Talquetamab Plus Daratumumab Improves PFS in Relapsed/Refractory Myeloma

Talquetamab-tgvs (Talvey) plus daratumumab (Darzalex), with or without pomalidomide (Pomalyst), significantly prolonged progression-free survival (PFS) compared with daratumumab, pomalidomide, and dexamethasone (DPd) in patients with relapsed or refractory multiple myeloma who had received at least 1 prior line of therapy, according to the primary analysis of the phase 3 MonumenTAL-3 trial (NCT05455320) presented during a plenary session at the 2026 European Hematology Association (EHA) Congress.¹ The results were simultaneously published in the New England Journal of Medicine.²

At a median follow-up of 24.6 months, median PFS was not reached in either talquetamab arm vs 24.4 months with DPd. Talquetamab plus daratumumab and pomalidomide (Tal-DP) reduced the risk of progression or death by 72% (HR, 0.28; 95% CI, 0.20-0.40; P <.0001), and talquetamab plus daratumumab (Tal-D) reduced that risk by 67% (HR, 0.33; 95% CI, 0.24-0.46; P <.0001). The 24-month PFS rate was 81.3% (95% CI, 75.8%-85.7%) with Tal-DP and 77.6% (95% CI, 71.7%-82.5%) with Tal-D, vs 51.2% (95% CI, 44.8%-57.1%) with DPd. The benefit was consistent across prespecified subgroups, including older patients, those with high-risk cytogenetics, ISS stage III disease, and soft tissue plasmacytomas. Among patients treated at first relapse, the PFS HR was 0.19 (95% CI, 0.10-0.35) for Tal-DP and 0.23 (95% CI, 0.13-0.40) for Tal-D vs DPd.

Both talquetamab regimens produced higher response rates than DPd. The overall response rate (ORR) was 88.2% with Tal-DP, 88.5% with Tal-D, and 77.6% with DPd, with rates of CR or better of 71.1%, 68.9%, and 34.5%, respectively. Minimal residual disease (MRD)–negative complete response (CR) at a sensitivity of 10⁻⁵ was achieved in 52.3% with Tal-DP, 46.3% with Tal-D, and 15.9% with DPd; corresponding rates at 10⁻⁶ were 47.7%, 42.2%, and 10.0% (all P ≤.0005 vs DPd).

Overall survival (OS) favored both talquetamab regimens, with more than 87% of patients alive at 2 years. The 24-month OS rate was 89.2% (95% CI, 84.9%-92.4%) with Tal-DP (HR for death, 0.47; 95% CI, 0.30-0.73; P =.0006) and 87.9% (95% CI, 83.0%-91.5%) with Tal-D (HR, 0.51; 95% CI, 0.33-0.78; P = .0015), vs 79.1% (95% CI, 73.7%-83.6%) with DPd. Although these differences were considered clinically meaningful, the P values did not cross the prespecified boundary for superiority; longer follow-up is needed to establish statistical significance.

“In total, our data support talquetamab with daratumumab, with or without pomalidomide, as a new standard of care for patients with relapsed/refractory multiple myeloma as early as first relapse,” said presenting author Peter M. Voorhees, MD, of Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, in Charlotte, North Carolina.

Investigators randomly assigned 864 patients in a 1:1:1 ratio to Tal-DP (n = 287), Tal-D (n = 287), or DPd (n = 290). Eligible patients were 18 years or older with measurable disease and at least 1 prior line of therapy that included lenalidomide (Revlimid) and a proteasome inhibitor. Patients refractory to an anti-CD38 monoclonal antibody or previously treated with a GPRC5D-targeted agent, pomalidomide, or T-cell–redirecting therapy within 3 months were excluded.

Talquetamab was administered subcutaneously at 0.8 mg/kg following step-up dosing. The primary end point was PFS as assessed by an independent review committee; key secondary end points included ORR, CR or better, MRD-negative CR, and OS.

Baseline characteristics were balanced across arms. The median age was 64 years (range, 40-83) in the Tal-DP arm, 64 years (range, 32-88) in the Tal-D arm, and 63 years (range, 30-88) in the DPd arm; most patients were male (55.5%-58.9%). Patients had received a median of 2 prior lines of therapy, and nearly 40% were treated at first relapse. Approximately 11.5% had prior daratumumab exposure, 85% were refractory to lenalidomide, and 93% 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, and ISS stage III disease in roughly 11% of patients across arms.

All patients in the safety population (Tal-DP, n = 276; Tal-D, n = 274; DPd, n = 283) experienced at least 1 treatment-emergent adverse event (TEAE). Grade 3 or 4 TEAEs occurred in 94.9%, 74.8%, and 91.5% of patients, respectively, and TEAEs led to treatment discontinuation in 10.5%, 8.0%, and 6.7%. TEAEs leading to death were reported in 1.8%, 4.0%, and 4.6%. Grade 3 or 4 neutropenia was more frequent in the pomalidomide-containing arms (76.4% with Tal-DP and 86.2% with DPd vs 29.2% with Tal-D).

Cytokine release syndrome occurred in 67.8% of the Tal-DP arm and 58.4% of then Tal-D arm and was predominantly grade 1; immune effector cell–associated neurotoxicity syndrome was reported in 2.9% and 1.8% of patients, respectively, and all events resolved. Grade 3 or 4 infections were numerically lower with Tal-D (29.2%) than with Tal-DP (37.7%) or DPd (42.2%), and fatal infections were less frequent across arms (0.7%-1.8%). GPRC5D-associated effects were consistent with the known talquetamab profile: taste changes occurred in roughly 73% to 75% of talquetamab-treated patients, weight loss in 38% to 46%, and ataxia or balance disorders in 12% to 15%, with most events low grade. Decreases in mean body mass index were greatest in the first 6 months and then stabilized, predominantly among patients who were overweight or obese at baseline.

The investigators concluded that talquetamab plus daratumumab, with or without pomalidomide, demonstrated substantial efficacy and a safety profile consistent with the individual agents, supporting these regimens as potential new standards of care for relapsed or refractory multiple myeloma as early as the second line of therapy.

Disclosures: The study was funded by Johnson & Johnson. Voorhees is the presenting author; a complete list of MonumenTAL-3 investigators and author disclosures is provided in the New England Journal of Medicine manuscript.

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 2026 European Hematology Association 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 online June 13, 2026. doi:10.1056/NEJMoa2604657