MCARH109 / Eureka Therap, BMS, Memorial Sloan-Kettering Cancer Center, Sanofi - LARVOL DELTA

Belantamab mafodotin, nirogacestat, and pomalidomide in patients with relapsed/refractory multiple myeloma (ASH 2025) - P1 | "Median priorlines of therapy was 5; 100% were triple exposed (PI, IMiD, anti-CD38 monoclonal antibody), and 5patients had prior high dose melphalan with autologous stem cell transplant. Two patients had priorBCMA treatment; 1 patient had received a BCMA CAR T and a GPRC5D CAR T, and 1 patient had receiveda BCMA CAR T and a BCMA bispecific antibody.The overall response rate (ORR) was 66% including 3 with partial response (PR) and 3 with very goodpartial response (VGPR)...The rate of ocular AEs wassimilar to prior belantamab mafodotin trials and real-world studies. The significant increase inmembrane bound BCMA after starting nirogacestat indicates a possible therapeutic synergy betweenGSIs and BCMA targeted therapies."

Clinical • IO biomarker • Age-related Macular Degeneration • Infectious Disease • Macular Degeneration • Multiple Myeloma • Neutropenia • Ophthalmology • Renal Disease • Retinal Disorders • Thrombocytopenia

Genetic Basis of Relapse after GPRC5D-Targeted CAR T Cells (ASH 2023) - "Our patients with heavily pretreated multiple myeloma may harbor greater tumor heterogeneity and genomic instability than previously described, which can facilitate clonal outgrowth of antigen-negative tumor cells under continuous selective pressure of GPRCRD-targeted CAR T cells. Potential strategies to mitigate antigen escape-mediated relapse in myeloma patients receiving T-cell engaging therapies including earlier use of these therapies, multi-antigen targeting, or combination approaches are being evaluated in ongoing trials."

CAR T-Cell Therapy • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • Plasmacytoma • GPRC5D

MCARH109 Chimeric Antigen Receptor (CAR) Modified T Cells for the Treatment of Multiple Myeloma (clinicaltrials.gov) - P1 | N=17 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Aug 2025 ➔ Aug 2026 | Trial primary completion date: Aug 2025 ➔ Aug 2026

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

Mezigdomide (MEZI) in Novel Combinations Effectively Reactivates Immune System in Patients with Relapsed/refractory Multiple Myeloma (RRMM) Including Those After T-cell–redirecting Therapies (TCRT) (IMS 2025) - "MEZI+dexamethasone (MEZId) combined with novel agents, such as tazemetostat (TAZ), the bromodomain inhibitor (BETi) BMS-986158, and trametinib (TRAM) showed promising efficacy and safety in the phase 1/2 CA057-003 trial in pts with RRMM, including pts post-TCRT...Last regimen included TCRT (n=28: BCMA CAR-T, n=8; GPRC5D CAR-T, n=6; BCMA TCE, n=3; GPRC5D TCE, n=8, BCMA TCE+GPRC5D TCE, n=2; trispecific T-cell–activating constructs, n=1), or various non-TCRT regimens (n=28)... MEZId-based novel regimens lead to activation of adaptive and innate immune populations in pts with RRMM regardless of prior TCRT exposure. Dynamics of immune changes with MEZId-based novel regimens agree with MEZId backbone data. Results suggest prior TCRT exposure and addition of novel agents do not affect the ability of MEZI to increase activation and proliferation of NK and T cells, supporting its use in combinations for pts with prior TCRT exposure."

Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • B3GAT1 • CCR7 • CD8 • HAVCR2 • IKZF1 • IL2RA • IL7R

Concurrent Administration of BCMA and GPRC5D Chimeric Antigen Receptor (CAR) T Cells for the Treatment of Relapsed or Refractory Multiple Myeloma: Results from the Phase I TANDEMM Clinical Trial (IMS 2025) - "However, relapses are common and multi-antigen targeting has been proposed as a potential approach to achieve durable responses. We conducted a phase I, dose escalation trial of concurrent infusion of BCMA and GPRC5D CAR T cells, MCARH125 and MCARH109 in patients with relapsed or refractory myeloma. All patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by CAR T cell infusion at one of 3 dose levels (DL): DL 0, 150 X 106 cells of MCARH125 alone; DL 1, 50 X106 cells of MCARH109 and 150 X 106 cells of MCARH125; DL 2, 150 X106 cells of MCARH109 and 150 X 106 cells of MCARH125... In this proof-of-concept trial, we demonstrate feasibility, safety, and efficacy of concurrently targeting two myeloma specific antigens BCMA and GPRC5D by co-administering two different CAR T products manufactured from a single apheresis."

Clinical • IO biomarker • P1 data • Hematological Malignancies • Hemophagocytic lymphohistiocytosis • Inflammation • Multiple Myeloma • CD8

Timing genomic antigen loss in multiple myeloma treated with T-cell redirecting immunotherapies. (PubMed, Blood Cancer Discov) - "In all cases, the biallelic loss was driven by genomic events acquired after exposure to BCMA- and GPRC5D-targeted CAR-T/TCE, and not present at baseline...Among 752 newly diagnosed patients only 2.7% and 9% had monoallelic inactivation of TNFRSF17 and GPRC5D, respectively, with no biallelic loss. Our findings suggest limited utility of mutational screening prior to CAR-T/TCE, while underscoring the importance of dynamic surveillance during therapy."

IO biomarker • Journal • Hematological Malignancies • Multiple Myeloma • Oncology • TNFRSF17

A Study of MCARH109 and MCARH125 in People With Multiple Myeloma (clinicaltrials.gov) - P1 | N=15 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

MEZIGDOMIDE (MEZI) IN NOVEL COMBINATIONS EFFECTIVELY REACTIVATES IMMUNE SYSTEM IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA (RRMM) INCLUDING THOSE AFTER T-CELL-REDIRECTING THERAPIES (EHA 2025) - P1/2 | "MEZI + dexamethasone (MEZId) in combination with novel agents, such as tazemetostat (TAZ), the bromodomain inhibitor (BETi) BMS-986158, and trametinib (TRAM) showed promising efficacy and safety in the phase 1/2 CA057-003 trial (NCT05372354) in pts with RRMM, including those post-TCRT...Last regimen included TCRT for 28 pts (BCMA CAR-T, n=8; GPRC5D CAR-T, n=6; BCMA TCE, n=3; GPRC5D TCE, n=8, BCMA TCE+GPRC5D TCE, n=2; trispecific T-cell-activating constructs, n=1), or various non-TCRT regimens for the other 28 pts... MEZId-based novel combinations lead to activation of adaptive and innate immune populations in pts with RRMM irrespective of prior TCRT exposure. Dynamics of immune changes upon tx with MEZId-based novel combinations is concordant with findings reported for the MEZId backbone. These results suggest previous exposure to TCRT and the addition of novel agents do not affect the ability of MEZI to increase activation and proliferation of NK and T cells,..."

Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • B3GAT1 • CCR7 • CD8 • HAVCR2 • IKZF1 • IL2RA • IL7R

A Study of MCARH109 and MCARH125 in People With Multiple Myeloma (clinicaltrials.gov) - P1 | N=15 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Recruiting ➔ Active, not recruiting | N=24 ➔ 15

Enrollment change • Enrollment closed • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

Mechanistic Modeling of CAR T-Cell Therapy for Multiple Myeloma (TCT-ASTCT-CIBMTR 2025) - " We utilized published pharmacokinetic and biomarker response data to calibrate a QSP model predictive of response to BCMA-targeted (Ciltacabtagene autoleucel [cilta-cel], Idecabtagene vicleucel [ide-cel]) and GPRC5D-targeted (MCARH109) CAR T-cell therapies. We calibrated/validated a QSP model of CAR T-cell therapy for RRMM that identified factors (high tumor proliferation, low antigen expression, and low CAR T-cell kill rate) associated with worse outcomes. Our model also predicted GPRC5D-targeted CAR T-cell therapy is more sensitive to antigen escape compared to BCMA-targeted CAR T-cell therapy. This model can serve as a framework to investigate response/relapse mechanisms as well as multi-antigen targeting."

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

Phase I Trial of MCARH109, a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-Targeted Chimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma: An Updated Analysis. (PubMed, J Clin Oncol) - "Possible GPRC5D loss via immunohistochemistry was observed in 6 (60%) of 10 patients at relapse. High-dimensional spectral cytometry-based immune profiling associated an activated T-cell phenotype at apheresis with a response to MCARH109."

CAR T-Cell Therapy • Journal • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology

Phase I trial of MCARH109, a first-in-class G Protein Coupled Receptor Class C Group 5 Member D (GPRC5D)-targeted CAR T-cell therapy for relapsed or refractory multiple myeloma: Updated Analysis (IMW 2024) - "Here we report updated safety and efficacy of MCARH109, a first-in-class GPRC5D targeted CAR-T therapy, in patients with RRMM... In this updated analysis of MCARH109, persistent cerebellar disorders were seen in 2 patients treated at the highest dose of 450×106 CAR-T cells but not at lower doses. At the maximum tolerated dose of 150×106, no new toxicities were observed. Responses were noted across all dose levels and in BCMA-exposed patients."

CAR T-Cell Therapy • IO biomarker • P1 data • CNS Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • CCR7 • CD8 • FAS

MCARH109 Chimeric Antigen Receptor (CAR) Modified T Cells for the Treatment of Multiple Myeloma (clinicaltrials.gov) - P1 | N=17 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Aug 2024 ➔ Aug 2025 | Trial primary completion date: Aug 2024 ➔ Aug 2025

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

A Study of MCARH109 and MCARH125 in People With Multiple Myeloma (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Jun 2024 ➔ Jun 2025 | Trial primary completion date: Jun 2024 ➔ Jun 2025

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

PREVALENCE, ETIOLOGY, AND OUTCOME OF DELAYS BETWEEN INITIATION OF LYMPHODEPLETING CHEMOTHERAPY AND CAR T CELL INFUSION (EHA 2024) - "408 pts (64%) received an FDA-approved CD19 targeted CAR, 77 (12%) aninvestigational CD19 CAR, 79 (13%) an FDA-approved BCMA CAR, 56 (9%) an investigational BCMA CAR, and8 (1%) an investigational GPRC5D CAR...In 1 case, the patient received one dose of cyclophosphamide/fludarabine (cy/flu), paused LDC due to biliarysepsis, and then restarted the full LDC regimen 6 days later, thus receiving four total doses... In our cohort, delay of infusion beyond 7d from initiation of LDC was rare (2. 7%). Infection/fever was the mostcommon reason."

CAR T-Cell Therapy • Acute Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Hepatology • Immunology • Infectious Disease • Inflammatory Arthritis • Leukemia • Lupus • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Systemic Lupus Erythematosus

Prognostic impact of corticosteroid and tocilizumab use following chimeric antigen receptor T-cell therapy for multiple myeloma. (PubMed, Blood Cancer J) - "In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36-1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy."

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

Dr Parrondo on the Investigation of GPRC5D-Targeted CAR T-Cell Therapy in Multiple Myeloma (OncLive) - P1 | N=17 | NCT04555551 | "Ricardo D. Parrondo...discusses the exploration of the non-BCMA CAR T-cell target GPRC5D in multiple myeloma...A phase 1 dose-escalation study (NCT04555551) of MCARH109, a first-in-GPRC5D-targeted CAR T-cell therapy, is being conducted in patients with relapsed/refractory myeloma, Parrondo continues....Previously reported results showed that MCARH109 demonstrated a manageable safety profile and achieved high rates of initial clinical responses and minimal residual disease negativity across multiple dose levels, Parrondo says. The ongoing dose escalation study aims to further evaluate the efficacy of MCARH109, with additional patients planned for treatment at higher doses."

P1 data • Trial status • Hematological Malignancies • Multiple Myeloma • Oncology

GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review. (PubMed, Blood Cancer J) - "We review the biology and target validation of GPRC5D, and clinical data from early phase trials of GPRC5D-targeting bispecific antibodies, talquetamab and forimtamig, and chimeric antigen receptor T cell (CAR-T) therapies, MCARH109, OriCAR-017, and BMS-986393...Further clinical trials, including those investigating GPRC5D-targeting T-cell-redirecting agents in combination with other anti-myeloma therapies and with different treatment modalities, may help to elucidate the future optimal treatment regimen and sequence for patients with multiple myeloma and improve survival outcomes. Video Summary."

Journal • Review • Dermatology • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Oncology

Genetic Basis of Relapse after GPRC5D-Targeted CAR T Cells. (PubMed, N Engl J Med) - No abstract available

CAR T-Cell Therapy • Journal

New T-Cell Therapy Shows Improved Response in Resistant Multiple Myeloma (Cure Today) - P1 | N=17 | NCT04555551 | "Patients with relapsed/refractory multiple myeloma benefited from treatment with MCARH109, a CAR-T cell therapy targeting the 'enigmatic' GPRC5D antigen which generated remissions in 70.6% of patients, according to data from a first-in-human phase 1 trial...Twelve of 17 patients experienced a measurable decline in their cancer after receiving MCARH109 CAR-T cells. Six patients (35%) achieved complete response and 10 patients (59%) had very good partial response or better. Eight patients (47%) had minimal residual disease negativity in bone marrow....The median duration of response (DOR) was 7.8 in the entire cohort. The median DOR was also 7.8 months in patients who received CAR-T cells."

P1 data • Hematological Malignancies • Multiple Myeloma • Oncology

A Study of MCARH109 and MCARH125 in People With Multiple Myeloma (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Memorial Sloan Kettering Cancer Center

CAR T-Cell Therapy • New P1 trial • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

GPRC5D-Targeted CAR T Cells for Myeloma. (PubMed, N Engl J Med) - P1 | "The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.)."

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

Clinical Activity of BMS-986393 (CC-95266), a G Protein–Coupled Receptor Class C Group 5 Member D (GPRC5D)–Targeted Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients with Relapsed and/or Refractory (R/R) Multiple Myeloma (MM): First Results from a Phase 1, Multicenter, Open-Label Study (ASH 2022) - P1 | "After screening and leukapheresis, pts received bridging therapy if needed, then lymphodepleting chemotherapy (fludarabine 30 mg/m2 + cyclophosphamide 300 mg/m2 daily for 3 days) followed by a single infusion of BMS-986393... At all tested dose levels, BMS-986393 demonstrated a favorable safety profile; both CRS and neurotoxicity were low-grade, and neurotoxicity was infrequent and short-lived. Dose escalation is ongoing; MTD has not been exceeded. Preliminary efficacy appeared promising; antitumor responses were observed, including pts with CR who were MRD-negative at month 3."

Clinical • IO biomarker • P1 data • Bone Marrow Transplantation • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Neutropenia • Oncology • Plasmacytoma • Thrombocytopenia • Transplantation • GPRC5D

GPRC5D-Targeted CAR T Cells for Myeloma. Reply. (PubMed, N Engl J Med) - No abstract available

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

Phase I First-in-Class Trial of MCARH109, a G Protein Coupled Receptor Class C Group 5 Member D (GPRC5D) Targeted CAR T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma (ASH 2021) - " This is a phase I first-in-human, dose escalation trial of MCARH109; patients received lymphodepleting chemotherapy with fludarabine 30 mg/m 2 daily and cyclophosphamide 300 mg/m 2 daily for 3 days followed by a single infusion of MCARH109...Cytokine release syndrome (CRS) grade 1-3 occurred in 11 (92%) patients with only one patient with grade 3 event; 4 (25%) patients received tocilizumab and 1 (8%) received dexamethasone for the treatment of CRS (Table)... MCARH109 is the first-in-class GPRC5D targeted CAR T cell therapy for MM and has a very manageable safety profile with no serious or unexpected toxicities; this dose escalation study is ongoing with additional patients planned for treatment at higher doses. Efficacy is promising in heavily pre-treated RRMM, reflected in high rates of clinical response as well as MRD-negativity, including at doses as low as 25x10 6 CAR T cells. Clinically important, all 6 patients who relapsed after BCMA CAR T therapy responded to..."

CAR T-Cell Therapy • Clinical • P1 data • Hematological Malignancies • Inflammation • Multiple Myeloma • Oncology • Plasmacytoma • PCR