Talquetamab, a bispecific antibody that redirects T-cells and specifically targets GPRC5D (G protein–coupled receptor family C group 5 member D), was combined with daratumumab with the aim of augmenting the immunomodulatory effects of the treatment. In the Phase II TRiMM-2 study, patients were required to meet specific criteria for enrollment, which included having received a minimum of three prior lines of therapy that involved both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Alternatively, patients could be classified as double refractory to a PI and IMiD. Additionally, it was necessary for patients to have abstained from CD38-directed therapy for a period of 90 days or less. The primary goals of parts I and II of the trial were to determine the recommended phase 2 dose (RP2D) of the treatment and assess its safety at the RP2D, respectively. Additionally, the study also observed notable antitumor activity.
Previously preliminary study results were reported at the 2022 EHA Congress. Updated findings with an additional 5 months of follow-up data were presented at the 2023 ASCO Annual Meeting. Patients in the TRiMM-2 study were treated with talquetamab at a SC RP2D of 0.8 mg/kg Q2W or 0.4 mg/kg QW (with step-up doses) in addition to DARZALEX FASPRO.
- Prior CD38-directed therapy Exposure
> In the 0.4-mg/kg cohort, the ORRs were 100%, 63.6%, and 63.6% in the CD38-naïve, exposed, and refractory populations, respectively.
> For the 0.8-mg/kg cohort, the ORRs were 100%, 82.2%, and 80.0% in the CD38-naïve, exposed, and refractory populations, respectively.
- Prior T-cell redirection therapy Exposure
> In the 0.4-mg/kg cohort, the ORRs were 50.0% for those who had undergone prior CAR T-cell therapy and 80.0% for those who had received prior bispecific antibody therapy.
> In the 0.8-mg/kg cohort, the ORRs were 88.9% and 70.0% in patients with prior CAR T-cell therapy and prior bispecific antibody therapy, respectively.
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In terms of response duration, the median duration of response (mDoR) was not reached in the 0.4-mg/kg cohort, while it was 20.3 months in the 0.8-mg/kg cohort. At the one-year mark, 80.9% of responders remained in response, with 93.3% of them achieving a complete response (CR) or higher. For patients with prior T-cell redirection therapy, the response retention rate at one year was 88.4%, and for those who switched to less frequent dosing, it was 94.1%.
Regarding treatment continuation, 65.4% of responders remained on treatment, including 63.6% with prior exposure to a CD38-directed antibody and 61.5% who were refractory to prior CD38-directed therapy.
In terms of progression-free survival (PFS), the median PFS was not reached in the 0.4-mg/kg cohort and was 19.4 months in the 0.8-mg/kg cohort. The 12-month PFS rates were 77.4% and 67.4%, respectively. Median overall survival (OS) was not reached in both cohorts, and the 12-month OS rates were 92.3% and 91.5% in the 0.4-mg/kg and 0.8-mg/kg cohorts, respectively.
Regarding safety, there were no additional toxicities observed when combining talquetamab with daratumumab. Common non-hematologic adverse effects included skin, nail, and oral issues, which were mostly low-grade. Talquetamab dose reductions occurred in 16.9% of patients, and discontinuations were observed in 1.5% of patients (one case was due to toxic skin eruption).
Additionally, the incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) was similar to that of talquetamab monotherapy.
KOL insights
“The latest results from the TRiMM-2 study further reinforce the potential of talquetamab in combination with subcutaneous daratumumab as an important treatment option for patients, including those previously treated with an anti-CD38 regimen or prior T-cell redirection therapy” – Expert Opinion.
“Talquetamab, targeting the novel antigen GPRC5D, combined with daratumumab is an off-the-shelf immunotherapy regimen that shows deep and durable responses in patients with relapsed/refractory multiple myeloma” – Expert Opinion.
Conclusion
Talquetamab is a T-cell redirecting bispecific antibody targeting GPRC5D. Darzalex is an anti-CD38 mAb with direct on-tumor and immunomodulatory actions. Combining the immunomodulatory effects of Talquetamab and Darzalex may lead to synergistic efficacy. Initial TRIMM-2 (NCT04108195) results showed that SC Talquetamab RP2Ds, 0.4 mg/kg QW or 0.8 mg/kg Q2W, plus SC DARZALEX FASPRO had promising efficacy and increased CD38+/CD8+ T cells and proinflammatory cytokines. During the 2022 EHA Congress, preliminary findings from the trial were presented, indicating that at a median follow-up duration of 6.7 months for the 0.4-mg/kg cohort and 4.2 months for the 0.8-mg/kg cohort, the overall response rates (ORRs) were 71.4% and 83.8%, respectively. Updated ASCO 2023 findings suggest that Talquetamab combined with DARZALEX FASPRO represents an off-shelf, immunotherapy regimen that showed deep and durable responses in patients with R/R MM. With long-term follow-up, no increased toxicities were observed and the combination regimen remained manageable. There are several BCMA-directed medicines that have US FDA approval for the treatment of multiple myeloma. Given that Talquetamab is a first-of-its-kind drug with a distinct target, these are such exciting results that are grabbing people's attention.
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