forimtamig (RG6234) / Roche - LARVOL DELTA

T-cell dynamics, CD8/NK ratio and tumor survival hallmarks determine response to T-cell bispecific forimtamig in myeloma. (PubMed, Blood Adv) - P1 | "T cells from responding and non-responding patients were equally fit in killing tumor cells ex vivo. Our results highlight that forimtamig treatment optimization may be possible by boosting T cell numbers over NK cells, targeting tumor intrinsic resistance mechanisms or individualized dosing approach."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology

RG6234, a GPRC5DxCD3 T-Cell Engaging Bispecific Antibody, Is Highly Active in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Intravenous (IV) and First Subcutaneous (SC) Results from a Phase I Dose-Escalation Study (ASH 2022) - P1 | "CRS management often involved tocilizumab (IV: 39.2% of pts; SC: 25.9%) and corticosteroids (IV: 52.9%; SC: 25.9%). RG6234 is highly active in pts with heavily pretreated RRMM when administered IV or SC. AEs are consistent with its MOA and target distribution. Evaluation and optimization of IV and SC dosing is ongoing."

Clinical • IO biomarker • P1 data • Anemia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Inflammation • Multiple Myeloma • Neutropenia • Oncology • Respiratory Diseases • Thrombocytopenia

Forimtamig, a novel GPRC5D-targeting T-cell bispecific antibody with a 2+1 format, for the treatment of multiple myeloma. (PubMed, Blood) - P1 | "Forimtamig is currently being evaluated in Phase 1 clinical trials in relapsed and refractory myeloma (RRMM) patients for monotherapy and in combination treatments. NCT04557150."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN

Efficacy of forimtamig, a GPRC5DxCD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM): analysis of patient- and disease-related factors associated with responses (IMW 2023) - P1 | "Forimtamig induced objective responses in all subgroups and showed high clinical activity in pts with high-risk features that are known to be clinically relevant in T-cell-directed therapy. Optimization of the forimtamig dose and schedule is ongoing, as well as evaluation of long-term treatment benefit, including in pts with high-risk disease."

Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • Plasmacytoma

Patient-Centric First-in-Human Dose Selection: An Ex Vivo Minimal Anticipated Biological Effect Level Approach for T-Cell Engagers in Multiple Myeloma. (PubMed, Clin Pharmacol Ther) - P1 | "Our ex vivo MABEL approach was accepted by regulatory authorities and yielded a tolerated forimtamig FIH starting dose which demonstrated clinical activity in the second dosing cohort. We encourage similar innovative patient-centric approaches to FIH dose calculation."

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

Forimtamig: a potent GPRC5D-targeted bispecific antibody in multiple myeloma. (PubMed, Ann Med Surg (Lond)) - "When combined with standard agents such as daratumumab, pomalidomide, or cereblon E3 ligase modulatory drugs, forimtamig has shown improved tumor clearance and reduced relapse rates. Currently undergoing phase 1 trials, forimtamig is being evaluated both as monotherapy and in combination regimens. Its high potency, favorable safety, and durable immune engagement make it a promising candidate in the evolving treatment landscape of multiple myeloma."

Journal • Endocrine Disorders • Hematological Disorders • Hematological Malignancies • Metabolic Disorders • Multiple Myeloma • Musculoskeletal Pain • Nephrology • Oncology • Pain • Renal Disease • Targeted Protein Degradation • CRBN

BP42233: A Study Evaluating the Safety and Pharmacokinetics of Escalating Doses of Forimtamig in Participants With Relapsed or Refractory Multiple Myeloma (r/r MM) (clinicaltrials.gov) - P1 | N=225 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed

First-in-human • Trial completion • Hematological Malignancies • Multiple Myeloma • Oncology

Early Intervention with Celmods, but Not Imids, Prevents Relapse to Forimtamig Driven By GPRC5D-Negative Myeloma Cells (ASH 2023) - "To evaluate if cereblon modulation represents a strategy to improve PFS, we combined fixed-duration forimtamig with either pomalidomide (pom) or iberdomide (iber) at C1 day 1 (C1D1). Taken together, our data suggest that combination with CELMoDs but not IMIDs can prevent relapse to forimtamig driven by GPRC5D negative tumor cells. We confirm timing of intervention with CELMoDs to have an significant impact on PFS and cytokine release and suggest a broad therapeutic window using low dose forimtamig and intermittent dosing of iberdomide or mezigdomide."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CCL3 • CRBN • CXCL8 • GPRC5D • IFNG • IL2 • TNFA

MODULE 4: Bispecific Antibodies in the Treatment of MM (ASH 2023) - "Supported by AbbVie Inc, GSK, Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC, Karyopharm Therapeutics, Legend Biotech, Regeneron Pharmaceuticals Inc, and Sanofi. Similarities and differences in the cellular targets and mechanisms of action among bispecific antibodies for MM Antitumor activity observed with teclistamab in the Phase I/II MajesTEC-1 study leading to its recent FDA approval for R/R MM; optimal incorporation into the treatment paradigm Rate, depth and duration of response observed with elranatamab in the pivotal Phase II MagnetisMM-3 trial for patients with R/R MM; FDA approval and current clinical role Key findings with other promising anti-BCMA bispecific antibody constructions, such as alnuctamab, linvoseltamab and ABBV-383, for heavily pretreated MM Available efficacy and safety findings with non-BCMA-targeted bispecific antibodies for MM, such as talquetamab, cevostamab and RG6234; FDA approval of talquetamab for patients with R/R MM..."

Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Mantle Cell Lymphoma • Oncology

Co-Expression of GPRC5D, FcRH5 and BCMA Suggests That Targeting More Than One Cell Surface Marker May be a Viable Strategy in Relapsed/Refractory Multiple Myeloma (RRMM): Biomarker Results from the Phase I Study of Forimtamig, a GPRC5DxCD3 Bispecific Antibody (ASH 2023) - P1 | "GPRC5D, FcRH5 and BCMA are highly prevalent across MM patient subgroups, including high-risk patients who may warrant targeted therapy approaches. Based on our data and previously published work for FcRH5- and BCMA-targeted T-cell bispecifics (Sumiyoshi et al. EHA 2021; Cortes-Selva et al."

Biomarker • IO biomarker • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology • GPRC5D

An ex-vivo reverse translational model demonstrates intact T cell functionality independently of clinical response to a T cell bispecific in multiple myeloma patients (SITC 2025) - P1 | "Here, with a newly developed ex-vivo reverse translational assay, we evaluated baseline functional T cell status from RRMM patients enrolled in a phase I dose escalation of forimtamig, a GPRC5DxCD3 TCB (NCT04557150) to correlate with clinical responses.Methods Baseline bone marrow aspirate samples were collected from patients prior to treatment...Further investigation is needed to understand the immunological and resistance mechanisms which underpin the clinical response. The described reverse translational model can be utilized to test other therapeutic options/combinations to achieve better clinical responses.Acknowledgements Jan Attig, Stephan Schmeing, Emilio Yangueez, Llucia Alberti Servera, Inga Clausen, Hans J. Grote, Claudia Ferreira, Hans-Joachim Helms, Sara Belli, Vu-Long Tran, Carmelo Carlo-Stella, Caroline Hasselbalch Riley, Salomon Manier, Antonio Pinto, Paolo Corradini, Cyrille Hulin, Sung-Soo Yoon, Rakesh Popat, Simon Harrison, Sabrina Danilin, Joanne..."

Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • GPRC5D

A Study Evaluating Safety, Tolerability, and Clinical Activity of Forimtamig-Based Treatment Combinations in Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=19 | Completed | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Completed

Trial completion • Hematological Malignancies • Multiple Myeloma • Oncology

RAPID AND UNEXPECTED THERAPEUTIC RESPONSE TO LOW-DOSE INTRAVENOUS MELPHALAN IN PATIENTS WITH PENTA-REFRACTORY MULTIPLE MYELOMA PROGRESSING AFTER TREATMENT WITH ANTI-GPRC5D T-CELL REDIRECTING BISPECIFIC ANTIBODIES (EHA 2025) - "After forimtamig failure, the patient showed a transient response to additional daratumumab-containing regimens (Fig 1A) but rapidly displayed thereafter a symptomatic progression with severe multicentric bone pain leading to bed confinement, transfusion-dependent anemia and worsening of her PS (ECOG 3)...This heavily pretreated patient with stage IIIA disease had received six lines of treatment before forimtamig, including belantamab mafodotin and five courses of high-dose cyclophosphamide (1200 mg/m2 d1,2,3)... We reported a rapid and deep response to LD-Mel in two PR-MM pts after failure of GPRC5D-directed BTEs. While it remains unclear if LD-Mel will be effective after other types of BTE failures, our findings suggest it may be a valuable option for these challenging cases, both in palliative care and as a bridge to further treatment. The mechanisms behind the impressive responses and the considerable myelotoxicity observed, even at low doses, require further..."

Clinical • Addiction (Opioid and Alcohol) • Anemia • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Musculoskeletal Pain • Neutropenia • Oncology • Pain • Palliative care • Septic Shock • Thrombocytopenia • TP53

BCMA-TARGETING T-CELL REDIRECTING BISPECIFIC ANTIBODY THERAPY POST-GPRC5D-DIRECTED BISPECIFIC ANTIBODY IN RELAPSED OR REFRACTORY MULTIPLE MYELOMA. (IFM 2024-13 BCMA POST-GPRC5D) (EHA 2025) - "Patients had previously received Talquetamab or Forimtamig in the MonumenTAL or Grace trials. Our study suggests that the use of BCMA-targeting BsAbs (Teclistamab or Elranatamab) following progression onGPRC5D-targeting BsAbs is feasible in heavily pretreated MM patients. No additional toxicities were observed. For responding patients, PFS was prolonged and for pts naïve to BCMA-directed therapy (CAR T cell or Belantamab), the efficacy was similar to what is typically expected.Therefore, sequencing BsAbs appears to be a viable strategy in MM treatment."

Hematological Malignancies • Infectious Disease • Multiple Myeloma • Oncology

A Study Evaluating Safety, Tolerability, and Clinical Activity of Forimtamig-Based Treatment Combinations in Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=19 | Active, not recruiting | Sponsor: Hoffmann-La Roche | N=316 ➔ 19

Enrollment change • Hematological Malignancies • Multiple Myeloma • Oncology

A Study Evaluating Safety, Tolerability, and Clinical Activity of Forimtamig-Based Treatment Combinations in Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=316 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jun 2027 ➔ Apr 2025

Trial completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Comprehensive Review of Bispecific Antibody Constructs In Multiple Myeloma: Affinities, Dosing Strategies and Future Perspectives. (PubMed, Clin Lymphoma Myeloma Leuk) - "Teclistamab, elranatamab (both BCMA × CD3), and talquetamab (GPRC5D × CD3) are approved for treating MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody...As linvoseltamab, alnuctamab, and ABBV-383 (all BCMA × CD3), as well as forimtamig (GPRC5D × CD3) and cevostamab (FcRH5 × CD3) progress through late-stage clinical development, emerging trispecific antibodies are now available that target either 2 different MM-associated antigens or provide additional co-stimulatory signals to prevent T-cell exhaustion. Despite this plethora of therapeutic options, resistance to bsAbs is an inevitability, and the optimal positioning of these drugs within the current MM treatment landscape remains to be determined. In this review, we examine the available data on all clinically accessible bsAbs, evaluating their potential, current limitations, and..."

Journal • Review • Hematological Malignancies • Multiple Myeloma • Oncology

T cell margination: investigating the detour of T cells following forimtamig treatment in humanized mice. (PubMed, MAbs) - "We hypothesize that low amounts of targets are sufficient to rapidly redirect T cells upon TCB engagement. Therefore, we propose TCM as a beneficial, highly sensitive and early effect of forimtamig that leads T cells to likely sites of bone marrow tumor lesions."

Journal • Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology

BP42233: A Study Evaluating the Safety and Pharmacokinetics of Escalating Doses of Forimtamig in Participants With Relapsed or Refractory Multiple Myeloma (r/r MM) (clinicaltrials.gov) - P1 | N=225 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting | N=480 ➔ 225 | Trial completion date: Aug 2026 ➔ Feb 2026 | Trial primary completion date: Aug 2026 ➔ Feb 2026

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

A Study Evaluating Safety, Tolerability, and Clinical Activity of Forimtamig-Based Treatment Combinations in Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=316 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial primary completion date: Jun 2027 ➔ Apr 2025 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Development of a Quantitative Systems Pharmacology (QSP) model describing T-cell bispecific induced immune activation and Multiple Myeloma (MM) cell killing (IMW 2024) - P1 | "The mechanistic model is able to describe forimtamig-induced immune activation and T cell-mediated MM cell killing in patients. It may therefore be utilized to predict response in virtual populations at different dosing regimens and for different patient subgroups. This example illustrates that in-silico modeling of T cell-engaging bispecific antibody MoA may support more accurate dose finding in Phase 1 studies."

Hematological Malignancies • Multiple Myeloma • Oncology • CXCL8

Impaired membrane trafficking of GPRC5D mediates resistance to anti-GPRC5D TCE (IMW 2024) - "We evaluated the binding of talquetamab (monovalent GPRC5D binding) and forimtamig (bivalent) on p.D239N expressing clones. GPRC5D antigen escape predominantly involve convergence of multiple clones harboring monoallelic chr.12p deletions coupled with GPRC5D mutations. GPRC5D mutations cluster within GPCR conserved motifs involved in protein trafficking and hence prevent its membrane localization."

Hematological Malignancies • Multiple Myeloma • Oncology • GPRC5D • SDC1

A Study Evaluating Safety, Tolerability, and Clinical Activity of Forimtamig-Based Treatment Combinations in Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=316 | Recruiting | Sponsor: Hoffmann-La Roche | Phase classification: P1 ➔ P1/2

Phase classification • 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

A Study Evaluating Safety, Tolerability, and Clinical Activity of Forimtamig-Based Treatment Combinations in Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=316 | Recruiting | Sponsor: Hoffmann-La Roche | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Multiple Myeloma • Oncology