All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the International Myeloma Foundation or HealthTree for Multiple Myeloma.
Introducing
Now you can personalise
your Multiple Myeloma Hub experience!
Bookmark content to read later
Select your specific areas of interest
View content recommended for you
Find out moreThe Multiple Myeloma Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the Multiple Myeloma Hub cannot guarantee the accuracy of translated content. The Multiple Myeloma Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.
The Multiple Myeloma Hub is an independent medical education platform, sponsored by Bristol Myers Squibb, GSK, Pfizer, Roche and Sanofi. The levels of sponsorship listed are reflective of the amount of funding given. Digital educational resources delivered on the Multiple Myeloma Hub are supported by an educational grant from Janssen Biotech, Inc. View funders.
Bookmark this article
GRPC5D, a G protein-coupled receptor, is a key therapeutic target in multiple myeloma (MM) as it is highly expressed on malignant plasma cells.1 The Multiple Myeloma Hub has previously reported on talquetamab, an anti-GPRC5D bispecific antibody that has recently been granted breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) for use in patients with relapsed/refractory (R/R) MM (RRMM). More information on talquetamab and GPRC5D can also be found here.
At the European Hematology Association (EHA) 2022 Congress, Hasselbalch Riley presented preliminary results from the first-in-human clinical trial of forimtamig (also known as RG6234) as a novel anti-GPRC5D T-cell engaging bispecific antibody in RRMM (NCT04557150).1 In addition, Dekhtiarenko presented supporting data that confirm the mode of action of this agent.2
Forimtamig utilizes a dual-binding mechanism, binding with high-avidity to GPRC5D on plasma cells and high-affinity to CD3 on T cells, which induces T-cell activation and killing of malignant plasma cells. Forimtamig also features a silent Fc region that reduces toxicity and increases its half-life. The configuration of forimtamig is shown in Figure 1.
Figure 1. Forimtamig configuration*
*Adapted from Dekhtiarenko.2 Created with BioRender.com
In the ongoing dose escalation study, patients with RRMM were given intravenous or subcutaneous infusions of forimtamig in a step-up dosing regimen, up to a target optimal dose, followed by forimtamig every 2 weeks for 1 year. The target optimal dose varied between 18 µg and 10,000 µg among patients.
Key inclusion criteria for the study included receiving a prior immunomodulatory imide drug and proteasome inhibitor, and an Eastern Cooperative Oncology Group performance status of 0–1. Primary endpoints included safety and tolerability, and determination of the maximum tolerated dose to inform the phase II dose.
Patient characteristics are shown in Table 1. There was a high proportion of patients with high-risk cytogenetics or triple- or penta-class refractory disease.
Table 1. Baseline patient characteristics*
Patient characteristics, % (unless otherwise stated) |
N = 51 |
---|---|
Age range, years |
27–78 |
Male |
54.9 |
High-risk cytogenetics (n = 30) |
46.7 |
Extramedullary disease |
13.7 |
Median number of prior lines of therapy† |
5 |
Triple-class refractory†‡ |
62.5 |
Penta-class refractory†§ |
31.3 |
Prior anti-CD38 antibody† |
81.3 |
Prior anti-BCMA†¶ |
20.8 |
BCMA, B-cell maturation antigen. |
Of the 51 patients included in the study, 42 were evaluated for efficacy, with an overall response rate of 71.4% (Figure 2). The median time to first response was 1.2 months (n = 30) and, as of April 5, 2022, responses were ongoing in 25 patients.
Figure 2. Response rate across all target doses (18–10,000 µg)
CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Adapted from Hasselbalch Riley, et al.1
The step-up dosing regimen was used to mitigate the risk of severe cytokine release syndrome (CRS). Of the 51 patients in the study, CRS of any grade occurred in 40; there was only one case of Grade 3 and no cases led to treatment discontinuation. Discontinuation due to any adverse event occurred in one patient, and there were no fatal events. Other adverse events of note are shown in Table 2.
Table 2. Any grade and Grade ≥3 adverse events*
Adverse event, % |
Any Grade |
Grade ≥3 |
---|---|---|
ICANS |
5.9 |
2.0 |
Skin |
64.7 |
9.8 |
GI epithelium or tongue |
64.7 |
0 |
Hair and nail changes |
15.7 |
0 |
Hematologic |
37.3 |
25.5 |
Anemia |
27.5 |
13.7 |
Thrombocytopenia |
25.4 |
13.7 |
Neutropenia |
23.6 |
11.8 |
Infections |
52.9 |
17.6 |
COVID-19 |
13.7 |
2.0 |
GI, gastrointestinal; ICANS, immune effector cell-associated neurotoxicity syndrome. |
In order to determine whether forimtamig can induce T-cell killing of myeloma cells, biomarker analysis was performed on bone marrow samples using flow cytometry, serum B-cell maturation antigen and an immunoassay, and CD138/CD8 immunohistochemistry staining. These analyses demonstrated the following:
Bispecific antibodies are a promising therapeutic option for patients with R/R MM. The presenters concluded that the high response rate observed in the study, alongside the low incidence of severe CRS, demonstrates the potential of forimtamig, although they noted the small sample size limitation. As the study continues, clarification on the optimum dose and additional safety data will be obtained. Biomarker analysis revealed that forimtamig induced rapid and effective T-cell mediated anti-myeloma activity, with further trials needed to further understand the mechanism of action.
Your opinion matters
Subscribe to get the best content related to multiple myeloma delivered to your inbox