Talquetamab Continues to Impress in Relapsed/ Refractory Multiple Myeloma

Niels W.C.J. van de Donk, MD

Talquetamab, an off-the-shelf T-cell redirecting, GP3C5D-targeting agent, has continued to show promising clinical activity in patients with relapsed/refractory multiple myeloma, especially when given at the recommended phase 2 dose (RP2D) of 405 μg/kg weekly subcutaneously, according to updated results from the phase 1 MonumenTAL-1 trial (NCT03399799) presented at the 18th International Myeloma Workshop in September.¹

At a median follow-up of 6.3 months (range, 1.4-12.0), the objective response rate (ORR) achieved with the agent was 70.0% at the RP2D (n = 21/30), which comprised a 3.3% complete response (CR) rate, a 6.7% stringent CR (sCR) rate, a 50.0% very good partial response rate (VGPR) or higher, and a 10.0% partial response (PR) rate.

In the cohort of patients who received all subcutaneous doses of talquetamab (n = 70), the ORR was 53.3%, with a CR rate of 2.7%, an sCR rate of 6.7%, a VGPR rate or higher of 34.7%, and a PR rate of 9.3%.

The median time to first confirmed response was 1 month (range, 0.2-3.8). Moreover, 65.2% of triple-refractory patients (n = 15/23) responded to treatment, along with 83.3% of patients with penta-refractory disease (n = 5/6).

Additionally, of the 6 evaluable patients across the intravenous and subcutaneous talquetamab cohorts, 4 achieved a minimal residual disease (MRD)–negative CR/sCR at 106; this included 1 patient who was in the RP2D cohort. In 1 evaluable patient, MRD negativity was sustained at 7 months following CR.

“Talquetamab is an off-the-shelf T-cell redirecting, GPRC5D-targeting agent that requires limited steroid use and has a manageable safety profile at the [RP2D],” lead study author Niels W.C.J. van de Donk, MD, a professor of hematology at the VU University Medical Center in Amsterdam, the Netherlands, said in a virtual presentation during the meeting. “Additional patients and longer follow-up support the RP2D…and responses were durable and continued to deepen over time. Talquetamab showed encouraging efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma.”

GPRC5D is a highly expressed receptor in multiple myeloma and has limited expression in healthy human tissue. Talquetamab is a GPRC5D x CD3 bispecific antibody designed to bind to CD3 and GPRC5D to redirect T cells, thereby killing myeloma cells. The 2-part, ongoing, first-in-human phase 1 MonumenTAL-1 trial is evaluating talquetamab at the RP2D of 405 μg/kg given weekly and via subcutaneous administration in patients with relapsed/refractory multiple myeloma.²

Part 1 of the trial focused on identifying the RP2D, and part 2 focused on safety and tolerability at the RP2D, along with antitumor activity, pharmacokinetics, and pharmacodynamics.

To be eligible for enrollment, patients had to have measurable disease that was relapsed/refractory or intolerant to standard myeloma therapies, a hemoglobin level that is 8 g/dL or higher, a platelet count of 50 x 10⁹/L or higher, and an absolute neutrophil count that was at least 1.0 x 10⁹/L. Prior BCMA-targeted therapy was permitted.

In the step-up dosing schedule, the maximum-tolerated dose was not reached, and the safety, efficacy, pharmacokinetic, and pharmacodynamic data supported the weekly subcutaneous dose of talquetamab at 405 μg/kg.

The data cutoff date was April 18, 2021. In the cohort of patients who received the agent at the RP2D (n = 30), the median age was 61.5 years (range, 46-80) and 23% of patientswere at least 70 years or older; most patientswere male (63%). The median years since diagnosis was 5.6 years (range, 2-20), and 33% of patients had at least 1 extramedullary plasmacytomas. Twenty-one percent of patients had at least 60% of bone marrow plasma cells, and 90% of patients previously underwent transplant. Forty percent of patients had International Staging System I disease, 43% had stage II disease, and 10% had stage III disease.

The median prior lines of therapy received was 6.0 (range, 2-14) and 27% of patients received prior BCMA-targeted therapy. Moreover, 77% of patients were triple-class refractory, 20% were penta-refractory, and 87% were refractory. Responses with talquetamab were durable and deepened over time. At the RP2D, the median duration of response was not reached, and 81% of responders continued therapy after the median 6.3-month follow-up. The response rates from those on the intravenous talquetamab cohorts were mature, and responses were ongoing at more than 22 months in patients with longer follow-up, explained van de Donk.

The RP2D of talquetamab also was found to have low peak/trough ratio and to maintain exposure over the maximum EC90 (effective concentration 90%); the agent was also noted to have immunogenicity.

“Antidrug antibodies did not appear to affect safety, pharmacokinetics profile, or efficacy,” van de Donk said. “Pharmacodynamic data showed that following the administration of talquetamab there is T-cell activation.”

Regarding safety, talquetamab had a tolerable safety profile at the RP2D; no dose-limiting toxicities were observed at this dose, and any-grade and grade 3/4 cytokine release syndrome (CRS) was reported in 73% and 2% of patients, respectively. In the overall subcutaneous cohort, any-grade CRS occurred in 67% of patients and was grade 3/4 in 1 patient.

In the subcutaneous and RP2D cohorts, the median time to onset of CRS was 2 days; supportive measures were given in 67% and 73% of patients, respectively. This included tocilizumab (Actemra; 52% vs 60%, respectively); steroids (6% vs 3%), low-flow oxygen by nasal cannula (7% vs 3%), and vasopressor (2% vs 3%). The CRS was generally confined to the step-up and first full doses, van de Donk noted.

Cytopenia was mostly confined to step-up doses and in cycles 1 and 2, and neutropenia often resolved within 1 week and also was limited to the first 2 cycles.

Infections were reported in the overall cohort of patients who received talquetamab subcutaneously (n = 82) and in those at the RP2D (n = 30); grade 3/4 infections occurred in 9% and 3%, respectively. Additionally, neurotoxicities occurred in 4 patients on the overall cohort, and 2 were reported at the RP2D; all these events were of grades 1/2.

Grade 1/2 injection-site reactions occurred in 17% of patients on the overall subcutaneous cohort. Sixty-seven percent of subcutaneous- treated patients experienced skin-related adverse events (AEs), which were mostly grade 1/2; 77% skin-related AEs occurred at the RP2D. Nail disorders were reported in 21% and 27% of patients in the subcutaneous and RP2D cohorts, respectively. No AE-related deaths occurred at the RP2D.

Talquetamab is being explored in a phase 2 expansion trial at the RP2D in patients with relapsed/refractory multiple myeloma (NCT04634552).

_REFERENCES:

_{1. van de Donk NWCJ, Krishnan AY, Oriol A, et al. Talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D)Å~CD3 bispecific antibody, in relapsed/refractory multiple myeloma (RRMM): updated results of a phase 1, first-in-human study. Presented at: 18th International Myeloma Workshop; September 8-11, 2021; Vienna, Austria. https://bit.ly/3E8uO9W}

_{2. Berdeja JG, Krishnan A, Oriol A, et al. Updated results of a phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) Å~ CD3 bispecific antibody, in relapsed/ refractory multiple myeloma (MM). J Clin Oncol. 2021;39(suppl 15):8008. doi:10.1200/JCO.2021.39.15_suppl.8008}