Johnson & Johnson Announces Positive Phase III MonumenTAL-3 Trial Results for Talquetamab-Based Regimens in Relapsed/Refractory Multiple Myeloma

On June 13, Johnson & Johnson announced positive results from the Phase III MonumenTAL-3 study, which evaluated the efficacy and safety of its GPRC5D-directed bispecific antibody TALVEY (talquetamab) in combination with DARZALEX FASPRO (daratumumab subcutaneous injection), with or without pomalidomide, for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who had received at least one prior line of therapy.

TALVEY is a bispecific T-cell-engaging antibody targeting GPRC5D and CD3. It functions by targeting the GPRC5D protein, which is highly expressed on myeloma cells, while largely preserving healthy B cells. DARZALEX FASPRO is the only approved subcutaneous CD38-targeting antibody for the treatment of multiple myeloma.

The MonumenTAL-3 study is a multicenter, randomized, ongoing Phase 3 clinical trial designed to evaluate the efficacy and safety of TALVEY in combination with DARZALEX FASPRO plus pomalidomide (Tal-DP arm) or TALVEY in combination with DARZALEX FASPRO (Tal-D arm), compared with the standard treatment of DARZALEX FASPRO plus pomalidomide and dexamethasone (DPd control arm). The study enrolled patients who had previously received at least one prior line of therapy and had been exposed to lenalidomide and a proteasome inhibitor. The primary endpoint is progression-free survival (PFS), and secondary endpoints include objective response rate (ORR), rates of complete response or better (≥CR), minimal residual disease (MRD) negativity among patients achieving ≥CR, and overall survival (OS).

The results demonstrated that the study met its primary endpoint of progression-free survival (PFS). After a median follow-up of 24.6 months, patients in both the Tal-DP and Tal-D groups achieved statistically significant improvements in PFS compared with standard DPd therapy.

Compared with the DPd group, the risk of disease progression or death was significantly reduced by 72% in the Tal-DP group and by 67% in the Tal-D group.

At 24 months, the PFS rates in the Tal-DP and Tal-D groups were 81.3% and 77.6%, respectively, compared to only 51.2% in the DPd control group.

In terms of OS, the Tal-DP and Tal-D groups also demonstrated clinically meaningful improvements compared with the DPd group, with reductions in the risk of death of 53% and 49%, respectively. At 24 months, the OS rates were 89.2% in the Tal-DP group, 87.9% in the Tal-D group, and 79.1% in the control group.

Regarding secondary endpoints, the ORR in the Tal-DP, Tal-D, and DPd groups was 88.2%, 88.5%, and 77.6%, respectively; the rates of ≥CR were 71.1%, 68.9%, and 34.5%, respectively; and the rates of MRD-negative ≥CR were 52.3%, 46.3%, and 15.9%, respectively, with all treatment groups showing significant superiority over the control group.

In terms of safety, the overall safety profile of the TALVEY plus DARZALEX FASPRO combination therapy was consistent with the known safety profiles of each monotherapy. The incidence rates of Grade 3/4 treatment-emergent adverse events (TEAEs) were comparable across groups, at 94.9% in the Tal-DP group, 74.8% in the Tal-D group, and 91.5% in the DPd group.

Compared with standard therapy, the Tal-D group had a lower risk of serious infections, with grade 3/4 infection rates of 29.2%, versus 37.7% and 42.2% in the Tal-DP and DPd groups, respectively. Furthermore, adverse reactions such as dysgeusia and weight loss were predominantly low-grade and rarely led to discontinuation of TALVEY.

This is the first Phase III clinical study to demonstrate the superior progression-free survival (PFS) benefit of a GPRC5D-targeted bispecific antibody combination therapy in the treatment of early-stage multiple myeloma. Based on these results, Johnson & Johnson has submitted a Supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) and a Class II variation application to the European Medicines Agency (EMA), seeking approval for this combination therapy in patients with relapsed/refractory multiple myeloma (RRMM) who have received at least one prior line of therapy.