Teclistamab Plus Talquetamab Demonstrates Encouraging ORR in Relapsed/Refractory Multiple Myeloma

The combination of the BCMA- and GPRC5D-targeted bispecific antibodies, teclistamab-cqyv (Tecvayli) and talquetamab, respectively, demonstrated encouraging overall response rates (ORR) and was well tolerated in patients with relapsed or refractory multiple myeloma, according to first results from the phase 1b RedirectTT-1 study (NCT04586426) that were presented at the 2023 European Hematology Association Congress.

Across all dose levels in the overall population (n = 93), the ORR was 86.6% after a median follow-up of 13.4 months (range, 0.3-25.6), which included complete responses (CRs) in 22.0% of patients and partial responses (PRs) in 9.8%. The median duration of response (DOR) was not evaluable (NE; 95% CI, NE-NE), the median time to first response was 1.97 months (range, 0-7.7), and the median time to best response was 3.98 months (range, 1.1-15.7). The median progression-free survival (PFS) was 20.9 months (95% CI, 13.0-NE), and the 9-month PFS rate was 70.1% (95% CI, 58.0%-79.4%).

With a median follow-up of 8.1 months (range, 0.7-15.0), the ORR for patients receiving the recommended phase 2 regimen (RP2R), consisting of 3.0 mg/kg of teclistamab every 2 weeks plus 0.8 mg/kg of talquetamab every 2 weeks subcutaneously (n = 34), was 96.3%, including CRs in 22.2% of patients and PRs in 7.4%. The median DOR in this group was not evaluable (95% CI, NE-NE), the median time to first response was 1.48 months (range, 0-4.0), and the median time to best response was 3.22 months (range, 1.4-10.7). Additionally, the median PFS was not evaluable (95% CI, 9.9 months to NE), and the PFS rate at 9 months was 77.1% (95% CI, 50.8%-90.5%).

Among patients with extramedullary disease, the ORR across all dose levels (n = 35) was 71.4%, including CRs in 17.9% of patients and PRs in 21.4%. The corresponding values among patients receiving the RP2R (n = 11) were 85.7%, 28.6%, and 14.3%. In each respective group, the median DOR was 12.9 months (95% CI, 4.17-NE) and not evaluable (95% CI, 4.17-NE), and the median PFS was 6.1 months (95% CI, 2.5-9.9) and 9.9 months (95% CI, 2.4-NE).

“In conclusion, teclistamab plus talquetamab is the first-ever reported dual-specific bispecific combination in hematologic malignancies,” study author María-Victoria Mateos, MD, PhD, said during a presentation on these data.

“These results support the initiation of larger studies with the combination of teclistamab and talquetamab. The RedirecTT-1 expansion cohort in patients with extramedullary disease is opening based on these promising results.”

Mateos is a consultant physician in the Haematology Department and associate professor of Medicine at the University of Salamanca in Spain. She is also the director of the Myeloma Program and coordinates the Clinical Trials Unit in Salamanca’s University Hospital Haematology Department.

In the phase 1b RedirectTT-1 study, patients received escalating dose levels of teclistamab plus talquetamab until investigators determined a RP2R. The primary objective of the study was to evaluate the safety of the regimen. Secondary objectives included the preliminary antitumor activity of the study treatment at the RP2R, pharmacokinetics, and immunogenicity.

Patients were eligible for enrollment on the trial if they presented with measurable multiple myeloma which was relapsed/refractory or intolerant to established therapies, including the most recent line of therapy. Eligible patients also needed to have received prior treatment with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.

The median patient age was 65.0 years in both the all-dose levels (range, 39-81) and RP2R groups (range, 41-80). In each respective group, most patients were male (51.6% vs 52.9%), White (79.6% vs 70.6%), and had stage I disease (45.9% vs 50.0%). Additionally, 33.3% of patients in both groups had high-risk cytogenetics.

Patients received a median of 4 prior lines of therapy in both the all-dose levels (range, 1-11) and RP2R groups (range, 2-10). Additionally, 89.2% and 88.2% of patients in each respective group were refractory to their last line of therapy.

Mateos stated that the hematologic safety profile of teclistamab plus talquetamab was consistent with those previously reported of each agent as monotherapy. The most common grade 3/4 hematologic treatment-emergent adverse effects (TEAEs) in the all-dose levels and RP2R groups, respectively, included neutropenia (61.3% vs 44.1%), anemia (34.4% vs 23.5%), and thrombocytopenia (29.0% vs 23.5%). No patients discontinued study treatment due to hematologic TEAEs.

The nonhematologic AE profile of the study regimen was also consistent with the profiles of both teclistamab and talquetamab as monotherapies, and rates of grade 3/4 TEAEs were generally low. In the all-dose levels and RP2R groups, respectively, the most common any-grade TEAEs included cytokine release syndrome (CRS; 76.3% vs 73.5%), dysgeusia (61.3% vs 47.1%), and pyrexia (50.5% vs 38.2%). There were 5 instances of immune effector cell-associated neurotoxicity syndrome (ICANS) among 3 patients, which included 1 patient with grade 3 ICANS.

The median time to CRS onset was 2 days in both the all-dose levels (range, 1-5) and the RP2R groups (range, 1-4). Most patients in both respective groups received supportive care with tocilizumab (Actemra; 26.9% vs 20.6%). Additionally, most instances of CRS occurred during step-up dosing or cycle 1 of treatment, and all CRS events resolved.

Overall, 96.8% of patients in the all-dose levels group and 94.1% of those in the RP2R group experienced any TEAE. In each respective group, most patients also had at least 1 grade 3/4 TEAE (88.2% vs 79.4%). Additionally, 6.5% and 5.9% of patients discontinued treatment due to agent-related TEAEs, and 6.5% and 2.9% of patients died due to agent-related TEAEs.

Any-grade infections occurred in 83.9% and 79.4% of patients in the all-dose levels and RP2R groups, respectively, with the most common including COVID-19 (33.3% vs 41.2%), pneumonia (26.9% vs 11.8%), and upper respiratory tract infection (11.8% vs 11.8%). Additionally, grade 3/4 infections occurred in 52.7% and 38.2% of patients.

Reference

Mateos M, Morillo D, Gatt M, et al. First results from the RedirecTT-1 study with teclistamab (TEC) + talquetamab (TAL) simultaneously targeting BCMA and GPRC5D in patients (PTS) with relapsed/refractory multiple myeloma (RRMM). Presented at the 2023 European Hematology Association Congress; Frankfurt, Germany. June 8-11, 2023. Abstract S190.