Talquetamab Plus Daratumumab Improves PFS vs SOC in R/R Multiple Myeloma

Talquetamab (Talvey) combined with daratumumab (Darzalex) with or without pomalidomide (Pomalyst) significantly improved progression-free survival (PFS) compared with daratumumab, pomalidomide, and dexamethasone in patients with relapsed/refractory multiple myeloma (R/R MM), according to primary results from the phase 3 MonumenTAL-3 trial (NCT05455320) presented at the European Hematology Association (EHA) 2026 Congress in Stockholm, Sweden.¹

With a median follow-up of 24.6 months, the 2-year PFS rate was 81.3% for talquetamab plus daratumumab and pomalidomide (Tal-DP) and 77.6% for talquetamab plus daratumumab (Tal-D), compared with 51.2% for the daratumumab, pomalidomide, and dexamethasone (DPd) control arm. Median PFS was not reached in either experimental arm vs 24.4 months for DPd.

“Talquetamab targets plasma cells while largely sparing healthy B-cell populations due to limited B-cell expression of GPRC5D, which leads to a unique infection profile that's quite distinct from [B-cell maturation antigen (BCMA)]–directed bispecific antibody therapies, and certainly helps facilitate combination therapy,” said Peter Voorhees, MD, of Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, North Carolina, who presented the findings. The results have been simultaneously published in the New England Journal of Medicine.²

Trial Design

MonumenTAL-3 is the first randomized phase 3 trial of a GPRC5D-targeted therapy in R/R MM. Talquetamab received accelerated approval as monotherapy based on the phase 1/2 MonumenTAL-1 trial (NCT03399799), and investigators hypothesized that daratumumab primes the immune system with CD8+ T-cell recovery whereas pomalidomide can further enhance the immune microenvironment.

A total of 864 patients were randomly assigned 1:1:1 to Tal-DP (n = 287), Tal-D (n = 287), or DPd (n = 290).^1,2 Key eligibility criteria included measurable R/R MM with 1 or more prior lines of therapy including lenalidomide (Revlimid) and a proteasome inhibitor, and ECOG performance status of 0 to 2. Patients with prior refractoriness to anti-CD38 monoclonal antibody therapy were excluded, as were those with prior exposure to GPRC5D-targeted therapy, pomalidomide, or T-cell redirecting therapy within 3 months before randomization. Importantly, patients who had received only 1 prior line of therapy were required to have lenalidomide-refractory disease.

Talquetamab was administered subcutaneously at 0.8 mg/kg following step-up dosing, with dosing every 2 weeks. Patients achieving at least a very good partial response by cycles 5 to 6 could transition to every 4-week dosing; those with at least a partial response after 6 cycles were required to transition. Daratumumab was given at 1800 mg, and pomalidomide was initiated at 2 mg daily (days 1-21) in the Tal-DP group, with the option to escalate to 4 mg. The primary end point was PFS by independent review committee (IRC). The data cutoff was November 3, 2025.

Patient Population

Baseline characteristics were well balanced across arms. The median age was 64 years across all groups. Patients had received a median of 2 prior lines of therapy (range, 1-8), with 38.3% receiving treatment at first relapse. Nearly 12% had prior anti-CD38 antibody exposure, 85.1% were refractory to lenalidomide, and 93.4% were refractory to their last line of therapy. High-risk cytogenetics were present in 30.7%, 33.8%, and 28.3% of patients in the Tal-DP, Tal-D, and DPd arms, respectively.

PFS and Subgroup Outcomes

Tal-DP reduced the risk of progression or death by 72% vs DPd (HR, 0.28; 95% CI, 0.20-0.40; P <.001), and Tal-D reduced that risk by 67% (HR, 0.33; 95% CI, 0.24-0.46; P <.001). Both P-values crossed the boundaries for superiority at the interim analysis. PFS benefit was consistent across clinically relevant subgroups, including older patients, those with prior daratumumab exposure, ISS stage 3 disease, high-risk cytogenetics, and soft tissue plasmacytomas. Among patients treated at first relapse, all of whom had lenalidomide-refractory disease, the PFS HRs were 0.19 for Tal-DP and 0.23 for Tal-D vs DPd.

Response and MRD

Overall response rates were 88.2% for Tal-DP and 88.5% for Tal-D vs 77.6% for DPd (P <.001 for both). The rate of complete response or better was 71.1% with Tal-DP and 69.0% with Tal-D vs 34.5% with DPd (P <.001 for both). Minimal residual disease–negative complete response at the 10⁻⁵ sensitivity threshold, a key secondary end point, was achieved in 52.3% of Tal-DP patients, 46.3% of Tal-D patients, and 15.9% of DPd patients (P <.001 for both comparisons). The median time to complete response or better was 7.0 months with Tal-DP, 7.7 months with Tal-D, and 6.6 months with DPd. The estimated rates of patients maintaining a response at 24 months was 86.0% with Tal-DP, 79.8% with Tal-D, and 59.6% with DPd.

Overall Survival

The 2-year overall survival (OS) rate was 89.2% with Tal-DP, 87.9% with Tal-D, and 79.1% with DPd. Both arms demonstrated clinically meaningful reductions in the risk of death vs DPd (Tal-DP: HR, 0.47; 95% CI, 0.30-0.73; P =.0006; Tal-D: HR, 0.51; 95% CI, 0.33-0.78; P =.0015), though neither P-value crossed the prespecified superiority boundary of 0.0001 at the interim analysis. Of note, only 18.1% of Tal-DP patients and 18.5% of Tal-D patients received at least one subsequent antimyeloma therapy vs 40.0% of patients in the control arm, and subsequent T-cell redirecting therapy was received by 6.6%, 7.3%, and 19.0% of patients, respectively, an imbalance that may affect OS interpretation with longer follow-up.

Safety

Grade 3 or 4 adverse events occurred in 96.7% of patients receiving Tal-DP, 78.8% with Tal-D, and 95.8% with DPd. Adverse events leading to discontinuation of all trial treatment components were uncommon: 10.5%, 8.0%, and 6.7%, respectively. Deaths due to adverse events occurred in 1.8%, 4.0%, and 4.6%.

Grade 3 or 4 neutropenia was the most common grade 3 or 4 event, occurring in 76.4% with Tal-DP, 29.2% with Tal-D, and 86.2% with DPd, consistent with the myelosuppressive profile of pomalidomide. Grade 3/4 infections occurred in 37.7%, 29.2%, and 42.4% of patients across the respective arms, with the most common serious infection being pneumonia (11.2%, 9.1%, and 19.4%). Fatal infections were rare, occurring in fewer than 2% of patients in each arm. Grade 3 or higher infections were most frequent in the first 6 months and declined thereafter.

Hypogammaglobulinemia occurred in 81.5%, 70.1%, and 62.5% of patients in the Tal-DP, Tal-D, and DPd arms; immunoglobulin G replacement therapy was administered to 63.8%, 56.2%, and 36.7%, respectively. Opportunistic infections were reported in 16.3%, 17.9%, and 12.0%.

Cytokine release syndrome (CRS) occurred in 67.8% of Tal-DP and 58.4% of Tal-D patients, with the majority being grade 1 (55.8% and 48.9%) and grade 2 events in 11.2% and 8.8%. Grade 3/4 CRS occurred in only 0.7% of each talquetamab arm; events were transient (median duration, 2 days), and all but 1 resolved. Immune effector cell–associated neurotoxicity syndrome (ICANS) was reported in 2.9% of Tal-DP and 1.8% of Tal-D patients; 3 patients in the Tal-DP group had grade 3 ICANS, and all resolved.

GPRC5D-related adverse events of interest were predominantly low grade and infrequently led to treatment discontinuation. Taste changes occurred in 72.8% and 74.8% of talquetamab-treated patients; no grade 4 events occurred, and discontinuation due to taste changes was uncommon (4.0% and 2.2%). Ataxia or balance disorders were reported in 14.5% of Tal-DP and 12.4% of Tal-D patients (grade 3, 2.9% and 2.2%), with median time to onset of 292 and 326 days from first dose. Decreased weight occurred in 45.7% and 38.3%, predominantly grade 1 or 2, with BMI stabilizing after the first 6 months. Second primary cancers were observed in 7.6% of Tal-DP, 3.6% of Tal-D, and 4.2% of DPd patients.

“Our data support talquetamab with daratumumab with or without pomalidomide as a new standard of care for patients with [R/R MM] as early as first relapse,” Voorhees concluded.¹

REFERENCES

1. Voorhees PM, Mina R, Rodríguez-Otero P, et al. Phase 3, randomized study of talquetamab plus daratumumab ± pomalidomide vs daratumumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: MonumenTAL-3. Presented at: the European Hematology Association 2026 Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S100.

2. Mina R, Beksac M, Rodríguez‑Otero P, et al. Talquetamab–daratumumab in relapsed or refractory myeloma. N Engl J Med. Published June 13, 2026. doi:10.1056/NEJMoa2604657