TALVEY Solution for injection Ref.[51257] Active ingredients: Talquetamab

Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates
ATC code: not yet assigned

Mechanism of action

Talquetamab is a immunoglobulin G4 proline, alanine, alanine (IgG4 PAA) bispecific antibody directed against GPRC5D and the CD3 receptor on T Cells.

Talquetamab promotes enhanced T cell-mediated cytotoxicity through recruitment of CD3-expressing T cells to GPRC5D-expressing cells. This leads to the activation of T cells and induces subsequent lysis of GPRC5D-expressing cells mediated by secreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. Based on the expression of GPRC5D on plasma cells with minimal to no expression detected on B cells and B cell precursors, talquetamab targets multiple myeloma cells particularly.

Pharmacodynamic effects

Within the first month of treatment with talquetamab, activation and redistribution of T cells and induction of serum cytokines were observed.

Clinical efficacy and safety

The efficacy of TALVEY monotherapy was evaluated in patients with relapsed or refractory multiple myeloma in a single-arm, open-label, multicentre study, MonumenTAL-1. The study included patients who had previously received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The study excluded patients who received T cell redirection therapy within 3 months, prior Grade 3 or higher CRS related to any T cell redirection therapy, an allogenic stem cell transplant within the past 6 months, autologous stem cell transplant within 3 months, stroke or seizure within the past 6 months, CNS involvement or clinical signs of meningeal involvement of multiple myeloma, plasma cell leukaemia, active or documented history of autoimmune disease, with the exception of vitiligo, resolved childhood atopic dermatitis, POEMS syndrome, primary light chain amyloidosis and prior Grave’s disease that was euthyroid based on clinical symptoms and laboratory testing. Patients received TALVEY 0.4 mg/kg subcutaneously weekly, following two step-up doses (0.01 and 0.06 mg/kg) in the first week of therapy, or TALVEY 0.8 mg/kg subcutaneously biweekly (every 2 weeks), following three step-up doses (0.01, 0.06 and 0.3 mg/kg), until disease progression or unacceptable toxicity. Patients were hospitalised for monitoring for at least 48 hours after each TALVEY dose during the step-up phase.

Of 143 patients treated with TALVEY 0.4 mg/kg weekly who were not exposed to prior T cell redirection therapy, the median age was 67 (range: 46 to 86) years, 55% were male, 90% were White, and 8% were Black or African American. Patients had received a median of 5 (range: 2 to 13) prior therapies, and 78% of patients had received prior autologous stem cell transplantation (ASCT). Ninety-four percent (94%) of patients were refractory to their last therapy, and 74% were refractory to a PI, immunomodulatory agent, and anti-CD38 antibody. Of the 132 patients for whom baseline cytogenetic data were available, high-risk cytogenetic factors (presence of t(4:14), t(14:16), and/or del(17p)) were present in 31% of patients. Twenty-three percent (23%) of patients had extramedullary plasmacytomas.

Of 145 patients treated with TALVEY 0.8 mg/kg biweekly (every 2 weeks) who were not exposed to prior T cell redirection therapy, the median age was 67 (range: 38 to 84) years, 57% were male, 86% were White, and 6% were Black or African American. Patients had received a median of 5 (range: 2 to 17) prior therapies, and 79% of patients had received prior autologous stem cell transplantation (ASCT). Ninety-four percent (94%) of patients were refractory to their last therapy, and 69% were refractory to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody. Of the 128 patients for whom baseline cytogenetic data were available, high-risk cytogenetic factors (presence of t(4:14), t(14:16), and/or del(17p)) were present in 29% of patients. Twenty-six percent (26%) of patients had extramedullary plasmacytomas.

Efficacy results were based on an overall response rate as determined by the Independent Review Committee assessment using IMWG criteria. The median duration of follow-up among patients receiving TALVEY 0.4 mg/kg weekly was 18.8 months; an estimated 51.5% of responders maintained response for at least 9 months.

Table 8. Efficacy results for MMY1001 (MonumenTAL-1) in patients receiving TALVEY 0.4 mg/kg weekly:

CI=confidence interval; MRD=minimal residual disease;
^a MRD-negativity rate is defined as the proportion of participants who achieved MRD negative status (at 10^-5) at any timepoint after initial dose and prior to progressive disease (PD) or subsequent anti-myeloma therapy.
^b Only MRD assessments (10^-5 testing threshold) within 3 months of achieving CR/sCR until death/progression/subsequent therapy (exclusive) are considered.

The median duration of follow-up among patients receiving TALVEY 0.8 mg/kg biweekly was 12.7 months; an estimated 76.3% of responders maintained response for at least 9 months.

Table 9. Efficacy results for MMY1001 (MonumenTAL-1) in patients receiving TALVEY 0.8 mg/kg biweekly (every 2 weeks):

CI=confidence interval; MRD=minimal residual disease; NE=not estimable
^a MRD-negativity rate is defined as the proportion of participants who achieved MRD negative status (at 10^-5) at any timepoint after initial dose and prior to progressive disease (PD) or subsequent anti-myeloma therapy.
^b Only MRD assessments (10^-5 testing threshold) within 3 months of achieving CR/sCR until death/progression/subsequent therapy (exclusive) are considered.

ORR results were consistent across pre-specified subgroups, including number of prior lines of therapy, refractoriness to prior therapy, and cytogenetic risk at baseline.

Immunogenicity

In MonumenTAL-1, 328 patients treated with subcutaneous talquetamab monotherapy at 0.4 mg/kg weekly or 0.8 mg/kg biweekly (every 2 weeks), with or without prior T cell redirection therapy, were evaluated for antibodies to talquetamab. Following treatment 0.4 mg/kg weekly or 0.8 mg/kg biweekly (every 2 weeks), 106 of 328 patients (32.3%) developed anti-talquetamab antibodies. The limited number of anti-talquetamab antibody (ADA) positive subjects and the lack of information of the neutralising ADA, preclude drawing a definite conclusion regarding the effect of the neutralising ADAs on clinical parameters.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with TALVEY in all subsets of the paediatric population in the treatment of multiple myeloma (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme.

This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.