Talquetamab Regimens Boost Survival in Multiple Myeloma

Talquetamab (Talvey) plus daratumumab (Darzalex) with or without pomalidomide (Pomalyst) significantly improved survival outcomes over an active regimen for relapsed or refractory multiple myeloma, a phase III trial showed.

Among patients who had previously received at least one line of therapy, estimated 24-month progression-free survival (PFS) rates reached 81.3% with talquetamab plus daratumumab and pomalidomide and 77.6% with talquetamab plus daratumumab compared with 51.2% with daratumumab plus pomalidomide and dexamethasone, reported Peter M. Voorhees, MD, of Wake Forest University School of Medicine in Charlotte, North Carolina, and colleagues.

This translated into a 72% reduction in the risk of disease progression or death with talquetamab plus daratumumab and pomalidomide (HR 0.28, 95% CI 0.20-0.40, P<0.001), and a 67% reduction with talquetamab plus daratumumab (HR 0.33, 95% CI 0.24-0.46, P<0.001), versus daratumumab plus pomalidomide and dexamethasone.

Results from the MonumenTAL-3 trial were reported at the European Hematology Association annual congress in Stockholm and published in the New England Journal of Medicine.

Overall survival rates at 24 months were 89.2% with talquetamab plus daratumumab and pomalidomide and 87.9% with talquetamab plus daratumumab versus 79.1% with daratumumab plus pomalidomide and dexamethasone (HR 0.47, 95% CI 0.30-0.73 and HR 0.51, 95% CI 0.33-0.78, respectively).

“These combinations represent additional options for early-line treatment of relapsed or refractory multiple myeloma,” Voorhees and colleagues wrote.

“Although the trial was not designed to formally compare Tal-DP [talquetamab plus daratumumab and pomalidomide] with Tal-D [talquetamab plus daratumumab], the addition of pomalidomide to talquetamab plus daratumumab therapy appeared to be associated with increases in progression-free survival, duration of response, and overall survival, as well as an increased risk of hematologic toxic effects and severe infections,” they observed. “Individual patient characteristics and treatment goals may be considered when selecting between Tal-D and Tal-DP.”

The two talquetamab combinations also outperformed the other regimen for:

• Overall response (88.2% and 88.5% vs 77.6%)
• Complete response (71.1% and 69.0% vs 34.5%)
• Measurable residual disease-negative complete response (52.3% and 46.3% vs 15.9%)
• Percentage of patients still responding at 24 months (86.0% and 79.8% vs 59.6%)

Talquetamab, a bispecific T-cell engager targeting GPRC5D and CD3, received accelerated approval in 2023 for patients with relapsed or refractory multiple myeloma who had previously received four or more lines of therapy.

In the MonumenTAL-2 study, the addition of talquetamab to pomalidomide demonstrated deep, durable responses in patients with relapsed/refractory multiple myeloma who had received two previous lines of therapy.

Adding daratumumab “modulates the immune microenvironment by reducing immunosuppressive regulatory T cells and enhancing cytotoxic T-cell activity, creating synergistic effects with talquetamab-mediated eradication of myeloma cells,” Voorhees and team noted.

MonumenTAL-3 was conducted from November 2022 to March 2025 and enrolled patients at 182 sites across 18 countries or regions. A total of 864 patients underwent randomization, with 287, 287, and 290 patients assigned to the three groups. Median age was 64, 57.4% were men, 64.5% were white, 27.4% were Asian, and 5.1% were Black. More than half (52.2%) had received two or three previous lines of therapy.

The safety profiles of the two talquetamab regimens “were consistent with previously reported effects of each agent in the combinations,” the authors noted.

The most common grade ≥3 adverse event was neutropenia, which occurred in 76.4% and 29.2% of the two talquetamab groups and 86.2% of those who received daratumumab plus pomalidomide and dexamethasone. The higher incidence of neutropenia in the first and third groups was due to the known myelosuppressive effect of pomalidomide, Voorhees and team said.

Serious adverse events occurred in 63.0%, 52.6%, and 53.7% of the three groups, respectively, with the most common being pneumonia (11.2%, 9.1%, and 19.4%).

Infections of any grade were reported in 87.3%, 84.3%, and 83.0% of the groups, while grade 3 or 4 infections were reported in 37.7%, 29.2%, and 42.4%.

Treatment discontinuation of all study treatments occurred in 10.5%, 8.0%, and 6.7% of the three groups.