Talquetamab-daratumumab with or without pomalidomide may be a new standard of care for relapsed/refractory multiple myeloma as early as first relapse.In the phase III MonumenTAL-3 trial, talquetamab plus daratumumab (Tal-D), with or without pomalidomide, shows substantial efficacy in the treatment of relapsed/refractory multiple myeloma (RRMM), compared with daratumumab, pomalidomide, and dexamethasone (DPd).
“Synergistic Tal-D–based immunotherapy combinations significantly improved progression-free survival (PFS), with clear benefit across clinically relevant subgroups,” said Dr Peter Voorhees from Wake Forest University School of Medicine, Charlotte, North Carolina, US, at EHA 2026.
Compared with DPd, Tal-D improved PFS (median not reached [NR] vs 24.4 months; hazard ratio [HR], 0.33; p<0.0001) after a median follow-up of 24.6 months. The effect was more pronounced when pomalidomide was added (Tal-DP), resulting in a 72-percent reduction in the risk of progression or death (median NR vs 24.4 months; HR, 0.28; p<0.0001).
The 24-month PFS rates were higher with Tal-DP (81.3 percent) and Tal-D (77.6 percent) than DPd (51.2 percent). The PFS benefit with the Tal-based regimens remained consistent across clinically relevant subgroups, with HRs ranging from 0.14 to 0.45. [EHA 2026, abstract S100]
Tal-DP also outperformed DPd in objective response rate (88.2 percent vs 77.6 percent; odds ratio [OR], 2.27) and ≥complete response (≥CR; 71.1 percent vs 34.5 percent; OR, 4.93), as did Tal-D (88.5 percent vs 77.6 percent; OR, 2.34 and 68.9 percent vs 34.5 percent; OR, 4.40, respectively; p≤0.0005 for all).
Both Tal-based regimens trumped DPd in MRD-negative CR (10-5) rates (Tal-DP: 52.3 percent vs 15.9 percent; OR, 5.84; Tal-D: 46.3 percent vs 15.9 percent; OR, 4.70; p<0.0001 for both).
Tal-DP and Tal-D also conferred meaningful overall survival improvements vs DPd (HR, 0.47; p=0.0006 and HR, 0.51; p=0.0015), with approximately 88 percent of participants alive at 2 years. “We would argue that this is clinically significant, but the p-values did not cross the prespecified boundary for superiority (p=0.0001). We would need longer follow-up to declare statistical significance,” Voorhees said.
Safety profile
Serious treatment-emergent adverse event (TEAE) rates in the Tal-DP, Tal-D, and DPd groups were 63, 52.6, and 53.7 percent, respectively. For TEAEs leading to treatment discontinuation, the corresponding rates were 10.5, 8, and 6.7 percent.
There were higher rates of grade 3/4 neutropenia with Tal-DP (76.4 percent) and DPd (86.2 percent) vs Tal-D (29.2 percent), which aligns with the known safety profile of pomalidomide. [Lancet Oncol 2021;22:801-812; Lancet Oncol 2019;20:781-794]
The rates of cytokine release syndrome with Tal-DP and Tal-D were 67.8 percent and 58.4 percent, respectively. However, these were mostly grade 1, and all but one event resolved. The incidence of immune effector cell–associated neurotoxicity syndrome was low (<3 percent), and all cases resolved.
The rates of grade 3/4 infections were lower with Tal-D and comparable with Tal-DP vs DPd, and grade ≥3 infections were common in the first 6 months but declined thereafter. “AEs of interest were predominantly low grade and infrequently led to talquetamab discontinuation,” Voorhees said.
Weight loss was also reported with the Tal-based regimens, with the greatest BMI reductions occurring in the first 6 months and stabilizing thereafter, he said. “Of note, patients with obesity/overweight were the ones who lost weight, whereas those with a healthy weight or were underweight were stable over the course of the trial.”
B-cell–sparing mechanism
Talquetamab is the first and only GPRC5D × CD3 bispecific antibody approved for RRMM. Its B-cell–sparing mechanism facilitates combination with other agents, enabling a synergistic effect in earlier lines where durable remissions are needed. [Clin Pharmacol Ther 2025;118:954-966; Blood Adv 2025;9:5752-5762; Blood Adv 2021;5:2196-2215]
A total of 864 participants (median age 64 years, 57 percent men) were randomized 1:1:1 to Tal-DP, Tal-D, or DPd. Talquetamab was administered subcutaneously with step-up dosing (0.01, 0.06, 0.4, then 0.8 mg/kg Q2W). Daratumumab was given at 1,800 mg (QW in cycle [C]1–2, Q2W in C3–6, Q4W in C7+), while pomalidomide was given at 2 mg (Tal-DP) or 4 mg daily (DPd).
“[Taken together,] our data support Tal-D with or without pomalidomide as a new standard of care for RRMM as early as first relapse,” Voorhees concluded.