfunctional CAR+ T cells. Orva-cel drug products showed robust antigen-specific degranulation, production of multiple cytokines, sustained in vitro and in vivo proliferation, and in vivo persistence."

CAR T-Cell Therapy • IO Biomarker • Preclinical • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • CASP3 • CD27 • CD8 • GZMB • IFNG • IL2 • PCR • PTPRC • TNFA

[VIRTUAL] Multiple Myeloma (MM) (ASCO 2021) - "Biologic rationale for targeting the B-cell maturation antigen (BCMA) with CAR T-cell therapy for MM Compositional and mechanistic similarities and differences among various BCMA-targeted CAR T-cell platforms under investigation for MM Design, eligibility criteria and available efficacy and safety results from the pivotal Phase II KarMMa trial of idecabtagene vicleucel for patients with R/R MM; recent FDA approval and optimal integration into treatment algorithms Clinical, biologic and pathologic factors in the selection of patients with MM for treatment with CAR T-cell therapy Updated results from the CARTITUDE-1, EVOLVE and CRB-402 trials of ciltacabtagene autoleucel, orvacabtagene autoleucel and bb21217, respectively, for patients with R/R MM Incidence, timing and severity of adverse events associated with BCMA-directed CAR T-cell therapies for MM; optimal monitoring and management strategies Other promising CAR T-cell platforms under investigation in MM (eg,..."

Hematological Malignancies • Multiple Myeloma • Oncology

[VIRTUAL] Association of Baseline and Postinfusion Biomarkers with Safety and Efficacy Endpoints in Patients Treated with Orvacabtagene Autoleucel (orva-cel; JCARH125) in the Phase 1/2 Evolve Study (NCT03430011) (ASH 2020) - P1/2 | "Peak postinfusion levels of several inflammatory factors were associated with CRS (eg, IL-6 and IL-8) and NE (eg, tumor necrosis factor-α) grades (P < 0.05). Correlative analysis is ongoing, and updated results will be presented."

Biomarker • Clinical • IO Biomarker • P1/2 data • Hematological Malignancies • Multiple Myeloma • B2M • CXCL8 • IL6 • TNFA

"The BCMApalooza continues: $BMY CC-98633/BMS-986354, Car-T based on Juno-derived orva-cel (not Bluebird Abecma) #ASH22" (@JacobPlieth)

An Interim Report on a Phase 1/2 Study of HPN217, a Half-Life Extended Tri-Specific T Cell Activating Construct (TriTAC®) Targeting B Cell Maturation Antigen for the Treatment of Relapsed/Refractory Multiple Myeloma (ASH 2021) - P1/2 | "Premedication to minimize cytokine release syndrome (CRS) includes dexamethasone, diphenhydramine, acetaminophen, and a proton pump inhibitor...Patients treated received a median of 8 (range of 4 – 16) prior systemic regimens, including 5 patients who received prior BCMA-targeted belantamab mafodotin or orvacabtagene autoleucel...Dose escalation, including implementation of step dosing, with the goal of establishing an RP2D regimen, is ongoing. NCT04184050"

IO biomarker • P1/2 data • Anemia • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Neutropenia • Oncology • Thrombocytopenia • CD69 • CXCL8 • IL10 • IL2RA • IL6 • TNFA

Dr. Dhakal on the Mechanism of Action of Orva-Cel in Multiple Myeloma (OncLive) - "Orva-cel is an investigational CAR T-cell therapy product that demonstrated an overall response rate of 91% in heavily pretreated patients with relapsed/refractory multiple myeloma, according to data from the phase 1/2 EVOLVE study (NCT03430011). The product targets BCMA, which is currently the leading target antigen for CAR T-cell therapies in multiple myeloma, says Dhakal. Compared with idecabtagene vicleucel, orva-cel is a fully humanized product, Dhakal explains. Additionally, although data have not demonstrated that soluble BCMA affects responses to CAR T-cell therapy, orva-cel has a very low affinity for soluble BCMA, concludes Dhakal."

Video

Early Time-to-Tocilizumab after B Cell Maturation Antigen-Directed Chimeric Antigen Receptor T Cell Therapy in Myeloma. (PubMed, Transplant Cell Ther) - "We retrospectively analyzed our institution's experience with 4 BCMA-directed CAR-T therapies (idecabtagene vicleucel, bb21217, ciltacabtagene autoleucel, and orvacabtagene autoceucel) for RRMM over a 3-year period ending in June 2020. However, total CRS duration may be shorter with early-toci workflows. Prospective validation of our findings may lead to improved safety and cost-effectiveness profiles for CAR-T therapy in RRMM."

CAR T-Cell Therapy • IO biomarker • Journal • Hematological Malignancies • Multiple Myeloma • Oncology • Transplantation

Current state and next-generation CAR-T cells in multiple myeloma. (PubMed, Blood Rev) - "Here, we review the main clinical trials of CAR-T cells in MM with the most advanced autologous BCMA-directed ide-cel and cilta-cel, the human CARs orva-cel and CT053, the alternative manufacturing process with P-BCMA-101 and bb21217, the dual CAR GC012F and the allogenic BCMA-directed CAR-T cells ALLO-715. In light of those clinical data, we provide an overview of CAR-T cells' main potential resistance mechanisms, including antigen loss, antigen spreading, anti-CAR antibodies, CAR-T cell exhaustion, and the emergence of a non-permissive microenvironment. Finally, we describe the principal area of research to build the next generation of CAR-T cells, with armored-, gated- or commuting-CARs, CARs associated with knock out of specific genes, and CAR-T cells made from γδT cells or NK cells."

CAR T-Cell Therapy • Journal • Review • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

"And then, of course, the age-old question emerges of whether ADAs actually matter clinically… And by age old, maybe like 12 months old ever since orva-cel got folded 😉" (@RahulBanerjeeMD)

Clinical

Early MRD negativity to predict deepening myeloma response in relapsed/refractory multiple myeloma (RRMM) patients treated with bb2121 anti-BCMA CAR T cells. (ASCO 2018) - P1; "bb2121 induced a high frequency of rapid MRD-neg response, independent of IMWG MM responses. These early MRD-neg responses starting at M1 offer insights into bb2121 kinetics and may portend achievement of deeper responses over time."

CAR T-Cell Therapy • Clinical • Multiple Myeloma