Talquetamab Plus Daratumumab Combination Reduces Progression Risk by Up to 72% in Phase 3 Relapsed Multiple Myeloma Trial

Johnson & Johnson has announced results from a phase 3 study (MonumenTAL-3) showing that talquetamab-tgvs (Talvey), a GPRC5D-targeting bispecific antibody, combined with daratumumab and hyaluronidase-fihj (Darzalex Faspro) with or without pomalidomide, significantly reduced the risk of disease progression or death by up to 72% and the risk of death by up to 53% compared to standard-of-care daratumumab-pomalidomide-dexamethasone (DPd) in patients with relapsed/refractory multiple myeloma (RRMM).¹

At 24 months, progression-free survival (PFS) rates reached up to 81.3% versus 51.2% with DPd, and overall survival (OS) rates reached up to 89.2% versus 79.1%. Results were presented at the 2026 European Hematology Association Annual Meeting and published simultaneously in the New England Journal of Medicine.¹

"[Talvey] works with [Darzalex Faspro] in earlier lines—a critical time for treating patients with the most effective regimens," said Peter Voorhees, MD, Professor of Hematology and Oncology at Atrium Health, Levine Cancer Institute at Wake Forest University School of Medicine, in a company press release.¹

What did the MonumenTAL-3 trial design and efficacy results show?

MonumenTAL-3 (NCT05455320) is an ongoing phase 3 study evaluating talquetamab plus subcutaneous daratumumab with (Tal-DP) or without (Tal-D) pomalidomide versus DPd in 864 patients with RRMM who had received at least one prior line of therapy including lenalidomide and a proteasome inhibitor. Most patients were refractory to lenalidomide (85.1%) and to their last line of therapy (93.4%); 11.8% had prior anti-CD38 antibody exposure.

At a median follow-up of 24.6 months, PFS was significantly improved with Tal-DP (hazard ratio [HR]: 0.28; 95% 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), with 24-month PFS rates of 81.3% and 77.6%, respectively. Overall response rates were 88.2% (Tal-DP), 88.5% (Tal-D), and 77.6% (DPd). Rates of complete response or better were 71.1%, 68.9%, and 34.5%, while measurable-residual-disease-negative ≥complete response rates (10⁻⁵, next-generation sequencing) were 52.3%, 46.3%, and 15.9%. OS was significantly improved with Tal-DP (HR: 0.47; 95% CI: 0.30–0.73) and Tal-D (HR: 0.51; 95% CI: 0.33–0.78), with 24-month OS rates of 89.2% and 87.9% versus 79.1% with DPd.1

What is the clinical context and unmet need in relapsed/refractory multiple myeloma?

RRMM is the third most common hematologic malignancy worldwide, with more than 180,000 new cases diagnosed annually and a 5-year survival rate of approximately 59.8%.² While treatment advances have extended survival from years to decades across disease stages, most patients eventually relapse and require sequential lines of therapy, with efficacy typically diminishing with each successive regimen.³ Bispecific T-cell-engaging (TCE) antibodies have demonstrated promising activity in heavily pretreated RRMM, and the MonumenTAL-3 trial represents an effort to determine whether this benefit extends to earlier treatment lines, in which patients may have greater physiologic reserve and less cumulative disease burden.

What is talquetamab's mechanism of action, and how does GPRC5D targeting differ from other myeloma immunotherapy targets?

Talquetamab is a bispecific TCE antibody that binds CD3 on T cells and GPRC5D, a G protein-coupled receptor highly expressed on multiple myeloma cells and normal plasma cells, with additional expression on epithelial tissues including skin and tongue.⁴ GPRC5D expression is independent of B cell maturation antigen (BCMA), the target of other approved myeloma immunotherapies, and is largely absent from normal B cells, an expression pattern that is thought to spare healthy B-cell populations relative to BCMA-directed approaches.⁴

Talquetamab received initial FDA approval in August 2023 for RRMM patients who had received at least four prior lines of therapy and has since been used to treat more than 11,000 patients.¹ Daratumumab, a CD38-directed antibody, has an established role across multiple myeloma treatment lines, with the subcutaneous daratumumab-hyaluronidase formulation approved in 11 myeloma indications since initial FDA approval in May 2020.¹

What safety findings were reported, and how should the benefit-risk profile be interpreted at this stage of development?

Johson & Johson reported that Grade 3/4 treatment-emergent adverse events occurred in 94.9% (Tal-DP), 74.8% (Tal-D), and 91.5% (DPd) of patients. Infection rates were comparable across arms (87.3%, 84.3%, 83.0%), though severe (Grade 3/4) infections were lower with Tal-D (29.2%) than with Tal-DP (37.7%) or DPd (42.2%). Cytokine release syndrome (CRS) occurred in 67.8% (Tal-DP) and 58.4% (Tal-D) of patients, predominantly Grade 1–2, with immune effector cell-associated neurotoxicity syndrome occurring infrequently (≤2.9%) and no Grade ≥4 events.

Taste change and weight loss were substantially more frequent with talquetamab-containing regimens (72.8%–74.8% and 38.3%–45.7%, respectively) than with DPd (3.9% and 7.4%), reflecting known on-target, off-tumor effects of GPRC5D engagement on epithelial tissue. According to the company, these events were primarily low-grade and infrequently led to discontinuation. Treatment discontinuation due to adverse events occurred in 10.5% (Tal-DP), 8.0% (Tal-D), and 6.7% (DPd). The Tal-DP and Tal-D arms had higher rates of patients remaining on treatment at data cutoff (70.3% and 69.7%) compared to DPd (47.3%).

What limitations apply to these findings, and what regulatory steps are underway?

This is the first phase 3 study to report PFS benefit with a GPRC5D bispecific combination in earlier-line RRMM, according to Johnson & Johson. While the magnitude of hazard ratio reductions is substantial, the high frequencies of CRS, taste change, and weight loss with talquetamab-containing regimens may raise questions about long-term tolerability and treatment persistence outside the controlled trial setting.

Comparative positioning relative to other bispecific and BCMA-directed combinations in earlier lines of RRMM has not been established through head-to-head data. Johnson & Johnson has submitted a supplemental biologics license application to FDA and a Type II variation application to the European Medicines Agency for this combination in RRMM after at least one prior line of therapy. The agencies’ regulatory decisions are pending.¹

References

1. Johnson & Johnson. New TALVEY(talquetamab-tgvs) plus DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) data demonstrate the strength of a bispecific combination in earlier-line relapsed or refractory multiple myeloma. Published June 13, 2026. Accessed June 15, 2026. https://www.jnj.com/media-center/press-releases/new-talvey-talquetamab-tgvs-plus-darzalex-faspro-daratumumab-and-hyaluronidase-fihj-data-demonstrate-the-strength-of-a-bispecific-combination-in-earlier-line-relapsed-or-refractory-multiple-myeloma
2. Kazandjian D. Multiple myeloma epidemiology and survival: a unique malignancy. Semin Oncol. 2016;43(6):676-681. doi:10.1053/j.seminoncol.2016.11.004
3. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122-1128. doi:10.1038/leu.2013.313
4. Pillarisetti K, Powers G, Luistro L, et al. Teclistamab is an active T cell-redirecting bispecific antibody against B-cell maturation antigen for multiple myeloma. Blood Adv. 2020;4(18):4538-4549. doi:10.1182/bloodadvances.2020002393