MONUMENTAL-3 Data Support Talquetamab Plus Daratumumab ± Pomalidomide as a New SOC in R/R Myeloma

Talquetamab combinations demonstrated significantly higher response rates and progression-free survival compared to standard therapy in a phase 3 study of patients with relapsed or refractory multiple myeloma, according to data presented by Voorhees at the 2026 EHA Congress. The MonumenTAL-3 trial found that pairing talquetamab with daratumumab and pomalidomide (Tal-DP) or daratumumab alone (Tal-D) outperformed the control regimen of daratumumab, pomalidomide, and dexamethasone (DPd).

How does talquetamab work in combination therapy?

Talquetamab is the first and only GPRC5D/CD3 bispecific antibody approved for relapsed/refractory multiple myeloma in patients with three or more prior lines of therapy. According to Voorhees, the drug targets plasma cells while sparing most healthy B-cell populations, creating an infection profile distinct from BCMA-directed therapies.

Voorhees explained that pairing talquetamab with pomalidomide and daratumumab extends beyond antimyeloma activity. Pomalidomide induces the proliferation of effector T-cells and inhibits regulatory T-cells, while daratumumab depletes CD38 regulatory T-cells. This combination could enhance the T-cell–mediated cytotoxicity of the bispecific antibody.

Did You Know? Talquetamab’s unique side effect profile, including taste changes and balance disorders, stems from GPRC5D expression in the tongue, skin, and the inferior olivary nucleus of the cerebellum.

What were the results of the MonumenTAL-3 study?

The study randomized 864 patients to receive either Tal-DP, Tal-D, or DPd. At a median follow-up of 24.6 months, Tal-DP showed an overall response rate (ORR) of 88.2% and a complete response (CR) or better rate of 71.1%. In contrast, the DPd arm reported an ORR of 77.6% and a CR or better rate of 34.5%.

Tal-D produced similar results, with an ORR of 88.5% and a CR or better rate of 68.9%. The likelihood of achieving a minimal residual disease (MRD)–negative CR was 52.3% for Tal-DP compared to 15.9% for DPd.

Voorhees noted that Tal-DP outperformed the control in several subgroups. These included patients aged 75 or older, those previously exposed to daratumumab, and patients with high-risk cytogenetics or stage III disease. For those receiving Tal-DP during their first relapse, the hazard ratio for progression-free survival was 0.19.

Expert Insight: Samantha Carter notes that the shift toward GPRC5D-targeted combinations may allow clinicians to maintain higher efficacy in heavily pretreated populations while avoiding the specific infection risks associated with earlier BCMA-directed bispecifics.

What are the safety and side effect profiles?

All study arms experienced treatment-emergent adverse effects, with grade 3 or 4 events occurring in 94.9% of Tal-DP patients, 74.8% of Tal-D patients, and 91.5% of DPd patients. Deaths due to adverse effects were uncommon, occurring in less than 5% of patients across all arms.

EHA 2026 MONUMENTAL-3

Neutropenia was more frequent in the pomalidomide-containing arms, Tal-DP (76.4% grade 3/4) and DPd (86.2% grade 3/4), than in the Tal-D arm (29.2% grade 3/4). Cytokine release syndrome was common in both talquetamab arms, though higher-grade cases were limited to two instances per arm.

Voorhees reported that grade 3 and 4 infections occurred in 37.7% of Tal-DP patients and 42.4% of DPd patients, compared to 29.2% for Tal-D. He contrasted this with a 54% risk of grade 3/4 infections seen when the bispecific antibody teclistamab-cqyv is combined with daratumumab.

Other notable effects included weight loss, reported in 45.7% of Tal-DP patients and 38.3% of Tal-D patients. Voorhees stated that weight loss often serves as a surrogate for oral adverse effects and typically stabilizes after the first six months of treatment.

What happens next for talquetamab?

Given the efficacy in first-relapse patients and high-risk subgroups, talquetamab combinations may be considered for earlier lines of therapy. The data suggests that the Tal-D doublet provides similar benefits to the Tal-DP triplet in certain contexts, which could lead to a preference for less intensive regimens to reduce neutropenia and infection risks.

Future clinical applications may focus on refining dosing schedules, as the study allowed patients in a very good partial response or better to pivot from every-two-week to every-four-week dosing.

Frequently Asked Questions

What is Talquetamab?
It is a GPRC5D/CD3 bispecific antibody approved for patients with relapsed/refractory multiple myeloma who have undergone three or more prior lines of therapy.

How did the Tal-DP regimen compare to the DPd control?
Tal-DP showed a higher overall response rate (88.2% vs 77.6%) and a significantly higher complete response or better rate (71.1% vs 34.5%).

What are the most distinct side effects of this therapy?
According to Voorhees, patients frequently experienced taste changes, skin-related adverse effects, nail changes, and ataxia or balance disorders.

Do you believe the reduction in infection risk compared to other bispecific antibodies will drive wider adoption of GPRC5D-targeted therapies?