forimtamig (RG6234) / Roche - LARVOL DELTA

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

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

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

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

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

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

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..."

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 | Not yet recruiting | Sponsor: Hoffmann-La Roche | Phase classification: P1/2 ➔ P1

Phase classification • 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 | Not yet recruiting | Sponsor: Hoffmann-La Roche

New P1/2 trial • Hematological Malignancies • Multiple Myeloma • Oncology

Combination of forimtamig with standard of care improves depth and duration of response in preclinical models of multiple myeloma (IMW 2023) - "Synergistic anti-tumoral and NK stimulatory effects suggest a benefit of daratumumab combination in patients with high tumor burden and high risk of developing CRS. Broad immunomodulatory effects of pomalidomide could help sustain T cell responses in patients but may increase the risk of CRS. Considering the importance of balancing CRS and efficacy, carfilzomib was identified as another promising combination partner for forimtamig."

IO biomarker • Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • CCL3 • CD69 • CD8 • GZMA • IFNG • IL2 • IL2RA • LAMP1 • PD-1 • TNFA • TNFRSF9

Forimtamig Yields Sustained Responses in R/R Multiple Myeloma (Cancer Network) - P1 | N=480 | NCT04557150 | Sponsor: Hoffmann-La Roche | "Treatment with forimtamig produced enduring responses in patients with relapsed/refractory multiple myeloma, according to a presentation from Simon J. Harrison...on findings from a phase 1a dose-escalation trial (BP42233; NCT04557150) at the 2023 International Myeloma Society Annual Meeting. At a median duration of response (DOR) of 12.2 months (range, 0.03-20.8), the objective response rates (ORR) across all dose levels was 66.7% and a very good partial response (VGPR) rate of 54.2%....Regarding safety, there were no new safety signals observed in terms of CRS, rash, or other on target events."

P1 data • Multiple Myeloma

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

sBCMA has utility for early response monitoring in the blood and is correlated with forimtamig pharmacodynamic activity, clinical response and MRD (IMW 2023) - P1 | "sBCMA is a blood-based biomarker that is easily applicable, cost effective, and has potential prognostic value. For the first time, our data indicates a correlation of sBMCA decrease with T-cell activation and MRD negativity. Based on the results of our study, sBCMA may be used as a patient-centric and dynamic surrogate biomarker of response complementary to MRD in the future."

Clinical • IO biomarker • PK/PD data • Hematological Malignancies • Multiple Myeloma • Oncology

Forimtamig, A GPRC5DxCD3 Bispecific Antibody, Shows Promising Activity in Patients With RRMM: Updated Results from a Phase I Study (ICBMT 2023) - No abstract available

Clinical • P1 data • Multiple Myeloma

T-cell redirecting bispecific and trispecific antibodies in multiple myeloma beyond BCMA. (PubMed, Curr Opin Oncol) - "Various T-cell redirecting BsAbs are in advanced stages of clinical development with promising activity and a manageable toxicity profile. Ongoing studies are evaluating combination strategies, fixed-duration treatment, and use of BsAbs in earlier lines of therapy. TsAbs hold great promise for the future."

Journal • Trispecific • Hematological Disorders • Hematological Malignancies • Immune Modulation • Infectious Disease • Multiple Myeloma • Oncology

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=480 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Jun 2025 ➔ Aug 2026 | Trial primary completion date: Jun 2025 ➔ Aug 2026

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

Bispecific Monoclonal Antibodies in Multiple Myeloma: Data from ASH 2022: A Podcast. (PubMed, Adv Ther) - "These BsAb show impressive clinical activity for the relapsed/refractory population targeted and will likely become an essential part of MM treatment protocols in the future. In this podcast, the authors summarize and highlight some of the T cell-redirecting BsAb currently in development for the treatment of relapsed/refractory MM with a focus on the data reported at the oral session for BsAb at the American Society of Hematology's 2022 meeting from clinical phase 1 and 2 studies. The six presentations reported the latest safety and efficacy data for the BsAb: talquetamab, elranatamab, teclistamab, forimtamig, and alnuctamab."

Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

INFECTIONS FOLLOWING BISPECIFIC ANTIBODIES IN MYELOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS (EHA 2023) - "Despite promising efficacy in MM, BsAbs may come with substantial infection risk, warranting more detailed analysis of infections and immune phenotyping to guide targeted supportive care. Table – Summary of included studiesAgent Target Source Phase Enrolment (mm/yy) N Median prior lines All- Grade Infection N (%) Grade ≥3 Infection N (%) Alnuctamab (CC-93269) BCMA Wong 2022 I 03/18- 68 4 23 (34) 6 (9) ABBV-383 BCMA Voorhees 2022 I 10/22- 174 5 61/124 (50) 39/124 (22) Elranatamab BCMA Raje 2022 I 10/21- 123 5 82 (67) 43 (35) Linvoseltamab (REGN545) BCMA Bumma 2022 Ib/II 1/19- 252 5 136 (54) 73 (29) Pacanalotamab (AMG-420) BCMA Topp 2020 I 3/19 – 4/22 42 5 14 (33) 10 (24) Teclistamab BCMA Moreau 2022 I/II 09/20- 165 5 126 (77) 57 (45) Teclistamab + daratumumab BCMA + CD38 Rodriguez- Otero 2022 II 03/21- 46 5 29 (63) 8 (17) Forimtamig (RG6234) GPRC5D Carlo- Stella 2022 I 11/20- IV: 51 SC: 57 IV: 5 SC: 4 IV: 31 (61) SC: 26 (46) IV:11 (22) SC:15 (27) Talquetamab GPRC5D Chari..."

Retrospective data • Review • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Oncology