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

BMS-986453, a Dual-Targeting BCMAxGPRC5D Autologous CAR T Cell Therapy in Patients (Pts) With Relapsed/Refractory Multiple Myeloma (RRMM): Initial Results From a Phase 1 Trial (IMS 2026) - P1 | "BMS-986453 is an investigational, dual-targeting BCMA×GPRC5D CAR T cell therapy. BMS-986453 demonstrated favorable safety and efficacy in pts with RRMM."

CAR T-Cell Therapy • Clinical • First-in-human • P1 data • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Thrombocytopenia

Treatment Naive GPRC5D Negative Multiple Myeloma With t(11;14) (IMS 2026) - P1 | "Clinical validation was performed in 32 RRMM patients enrolled in two anti-GPRC5D CART trials (NCT04555551, NCT05431608) and 117 patients treated with Talquetamab...As additional validation, in the Talquetamab cohort (n=117), patients with t(11;14) and prior Venetoclax sensitivity showed no GPRC5D expression and primary refractoriness to anti-GPRC5D... This study identifies a strong association of GPRC5D negativity with a t(11;14), B-cell-like profile, and genomically indolent myeloma subgroup, potentially conferring refractoriness to anti-GPRC5D therapy. As this group accounts for 10% of NDMM, and GPRC5D protein measurement can be performed by IHC, this represents a feasible and accessible biomarker for immunotherapy selection in myeloma. Importantly, these patients usually have a genomically indolent profile and are particularly sensitive to anti-BCMA therapies (Maura et al."

IO biomarker • Hematological Malignancies • Multiple Myeloma • CD2 • GPRC5D • TP53

Treatment-Naïve GPRC5D-Negative Multiple Myeloma With t(11;14) (IMS 2026) - P1 | "Clinical validation was performed in 32 RRMM patients enrolled in two anti-GPRC5D CART trials (NCT04555551, NCT05431608) and 117 patients treated with Talquetamab...As additional validation, in the Talquetamab cohort (n=117), patients with t(11;14) and prior Venetoclax sensitivity showed no GPRC5D expression and primary refractoriness to anti-GPRC5D... This study identifies a strong association of GPRC5D negativity with a t(11;14), B-cell-like profile, and genomically indolent myeloma subgroup, potentially conferring refractoriness to anti-GPRC5D therapy. As this group accounts for 10% of NDMM, and GPRC5D protein measurement can be performed by IHC, this represents a feasible and accessible biomarker for immunotherapy selection in myeloma. Importantly, these patients usually have a genomically indolent profile and are particularly sensitive to anti-BCMA therapies (Maura et al."

IO biomarker • Hematological Malignancies • Multiple Myeloma • CD2 • GPRC5D • TP53

Development of BMS-986453, a Dual-Targeting BCMAxGPRC5D Chimeric Antigen Receptor (CAR) for the Treatment of Multiple Myeloma (IMS 2026) - P1 | "The objective was to design, optimize, and evaluate dual-targeting BCMA×GPRC5D CAR T cell therapy for MM. High BCMA and GPRC5D expression in patients with ≥3 prior LOT confirms their suitability as dual-targeting CAR antigens. The loop tandem design was superior to bicistronic or linear tandem approaches, and the resulting CAR demonstrated potent dual-antigen activity in preclinical studies. These data supported advancement of BMS-986453 into clinical development, where early phase 1 results (NCT06153251) indicate a highly functional and potent CAR capable of effectively targeting BCMA and GPRC5D in patients."

First-in-human • IO biomarker • Hematological Malignancies • Multiple Myeloma • GPRC5D

BCMA x GPRC5D-Targeted CAR T-Cell Therapy: A Novel Approach in Relapsed/Refractory Multiple Myeloma (IMS 2026) - No abstract available

CAR T-Cell Therapy • Hematological Malignancies • Multiple Myeloma

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

Arlocabtagene autoleucel-a GPRC5D-targeted CAR T-cell therapy in heavily pretreated relapsed/refractory multiple myeloma. (PubMed, Blood) - P1 | "The 1-year OS rate was 90% (N=84). In conclusion, arlo-cel had a safety profile supportive of future study and demonstrated deep and durable responses, with promising PFS and OS in patients with heavily pretreated RRMM."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • Skin Cancer

GPRC5D-Targeted Therapies in Relapsed/Refractory Multiple Myeloma: A Systematic Review and Single-Arm Meta-Analysis (SOHO 2026) - " In total, 8 cohorts comprising 549 efficacy-evaluable patients were included: 4 BsAb cohorts from MonumenTAL-1 (talquetamab; N = 405) and 4 CAR-T cohorts (arlocabtagene autoleucel [arlo-cel], MCARH109, OriCAR-017, RD118; N = 124)... GPRC5D-targeted therapies achieve high and deep responses in heavily pretreated RRMM, with a pooled ORRexceeding 80%. CART approaches appear to deliver higher response rates and deeper remissions than BsAb therapy does, although cross-modal comparisons are limited by small CAR-T therapy patient sample sizes and trial heterogeneity. The class-defining on-target toxicity profile—skin, nail, and taste toxicities—is frequent but manageable."

Retrospective data • Review • Hematological Malignancies • Multiple Myeloma • Oncology

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

Concurrent administration of BCMA and GPRC5D chimeric antigen receptor (CAR) T cells in advanced multiple myeloma. (PubMed, Blood) - P1 | "We conducted a phase I dose escalation trial of the BCMA CAR T cell therapy MCARH125 alone or in combination with the GPRC5D CAR T cell therapy MCARH109 in patients with heavily pre-treated relapsed or refractory multiple myeloma. The overall response for co-infusion was 78% with a median PFS of 18.2 months. Correlative analysis suggests that antigen loss maybe an important mechanism of resistance even with dual-antigen targeting and we show for the first time that expansion of one CAR population can limit expansion of the second population, as dual-CAR treated patients had significantly less BCMA-CAR expansion than BCMA-CAR alone treated patients, despite equivalent BCMA CAR T cell doses at infusion."

IO biomarker • Journal • CNS Disorders • Hematological Malignancies • Hemophagocytic lymphohistiocytosis • Multiple Myeloma • Oncology • GPRC5D

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

Arlocabtagene Autoleucel in Patients With Heavily Pretreated Relapsed/Refractory Multiple Myeloma: Final Analysis From the Phase 1 Study (SOHO 2026) - P1 | "Context: Arlocabtagene autoleucel (arlo-cel) is a CAR-T therapy targeting G protein-coupled receptor class C group 5 member D (GPRC5D), a validated target in RRMM. Final results from the first-in-human phase 1 study of arlo-cel represent longest follow-up with GPRC5D CAR T therapy in RRMM and continue to demonstrate deep, durable responses following a single arlo-cel infusion; no new safety signals were observed. Findings support arlo-cel as a safe and effective potential late-line treatment option in RRMM. AEs: adverse events, CAR-T: chimeric antigen receptor T-cell, MM: multiple myeloma, NA: not available, RRMM: relapsed/refractory multiple myeloma, TEAEs: treatment emergent adverse events."

Clinical • First-in-human • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology

Arlocabtagene Autoleucel, a GPRC5D-Targeted CAR T-Cell Therapy for Patients With Relapsed/Refractory Multiple Myeloma: Updated Phase 1 Safety and Efficacy Results in Patients With 1–3 Prior Regimens (SOHO 2026) - P1, P3 | "A single infusion of arlo-cel in patients with RR MM and 1–3 pLOT was well tolerated and led to a high response rate that deepened over time. Notably, the frequency and grade of infections were lower than those reported for BCMA-targeted therapies. These data support arlo-cel as a safe and effective potential early-line treatment in RRMM, with a phase 3 trial (QUINTESSENTIAL 2; NCT06615479) underway."

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

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

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

TANDEMM: 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 2026 ➔ Jun 2027 | Trial primary completion date: Jun 2026 ➔ Jun 2027

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

Patient-Specific Determinants of Response to BCMA- and GPRC5D-Targeted CAR T-Cell Therapy in Multiple Myeloma: A QSP Analysis of Clinical Trial and Real-World Data. (PubMed, Clin Pharmacol Ther) - "Sequential combination therapy simulations predicted a better response in scenarios starting with anti-GPRC5D CAR T infusion, followed by anti-BCMA CAR T infusion. Our model can serve as a framework to investigate response mechanisms as well as multi-antigen targeting, and to optimize clinical trial design and dosing regimens."

IO biomarker • Journal • Real-world evidence • Hematological Malignancies • Multiple Myeloma • Oncology

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 2026 ➔ Aug 2027 | Trial primary completion date: Aug 2026 ➔ Aug 2027

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

DEVELOPMENT OF BMS-986453, A DUAL-TARGETING BCMA×GPRC5D CHIMERIC ANTIGEN RECEPTOR (CAR) FOR THE TREATMENT OF MULTIPLE MYELOMA (EHA 2026) - P1 | "Aims To design, optimize, and evaluate the activity of dual-targeting BCMA×GPRC5D CAR T cell therapy for the treatment of MM. DJ and RS contributed equally as co-senior authors. Figure 1"

First-in-human • IO biomarker • Hematological Malignancies • Multiple Myeloma • GPRC5D

Unmasking the Hidden Burden: Non-Icans Neurotoxicities after CAR-T Therapy — a Systematic Review (TCT-ASTCT-CIBMTR 2026) - "In CARTITUDE-4, a phase III trial comparing cilta-cel to standard therapy in lenalidomide-refractory multiple myeloma, 1 of 176 patients in the cilta-cel arm developed movement and neurocognitive treatment-emergent adverse events (MNTs), while 16 (9%) experienced cranial nerve palsies and 5 (2.8%) developed peripheral neuropathy...In a phase I study of GPRC5D-targeted CAR-T cells (MCARH109) by Mailankody et al., 2 of 17 patients (11.8%) developed grade 3 cerebellar dysfunction at 6.5 and 8.4 months post-infusion, manifesting as severe, delayed motor coordination deficits unrelated to ICANS... Non-ICANS neurologic toxicities after CAR-T therapy are diverse in presentation, delayed in onset, and potentially irreversible. Observed patterns include parkinsonism, cranial nerve palsies, cerebellar dysfunction, peripheral neuropathy, dementia, and cerebrovascular events. These findings underscore the critical need for long-term neurologic surveillance, incorporation of..."

Review • Alzheimer's Disease • Cardiovascular • Chronic Lymphocytic Leukemia • CNS Disorders • Dementia • Hematological Malignancies • Movement Disorders • Multiple Myeloma • Parkinson's Disease

Salvage Therapies After Anti-BCMA CAR-T Failure in Patients With Multiple Myeloma: A Meta-Analysis of Response Rates. (PubMed, Eur J Haematol) - "In the first-line setting, selinexor-based regimens yielded the highest overall response rates (ORR) of 67% (95% CI: 38%-91%), followed by bsAbs (60%; 95% CI: 43%-76%). In the combined setting, anti-GPRC5D CAR-T cells achieved the highest ORR (88%; 95% CI: 65%-100%), followed by anti-BCMA CAR-T cells (75%; 95% CI: 42%-98%). Belantamab mafodotin demonstrated the lowest efficacy (0%; 95% CI: 0%-17%)...In summary, our meta-analysis suggested that CAR-T cells and bsAbs are suitable for salvage use after anti-BCMA CAR-T failure in MM. Trial Registration: PROSPERO number: CRD42024621077."

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

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

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