At 24 months, 81.3 percent of patients receiving talquetamab plus daratumumab and hyaluronidase-fihj with pomalidomide remained progression-free, compared to 51.2 percent on the current standard regimen of daratumumab, pomalidomide, and dexamethasone. That 30-point gap, drawn from 864 patients across the Phase 3 MonumenTAL-3 trial, is not incremental improvement. It signals a structural shift in where bispecific antibodies belong in the myeloma treatment sequence, and it lands at a moment when the field has been debating whether these agents can anchor earlier lines or are permanently confined to heavily pretreated patients.
The MonumenTAL-3 design enrolled patients who had received at least one prior line of therapy, all previously exposed to lenalidomide and a proteasome inhibitor, with 85 percent refractory to lenalidomide. That is a population still early enough in the treatment journey to have meaningful survival runway, which makes the overall survival numbers consequential. The talquetamab-plus-daratumumab combination without pomalidomide achieved an OS rate of 87.9 percent at 24 months versus 79.1 percent on standard care, a hazard ratio of 0.51. The triple combination hit 89.2 percent. Crucially, the two-drug arm showed the lowest rate of Grade 3/4 infections in the study at 29.2 percent, below both the triple regimen and the control arm, which matters when the argument against earlier bispecific use has long centered on cumulative toxicity. TALVEY’s accelerated approval in August 2023 was restricted to patients who had received at least four prior lines of therapy. MonumenTAL-3 is the clinical argument for erasing that restriction.
The depth-of-response data reinforces the case. MRD-negative complete response rates reached 52.3 percent with the triple combination and 46.3 percent with the doublet, against 15.9 percent on standard care. Those are not marginal differences in a binary endpoint; they represent a threefold improvement in the fraction of patients achieving the deepest measurable responses. GPRC5D’s independence from BCMA as a target, and its low expression on normal B-cells, gives talquetamab a mechanistic profile that complements rather than competes with daratumumab’s anti-CD38 activity, and the tolerability data from this trial largely validates that rationale in practice. Taste changes and weight loss remained predominantly low-grade and rarely drove discontinuation.
Johnson and Johnson has already submitted a supplemental BLA based on these results. The number to watch as that review proceeds is the discontinuation rate due to adverse events in the two-drug arm, which at 8.0 percent is low enough to suggest the regimen can be sustained through the treatment cycles where durable MRD negativity is most likely to translate into prolonged remission. Regulatory timelines on that sBLA will determine whether this data reshapes prescribing in second-line myeloma within the next 12 months or remains a Phase 3 benchmark awaiting label expansion.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
