Talquetamab, a GPRC5D×CD3 Bispecific Antibody, in Combination with Daratumumab and Lenalidomide in Patients with Newly Diagnosed Multiple Myeloma: Safety and Efficacy Results from the Phase 1b Monumental-2 Study
Authors: Nooka Ajay K. , Cochrane Tara , D'Souza Anita , Matous Jeffrey V , Voorhees Peter M. , Ramasamy Karthik , Perrot Aurore , Spencer Andrew , Hulin Cyrille , Quach Hang , Vishwamitra Deeksha , Nguyen Ashley , Ghosh Debopriya , Shearin Elizabeth , Mason Gary E , Renaud Thomas , Parmar Gurdeep 
Published: December 2024

Background: Talquetamab (tal) is the first approved G protein-coupled receptor class C group 5 member D (GPRC5D)-targeting bispecific antibody for the treatment of patients (pts) with relapsed/refractory multiple myeloma (MM). Daratumumab (D), an anti-CD38 monoclonal antibody, is a foundational therapy across all lines of MM therapy with direct on-tumor and immunomodulatory actions. Lenalidomide (R) is an established immunomodulatory drug that has direct on-tumor apoptotic activity. Combining D and R with T-cell redirection therapy may potentiate antimyeloma effects. We report initial efficacy and safety results of the fully immune tal-DR regimen in newly diagnosed MM (NDMM) from the MonumenTAL-2 (NCT05050097) study.

Methods: MonumenTAL-2 is a multicohort, phase 1b study of tal in combination with antimyeloma agents. In this analysis, pts had NDMM and were transplant ineligible or not intended for transplant. Pts received subcutaneous (SC) tal 0.6 mg/kg every other week (Q2W) or 0.8 mg/kg every 4 weeks (Q4W), with step-up dosing, + SC D 1800 mg (starting in cycle 1) + oral R 25 mg daily (starting in cycle 2). Dexamethasone (d) was permitted in cycles 2-4. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by American Society of Transplantation and Cellular Therapy criteria; all other adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events v5.0. Response was assessed by investigators using International Myeloma Working Group criteria.

Results: As of July 11, 2024, 32 pts were enrolled. Median follow-up was 10.5 months in the Q2W cohort (n=8) and 3.5 months in the Q4W cohort (n=24). Median ages were 68.5 years (Q2W) and 74.0 years (Q4W). Pts were mostly White (75% in Q2W and 71% in Q4W), male (88% and 58%), and had an International Staging System stage of I/II (88% [7/8] and 82% [18/22]). Pts had an Eastern Cooperative Oncology Group performance status of 0 (50% and 38%) or 1 (50% and 63%). In the Q4W cohort, 29% (5/17) had high-risk cytogenetics and 8% (2/24) had extramedullary disease; no pts in the Q2W cohort had either characteristic. The most common AEs were taste-related AEs (100% in Q2W and 83% in Q4W), CRS (88% and 71%; all grade 1/2), and skin (75% and 63%), rash (63% and 54%), and nail AEs (63% and 42%). Grade 3/4 AEs occurred in 100% and 67% of pts, respectively, most commonly neutropenia (63% and 38%), anemia (38% and 8%), and rash AEs (38% and 8%). No pts had ICANS in either cohort. Weight loss occurred in 25% (Q2W) and 38% (Q4W) of pts. Infections occurred in 100% (38% grade 3/4; gastroenteritis, pneumonia, and COVID-19 pneumonia) in the Q2W cohort and 33% (no grade 3/4) in the Q4W cohort. Hypogammaglobulinemia occurred in 63% (Q2W) and 42% (Q4W) of pts, respectively; 38% and 13% received ≥1 dose of intravenous immunoglobulin during treatment. AEs led to tal dose reductions in 38% and 21% of pts in the Q2W and Q4W cohorts, respectively; skipped tal doses in 75% and 25%, respectively; and tal dose delays in 88% and 13%, respectively. No pts discontinued treatment due to AEs in either cohort. One pt had a grade 5 AE in the Q4W cohort (large intestine perforation due to sigmoid mass, which was not drug related). In response-evaluable pts, overall response rates (ORRs) were 100% (8/8) in Q2W and 95% (19/20) in Q4W, with very good partial response or better in 88% (Q2W) and 80% (Q4W) of pts. Median time to first response was 1 month in each cohort. Median time to best response was 2.9 months (Q2W) and 1.9 months (Q4W).

Conclusions: This novel, fully immune combination regimen of tal-DR showed high ORR and rapid responses in pts with NDMM with 3.5-10.5 months of follow-up. The safety profile was consistent with individual agents, with no evidence of additive hematologic AEs, and no discontinuations due to AEs. These data are consistent with results from the MajesTEC-7 study evaluating teclistamab-DR vs DRd in NDMM; initial results with teclistamab-DR showed high and durable responses (ORR in 92% of pts and 12-month duration of response rate of 100%) with 14 months of follow-up. Together, the promising efficacy and manageable safety profile support tal as a versatile combination partner and continued investigation in MajesTEC-7.