Background
Phase 3, open-label, randomised controlled trial. N=864 with relapsed/refractory multiple myeloma after ≥1 prior line of therapy. Three arms compare combinations of the GPRC5D×CD3 bispecific antibody talquetamab against a daratumumab–pomalidomide–dexamethasone (DPd) backbone, moving the off-the-shelf bispecific into earlier relapse.
Results
Interventions and follow up: Arm A (Tal-DP): Talquetamab + daratumumab + pomalidomide (n=287)
Arm B (Tal-D): Talquetamab + daratumumab (n=287)
Arm C (DPd): Daratumumab + pomalidomide + dexamethasone (n=290)
Primary endpoint: PFS by independent review committee
mFollow up: 24.6 months (interim analysis)
Results: PFS (24-mo estimate): Tal-DP 81.3% / Tal-D 77.6% vs DPd 51.2%
HR for PFS: Tal-DP vs DPd 0.28 (95% CI 0.20–0.40); Tal-D vs DPd 0.33 (0.24–0.46); P<.001 both
ORR: 88.2% / 88.5% vs 77.6%
≥CR: 71.1% / 69.0% vs 34.5%
MRD-negative CR: 52.3% / 46.3% vs 15.9%, P<.001
OS (24-mo): 89.2% / 87.9% vs 79.1%; HR death Tal-DP vs DPd 0.47 (0.30–0.73), Tal-D vs DPd 0.51 (0.33–0.78)
Arm B (Tal-D): Talquetamab + daratumumab (n=287)
Arm C (DPd): Daratumumab + pomalidomide + dexamethasone (n=290)
Primary endpoint: PFS by independent review committee
mFollow up: 24.6 months (interim analysis)
Results: PFS (24-mo estimate): Tal-DP 81.3% / Tal-D 77.6% vs DPd 51.2%
HR for PFS: Tal-DP vs DPd 0.28 (95% CI 0.20–0.40); Tal-D vs DPd 0.33 (0.24–0.46); P<.001 both
ORR: 88.2% / 88.5% vs 77.6%
≥CR: 71.1% / 69.0% vs 34.5%
MRD-negative CR: 52.3% / 46.3% vs 15.9%, P<.001
OS (24-mo): 89.2% / 87.9% vs 79.1%; HR death Tal-DP vs DPd 0.47 (0.30–0.73), Tal-D vs DPd 0.51 (0.33–0.78)
Adverse events
Serious AEs: 63.0% (Tal-DP) vs 52.6% (Tal-D) vs 53.7% (DPd)
Fatal AEs: 1.8% vs 4.0% vs 4.6%
GPRC5D class effects: dysgeusia, skin and nail toxicity, weight loss, oral effects, plus infection and cytokine release syndrome (talquetamab) — detailed grade rates not given in the primary report
Fatal AEs: 1.8% vs 4.0% vs 4.6%
GPRC5D class effects: dysgeusia, skin and nail toxicity, weight loss, oral effects, plus infection and cytokine release syndrome (talquetamab) — detailed grade rates not given in the primary report
Conclusions
Both talquetamab–daratumumab combinations (with or without pomalidomide) produced large PFS gains (HR 0.28 and 0.33), deep MRD-negative responses (~46–52% vs 16%), and an early overall-survival advantage over DPd in RRMM after just one prior line. Establishes off-the-shelf bispecific combinations as a powerful earlier-line option.
Key Limitations
Open-label (bispecific-containing arms vs a non-bispecific control); interim analysis with immature OS; GPRC5D-specific toxicities (dysgeusia, skin/nail changes, weight loss) and infection/CRS risk meaningfully affect quality of life but are not reflected in the headline efficacy; two experimental arms increase multiplicity; the DPd comparator is reasonable but not the only earlier-line standard.
Clinical Context
Talquetamab (Talvey) holds FDA accelerated approval (Aug 2023) for RRMM after ≥4 prior lines. MonumenTAL-3 (presented EHA 2026, published simultaneously; Johnson & Johnson) moves talquetamab-based bispecific combinations to ≥1 prior line, supporting a likely earlier-line label expansion and positioning off-the-shelf bispecifics against CAR-T and conventional triplets. OS maturation and management of GPRC5D effects will shape uptake. ESMO-MCBS pending.