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RG2634, a novel bispecific antibody targeting GPRC5D, for the treatment of RRMM

Aug 18, 2022
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Learning objective: After reading this article, learners will be able to cite a new clinical development in relapsed/refractory MM.

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 RG2634 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

RG2634 mode of action2

RG2634 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. RG2634 also features a silent Fc region that reduces toxicity and increases its half-life. The configuration of RG2634 is shown in Figure 1.

Figure 1. RG2634 configuration* 

*Adapted from Dekhtiarenko.2 Created with BioRender.com

Study design1,2

In the ongoing dose escalation study, patients with RRMM were given intravenous or subcutaneous infusions of RG2634 in a step-up dosing regimen, up to a target optimal dose, followed by RG2634 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.

Results

Baseline characteristics1

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.
*Adapted from Hasselbalch Riley, et al.1
n = 48; 3 patients had missing prior therapy data.
≥1 immunomodulatory imide drug, ≥1 proteasome inhibitor, and ≥1 anti-CD38 antibody.
§≥2 immunomodulatory imide drug, ≥2 proteasome inhibitor, and ≥1 anti-CD38 antibody.
Antibody–drug conjugates, n = 6; bispecific antibody, n = 3; chimeric antigen receptor T-cell, n = 2; prior antibody–drug conjugate and prior chimeric antigen T-cell, n = 1.


Efficacy1

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

Safety1

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.
*Adapted from Hasselbalch Riley, et al.1

Biomarker analysis2

In order to determine whether RG2634 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:

  • Cytokine release occurred after all given target doses (18–10,000 µg) of RG2634, peaking 4–24 hours after the first dose; however, the magnitude of cytokine release decreased after subsequent step-up doses.
  • Following RG6234 infusion, activation of CD8+ T cells in peripheral blood occurred, peaking 4 days into the first treatment cycle.
  • In the majority of responding patients (8 of 12), RG6234 induced tumor infiltrating CD8+ T cells.
  • By Day 1 of Cycle 3, all patients responding to treatment showed a decrease in plasma serum B-cell maturation antigen levels.
  • The efficacy of RG6234 appeared to be independent of GPRC5D expression.
    • By Day 1 of Cycle 2, most patients (17 of 18) had <1% of MM cells in their bone marrow aspirate.

Conclusion

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 RG2634, 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 RG2634 induced rapid and effective T-cell mediated anti-myeloma activity, with further trials needed to further understand the mechanism of action.

  1. Hasselbalch Riley AC. A novel GPRC5D T-cell engaging bispecific antibody, induces rapid responses in patients with relapsed/refractory multiple myeloma: preliminary results from a first-in-human trial. Oral abstract #S180. European Hematology Association 2022 Congress; Jun 11, 2022; Vienna, AT
  2. Dekhtiarenko I. T-cell activation and myeloma cell killing confirm the mode of action of RG6234, a novel GPRC5D T-cell engaging bispecific antibody, in patients with relapsed/refractory multiple myeloma. Oral abstract #S173. European Hematology Association 2022 Congress; Jun 11, 2022; Vienna, AT

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