New standard of care for relapsed/refractory multiple myeloma

Reference: August 2026 | Issue 8 | Vol 12 | Page 34

The pre-planned interim analysis of the Monumental-3 trial suggests the anti-GPRC5D bispecific antibody talquetamab (TAL), plus daratumumab (DARA) and pomalidomide (POM), from as early as second line, may become the new standard of care for relapsed/refractory multiple myeloma (RRMM).

The latest results from the phase 3 trial, presented at a plenary session at the European Hematology Association (EHA) 2026 Congress, report the efficacy and safety of Tal+Dara+Pom (Tal-DP) and Tal+Dara (Tal-D) vs daratumumab, pomalidomide, and low-dose dexamethasone (DPd) in 864 patients with RRMM who had received at least one prior line of therapy (LOT), including lenalidomide (Len) and a proteasome inhibitor.

Baseline characteristics were balanced across arms. Median age was 64.0 yrs, ranging from 30 to 88. The median number of prior LOT was two, ranging from one to eight. Approximately 11.8 per cent had been exposed to anti-CD38, 85.1 per cent were refractor to Len, and 93.4 per cent were refractory to their last LOT. Almost a third (30.9 per cent) had high risk cytogenetics.

The primary endpoint was progression-free survival (PFS), assessed by an independent review committee. Secondary endpoints included overall response rate (ORR), complete response or better (≥CR), minimal residual disease (MRD)-negative ≥CR, overall survival (OS), and safety.

At median follow-up of 24.6 months, Tal-DP and Tal-D significantly improved PFS vs DPd (HR 0.28; 95% CI 0.20-0.40; P<0.0001) and (HR 0.33; 95% CI 0.24-0.46; P<0.0001). Two-year PFS rates favoured Tal-DP (81.3 per cent) and Tal-D (77.6 per cent) vs DPd (51.2 per cent). PFS benefit was consistent across clinically relevant subgroups.

ORRs for Tal-DP, Tal-D, and DPd were 88.2 per cent, 88.5 per cent, and 77.6 per cent, while ≥CR rates were 71.1 per cent, 69.0 per cent, and 34.5 per cent, respectively. MRD-negative ≥CR rates were 52.3 per cent, 46.3 per cent, and 15.9 per cent. The OS HR for Tal-DP versus DPd was 0.47 (95% CI 0.30-0.73; P=0.0006), and 0.51 (95% CI 0.33-0.78; P=0.0015) for Tal-D.

At data cut-off, 70.3 per cent of the Tal-DP arm, 69.7 per cent of the Tal-D group, and 47.3 per cent of DPd patients remained on the study treatment.

Adverse events (AEs) were manageable and consistent with expectations for each agent. With Tal-DP, the overall AE rate was 96.7 per cent for grade 3-4 AEs and 1.8 per cent for grade 5 AEs. For Tal-D, the rates were 78.8 per cent and 4.0 per cent, and for DPd, the rates were 95.8 per cent and 4.6 per cent. AEs leading to discontinuation (d/c) of all study treatments occurred in 10.5 per cent of Tal-DP patients, 8.0 per cent of Tal-D patients, and 6.7 per cent of DPd patients. Rates of grade 3-4 cytopenias were 87.7 per cent, 51.8 per cent, and 89.0 per cent, respectively. Infection rates of any grade occurred in 87.3 per cent, 84.3 per cent, and 83.0 per cent, while grade 5 infections occurred in 0.7 per cent, 1.5 per cent, and 1.8 per cent, respectively.

With Tal-DP and Tal-D, cytokine release syndrome (CRS) of any grade occurred in 67.8 per cent and 58.4 per cent, and any grade ICANS occurred in 2.9 per cent and 1.8 per cent, respectively.

Any grade GPRC5D-related AEs with Tal-DP, Tal-D and DPd, respectively, included taste changes (72.8 per cent, 74.8 per cent, 3.9 per cent) and decreased weight (45.7 per cent, 38.3 per cent, 7.4 per cent). Ataxia/balance disorders were primarily low grade (none higher than grade 4).

The new data suggest Tal-DP and Tal-D have a significant and profound PFS benefit over DPd in patients with RRMM, with clinically meaningful OS improvements and grade ≥3 infection rates similar to or lower than DPd. Efficacy appeared numerically better with Tal-DP vs Tal-D but with a higher rate of grade 3-4 cytopenia, as is to be expected with pomalidomide. The findings suggest Tal-D with or without pomalidomide may be a new standard of care for RRMM as early as second line across all practice settings.

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