The results of the investigational phase 3 MonumenTAL-3 study have been announced, showing that talquetamab-tgvs, a GPRC5D bispecific antibody, in combination with daratumumab and hyaluronidase-fihj with or without pomalidomide demonstrated significant reduction in the risk of disease progression or death of up to 72% and clinically meaningful reduction of up to 53% in the risk of death compared to the standard regimen of daratumumab and hyaluronidase-fih, pomalidomide, and dexamethasone (DPd) in patients with relapsed/refractory multiple myeloma (RRMM).

Results showed a progression-free survival (PFS) rate of up to 81.3% versus standard of care (51.2%) and an overall survival (OS) rate of up to 89.2% versus standard of care (79.1%) at 24 months. 

This is the first Phase 3 study to demonstrate superior PFS with a GPRC5D bispecific antibody combination in earlier-line multiple myeloma, underscoring the potential of this regimen to advance bispecific combinations earlier in the treatment paradigm. Results were presented at the 2026 European Hematology Association (EHA) Annual Meeting (Abstract #S100), with simultaneous publication in The New England Journal of Medicine.

Expert and company perspectives support bispecific combinations in earlier lines

"The impressive results from this study point to the promise of talquetamab-tgvs plus daratumumab and hyaluronidase-fih as a potential new bispecific combination for patients with relapsed or refractory multiple myeloma," said Peter Voorhees, M.D., Professor of Hematology and Oncology at Atrium Health, Levine Cancer Institute at Wake Forest University School of Medicine.* "talquetamab-tgvs works with daratumumab and hyaluronidase-fih in earlier lines—a critical time for treating patients with the most effective regimens."

"The MonumenTAL-3 findings underscore our commitment to bringing bispecific combinations into earlier lines of therapy, building on the strength and breadth of Johnson & Johnson's multiple myeloma portfolio," said Yusri Elsayed, M.D., M.H.Sc., Ph.D., Global Therapeutic Head, Oncology, Johnson & Johnson. "These results add to our growing body of evidence across bispecific antibodies and reinforce our strategy of advancing differentiated immunotherapies to better match the right therapy to the right patient at each stage of disease."

Novel mechanism spares healthy immune cells

Talquetamab-tgvs targets a protein called GPRC5D, which is found on multiple myeloma cells (as well as some healthy cells in the body).2 GPRC5D expression is independent of other targets, including BCMA, and is absent or expressed at low levels on normal B-Cells.

Talquetamab-tgvs works by targeting myeloma cells while largely sparing healthy B-cells.2

Phase 3 MonumenTAL-3 study results

The MonumenTAL-3 study evaluated talquetamab-tgvs with daratumumab and hyaluronidase-fih (Tal-D) or talquetamab-tgvs with daratumumab and hyaluronidase-fih and pomalidomide (Tal-DP) compared to DPd in patients with RRMM who have received at least one prior line of therapy.

At a median follow-up of two years (24.6 months), results showed significant improvement in PFS for Tal-DP (hazard ratio [HR], 0.28; 95 percent confidence interval [CI], 0.20-0.40; p<0.0001) and Tal-D (HR, 0.33; 95% CI, 0.24-0.46; p<0.0001). At 24 months, Tal-DP showed a PFS rate of 81.3% and Tal-D showed a PFS rate of 77.6%.

All participants (n=864) were previously exposed to lenalidomide and a proteasome inhibitor and received at least one prior line of therapy.1 Most patients enrolled were refractory to lenalidomide (85.1%) and their last line of therapy (93.4%), and some were exposed to an anti-CD38 antibody (11.8%).

Statistically significant improvements compared to DPd were observed across key secondary endpoints of overall response rate (ORR), complete response or better (≥CR), and minimal residual disease (MRD)-negative ≥CR (10-5, next-generation sequencing [NGS]) for Tal-DP and Tal-D. ORRs (88.2%, 88.5%, 77.6%), ≥CR rates (71.1%, 68.9%, 34.5%) and MRD-negative ≥CR rates (52.3%, 46.3%, 15.9%) were significantly higher for Tal-DP and Tal-D vs DPd, respectively, after two years median follow-up.

Clinically meaningful improvement in OS was shown with Tal-DP (HR, 0.47; 95% CI, 0.30-0.73) and Tal-D (HR, 0.51; 95% CI, 0.33-0.78) vs DPd. At 24 months, Tal-DP delivered an OS rate of 89.2% and Tal-D delivered an OS rate of 87.9%.

The overall safety profiles for the talquetamab-tgvs plus daratumumab and hyaluronidase-fih treatment arms were consistent with the known safety profiles of each monotherapy, and a reduced risk of severe infections were observed in the Tal-D arm compared to the standard of care.

Overall, rates of Grade 3/4 treatment-emergent adverse events (TEAEs) were comparable across treatment arms (94.9% with Tal-DP, 74.8% with Tal–D, and 91.5% with DPd). Infections occurred at rates of 87.3% (Tal–DP), 84.3% (Tal–D), and 83.0% (DPd).

When analyzing severe infections, Tal-D had the lowest rate of Grade 3/4 infections (29.2%), followed by Tal-DP (37.7%), and DPd (42.2%). There were some instances of Grade 5 adverse events (AEs) across the entire population of the study; the Tal-DP arm saw the fewest (1.8%), followed by Tal-D (4%) and DPd (4.6%), with approximately 0.7% (Tal-DP), 1.5% (Tal-D), and 1.8% (DPd) due to infections.

Treatment discontinuations due to AEs occurred in 10.5% of Tal–DP, 8.0% of Tal–D, and 6.7% of DPd patients.

At data cutoff, 70.3% (Tal-DP), 69.7% (Tal-D), and 47.3% (DPd) of patients remained on study treatment. Cytokine release syndrome occurred in 67.8% (Tal–DP) and 58.4% (Tal–D) of patients and was predominantly Grade 1–2, while immune effector cell–associated neurotoxicity syndrome was infrequent (2.9% and 1.8%, respectively), with no Grade ≥4 events reported.

Across Tal-DP, Tal-D and DPd, respectively, taste change (72.8%; 74.8%; 3.9%) and weight loss (45.7%; 38.3%; 7.4%) AEs along with ataxia/balance disorders (gr 1-2: 11.6%, 10.2%, 0.4%; gr3: 2.9%, 2.2%, 0%) were primarily low grade and rarely led to talquetamab-tgvs discontinuation, supporting the manageable safety profile.

Based on these results, Johnson & Johnson is working with regulatory bodies globally to bring the benefits of talquetamab-tgvs plus daratumumab and hyaluronidase-fih with or without pomalidomide to eligible patients as quickly as possible. The Company has submitted a supplemental Biologics License Application (sBLA) for the use of talquetamab-tgvs and daratumumab and hyaluronidase-fih, with or without pomalidomide, in combination as a treatment for RRMM after at least one prior line of therapy to the U.S. Food and Drug Administration (FDA). A Type II variation application has also been submitted to the European Medicines Agency (EMA).

Source: The New England Journal of Medicine