Background
Phase 1, open-label, dose-escalation/expansion trial (MonumenTAL-1). N=232 total; recommended phase 2 dose cohorts 405 µg/kg SC weekly (n=30) and 800 µg/kg SC every other week (n=44). Relapsed or refractory multiple myeloma with ≥3 prior lines (median 6) including a PI, IMiD, and anti-CD38. Talquetamab is a first-in-class GPRC5DxCD3 bispecific antibody; GPRC5D is expressed on plasma cells and hair follicles, skin, and taste buds.
Interventions and follow up
Regimen: Talquetamab SC weekly (0.4 mg/kg) or every-other-week (0.8 mg/kg) with step-up dosing (GPRC5D × CD3 bispecific)
Population: Triple-class–exposed R/R MM
Primary endpoint: Dose-limiting toxicities and adverse events/laboratory abnormalities to select the recommended phase 2 dose
mFollow up: 11.7 months (QW cohort); 4.2 months (Q2W cohort)
Population: Triple-class–exposed R/R MM
Primary endpoint: Dose-limiting toxicities and adverse events/laboratory abnormalities to select the recommended phase 2 dose
mFollow up: 11.7 months (QW cohort); 4.2 months (Q2W cohort)
Results
ORR (405 µg/kg QW): 70% (95% CI 51–85%)
mDOR (QW): 10.2 months
ORR (800 µg/kg Q2W): 64% (95% CI 48–78%)
mDOR (Q2W): 7.8 months
mDOR (QW): 10.2 months
ORR (800 µg/kg Q2W): 64% (95% CI 48–78%)
mDOR (Q2W): 7.8 months
Adverse events
On-target GPRC5D effects: Skin events (rash, dry skin, nail changes, pruritus) any grade 67% (QW)/70% (Q2W); dysgeusia any grade 63%/57%, with clinically significant weight loss
CRS: Any grade 77%/80%, grade ≥3 0%/2%
CRS: Any grade 77%/80%, grade ≥3 0%/2%
Conclusions
Talquetamab achieved 64–70% ORR at the two recommended doses in heavily pretreated RRMM, with a novel toxicity profile of skin/nail effects and dysgeusia reflecting on-target GPRC5D expression — establishing GPRC5D as a valid therapeutic target even after BCMA-directed therapy.
Key Limitations
Phase 1 dose-finding design with small RP2D cohorts (n=30 and n=44) and no randomized comparator. Short follow-up for the Q2W cohort (4.2 months) limits durability assessment. GPRC5D-mediated dysgeusia and skin/nail toxicity are difficult to manage, frequently impair quality of life, and cause weight loss and dose modifications. Long-term durability beyond ~10 months remains uncertain.
Clinical Context
FDA granted accelerated approval to talquetamab (Talvey) in August 2023 for RRMM after ≥4 prior lines; EMA approval followed. It is the first GPRC5D-directed bispecific approved for myeloma, offering a non-BCMA target useful after BCMA-directed failure. ESMO-MCBS reflects meaningful benefit in an unmet-need setting.