Talquetamab, a GPRC5D×CD3 bispecific antibody, in combination with pomalidomide in patients with Relapsed/Refractory multiple myeloma: Updated safety and efficacy results from the Phase 1b monumental-2 study

Abstract

Abstract Introduction: Talquetamab (Tal) is the first G protein–coupled receptor class C group 5 member D (GPRC5D) × CD3 bispecific antibody (BsAb) approved for treatment of patients with relapsed/refractory multiple myeloma (RRMM). Pomalidomide (Pom) is an established immunomodulatory drug with direct on-tumor apoptotic activity. Initial results of the phase 1b MonumenTAL-2 study (NCT05050097) combining Tal and Pom showed rapid and deep responses in patients (pts) with RRMM, with a safety profile consistent with the individual agents. We report updated safety and efficacy results of Tal + Pom from MonumenTAL-2 with longer follow-up (~2 years). Methods: Pts had ≥2 prior lines of therapy (LOT), including a proteasome inhibitor and lenalidomide. Prior exposure to BsAbs, chimeric antigen receptor (CAR)-T cell therapy, and Pom was permitted. Pts received subcutaneous Tal 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W), with step-up dosing, plus oral Pom 2 mg daily (days 1−21 of each 28-day cycle) starting in cycle 2 (increase to 4 mg permitted as of cycle 3). Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded by ASTCT criteria; all other AEs were graded by CTCAE v5.0. Response was assessed by investigators using IMWG 2016 criteria. Results: As of March 31, 2025, 35 pts were enrolled (n=16 QW and n=19 Q2W), with a median follow-up of 20.7 mo; relative dose intensity of Tal QW and Q2W was similar with longer follow-up. Twelve (34.3%) pts remain on treatment. Baseline characteristics were as previously reported. Briefly, median age was 65 years, median prior LOT was 3, 45.0% (9/20) had high-risk cytogenetics, and 20.0% had extramedullary disease. Prior treatment exposure included Pom (22.9%), BCMA CAR-T (8.6%), and BsAbs (2.9%); 65.7% were refractory to daratumumab. Efficacy outcomes were consistent with previous results: ORR was 85.7% (≥CR, 45.7%) and median duration of response (DOR) was not reached (12.5–NE) (12-mo DOR rate, 71.1%). Median progression-free survival (PFS) was 25.8 mo (12.9–NE) (12-mo PFS rate, 72.6%). High ORRs were observed in pts with prior exposure to CAR-T (100.0%, 3/3) or Pom (100.0%, 8/8). The safety profile was comparable with previously reported data and consistent with longer treatment duration. Common AEs were taste-related events (85.7%; grade [gr] 1, 40.0%, gr 2, 45.7%), infections (85.7%; gr 3/4, 31.4%), and CRS (74.3%; gr 3/4, 2.9%); neutropenia (68.6%), anemia (42.9%), and thrombocytopenia (31.4%) remained the most common hematologic AEs. CRS primarily occurred during step-up and cycle 1 doses, with no additional effect of Pom at cycle 2. ICANS occurred in 3 pts (all gr 1). Skin and nail GPRC5D-related AEs occurred in 74.3% (gr 3/4, 5.7%) and 68.6% (gr 3/4, 0%) of pts, respectively; no pts discontinued treatment due to these AEs. Weight loss occurred in 25.7% of pts (gr 3/4, 5.7%) and recovered in 66.7% at the time of data cutoff. No further discontinuations of any study treatment due to AEs were observed with longer follow-up vs the initial report (3 pts, 8.6%), indicating the absence of cumulative toxicity. AEs led to dose reduction of Tal or Pom in 25.7% and 48.6% of pts, respectively, to dose omissions in 65.7% and 80.0%, and to dose delays in 77.1% and 22.9%. With longer follow-up, fewer dose reductions of Tal were observed. In translational analyses, enhanced production of interferon (IFN)-γ and tumor necrosis factor was observed following addition of Pom, aligned with the mechanism of action of Pom and supporting preclinical data. Responding pts showed a trend toward higher induction of IFN-γ and markers associated with CD8+ T-cell activation compared with non-responding pts. Conclusions: With longer follow up, Tal + Pom continued to show high, deep, and durable responses in pts with RRMM. The safety profile remained consistent with early treatment, with few additional dose modifications or discontinuations observed in later cycles, highlighting the long-term tolerability of this regimen. These findings support the rationale for the phase 3 MonumenTAL-6 study (NCT06208150), which compares the efficacy of Tal + Pom vs investigator's choice of elotuzumab + Pom + dexamethasone or Pom + bortezomib + dexamethasone in pts with RRMM with 1–4 prior LOT.