P29 phase 1/2 results of talquetamab, a g protein-coupled receptor family c group 5 member d x cd3 bispecific antibody, in patients with relapsed/refractory multiple myeloma (rrmm) (monumental-1)

Introduction: G protein-coupled receptor family C group 5 member D (GPRC5D) is a promising immunotherapy target for patients (pts) with multiple myeloma (MM). Talquetamab (Tal), a first-in-class, off-the-shelf, T-cell redirecting bispecific antibody, targets both GPRC5D and CD3. In phase (ph) 1 of MonumenTAL-1, two recommended ph 2 doses (RP2Ds) for Tal were identified. We report ph 1/2 results pts with RRMM treated at the RP2Ds. Methods: Ph 1 enrolled pts with measurable MM that progressed or were intolerant to standard therapies. Pts enrolled in ph 2 received ≥3 prior lines of therapy (LOT, including ≥1 proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody [triple-class exposed]). Ph 1 putative RP2D 0.405mg/kg SC once weekly (QW) was modified to 0.4mg/kg SC QW in ph 2, with step-up dosing used to mitigate risk of severe cytokine release syndrome (CRS). Ph 1/2 data were combined for analysis. Ph2 primary endpoint was overall response rate (ORR). Secondary endpoints were duration of response (DOR), rate of very good partial response or better (≥VGPR), rate of complete response or better (≥CR), time to response (TOR), progression-free survival (PFS), and adverse events (AEs). Pharmacodynamics (PD) parameters were measured at baseline (BL) and through Cycle 2 Day 1. Results: As of May 16, 2022, 288 pts with no prior exposure to T-cell redirecting therapies received Tal RP2Ds in ph 1 or 2. In 143 pts (median age, 67 years [y]) treated at 0.4mg/kg QW (median time since diagnosis: 6.7 y), pts received a median of 5 prior LOT, 100%/74% were triple-class exposed/refractory, and 73%/29% were penta-drug exposed/refractory. Median follow-up was 11.0 months (mo) (range 0.5±26.1). BL characteristics were similar in 145 pts treated at 0.8 mg/kg every two weeks (Q2W) (median follow-up 5.1 mo). In 143 pts treated at 0.4 mg/kg QW, ORR was 73% (≥VGPR: 58%; ≥CR: 29%), and responses were durable and deepened over time (Figure). Median TOR was 1.2 mo (range 0.2–5.0), median time to CR was 2.1 mo (range 1.1–12.4), median DOR was 9.3 mo (95% CI, 6.6–20.2; range 1–23+), and median PFS was 7.5 mo (95% CI, 5.7–9.2 [38% censored]). ORRs in triple-class refractory (72% [76/106]) and penta-drug refractory (71% [30/42]) pts were comparable to overall population. Efficacy at 0.8 mg/kg Q2W will be presented at meeting. Most common AEs (0.4 mg/kg QW/0.8 mg/kg Q2W) were CRS (79%/72%; grade 3 [gr]: 2%/1%; gr 4: 0%/0%), dysgeusia (48%/46%; gr 3/4: not applicable [NA]), anemia (45%/39%; gr 3: 31%/25%; gr 4: 0%/0%]), skin-related AEs (56%/68%; gr 3: 0%/1%; gr 4: NA), and nail disorders (52%/43%; gr 3: 0%/0%; gr 4: NA). Neutropenia 34%/28% (gr 3: 20%/17%; gr 4: 10%/6%) and thrombocytopenia 27%/27% (gr 3: 10%/8%; gr 4: 10%/8%) were limited to few cycles. Infections occurred in 57%/50% pts (gr ≥3: 19%/13%), 4.9%/6.2% discontinued, 8.4%/13.8% had dose delays, and 14.7%/6.2% had dose reductions due to AEs. Two deaths reported due to COVID-19 (1 pt at each RP2D). Tal exposure was comparable at the 2 RP2Ds. No clinically significant effect of anti-Tal antibodies on pharmacokinetics, efficacy, or AEs were observed. PD changes were comparable at both RP2Ds and consistent with Tal activity, including T-cell activation, redistribution, and induction of cytokines. Conclusion: Tal demonstrated robust efficacy and manageable safety in heavily pretreated pts with RRMM. Tal in combination with other agents is being evaluated in additional ph 1 studies (NCT04586426; NCT04108195; NCT05050097) in pts with RRMM.