Combinations of the bispecific antibody talquetamab and daratumumab — with or without pomalidomide — outperformed standard therapy in patients with relapsed or refractory (r/r) multiple myeloma, according to an interim analysis of the randomized phase 3 trial MonumenTAL-3.

At 24 months, the two talquetamab groups demonstrated superior progression-free survival, along with higher overall survival, overall response rates, and rates of complete response or better than standard therapy with daratumumab, pomalidomide, and dexamethasone, reported Peter M. Voorhees, MD, professor of medicine at Wake Forest University School of Medicine, Charlotte, North Carolina, at the European Hematology Association (EHA) 2026 Congress in Stockholm. The findings were published simultaneously in The New England Journal of Medicine.

Although the trial was not designed to compare the two talquetamab regimens, efficacy outcomes numerically favored the pomalidomide-containing regimen, although this came at the cost of higher rates of serious adverse events.

Overall, these data support talquetamab with daratumumab, with or without pomalidomide, as a potential new standard of care for patients with r/r multiple myeloma, Voorhees said during a presentation at the EHA meeting.

While treatment for r/r multiple myeloma has evolved with the introduction of new drugs, most patients ultimately relapse and many have disease that is refractory to one or more agents, supporting the need for therapies that target novel antigens and mechanisms of resistance.

Talquetamab, a first-in-class bispecific antibody targeting the GPRC5D receptor, has already received FDA approval for heavily pretreated adults with r/r multiple myeloma — specifically, those who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

The approval was based on the earlier phase 1/2 MonumenTAL-1 study of 187 patients. The current trial highlights the phase 3 findings.

The study enrolled patients from November 2022 to March 2025 in 18 countries or regions and randomly assigned them in a 1:1:1 ratio to the two talquetamab groups (287 in each) and the standard therapy group (n = 290).

The patients in the study had undergone a median of two prior lines of therapy. The median age was 64 years, and 57.4% of patients were men. The researchers laid out the complex dosing schedules in a supplementary appendix. At the interim analysis, patients were followed for a median of 24.6 months.

Both response rates were higher in the talquetamab groups. The overall response rates were 88.2% with pomalidomide and 88.5% without vs 77.6% in the control arm, whereas rates of complete response or better were 71.1% and 69.0% vs 34.5%, respectively.

Overall survival at 24 months was also higher in both talquetamab arms — 89.2% with talquetamab plus pomalidomide, 87.9% without pomalidomide, and 79.1% with the control regimen. Compared with the control arm, talquetamab plus pomalidomide was associated with a 53% lower risk for death, whereas talquetamab without pomalidomide was associated with a 49% lower risk for death.

Progression-free survival, the trial’s primary efficacy endpoint, was also significantly higher in both talquetamab arms — 81.3% and 77.6% vs 51.2%, respectively (hazard ratio for disease progression or death, 0.28 and 0.33).

Those in the control group were much more likely to go on to subsequent antimyeloma, T cell-redirecting, or B-cell maturation antigen-targeted therapies compared with either treatment group.

Serious adverse events occurred in more patients in the talquetamab plus pomalidomide arm — 63% vs 52.6% for those receiving talquetamab without pomalidomide and 53.7% in the control group. Grade 3 or 4 infections were more common in the control arm — 42.4% vs 37.7% of the talquetamab plus pomalidomide group and 29.2% in the talquetamab without pomalidomide arm.

Cytokine release syndrome was common in the talquetamab arms — almost 68% of those receiving pomalidomide and just over 58% of those not receiving pomalidomide — but only two instances of higher-grade cytokine release syndrome in each talquetamab arm, Voorhees explained. Additionally, immune effector cell-associated neurotoxicity syndrome occurred in < 3% of patients who received talquetamab.

Deaths from any cause occurred in 8.7%, 10.2%, and 20.1% of patients, respectively. However, fatal adverse events occurred less frequently in the talquetamab plus pomalidomide group: 1.8%, 4.0%, and 4.6%, respectively.

Nearly three quarters of patients in the talquetamab groups reported taste changes, and weight loss was common. “Mean BMI decreases occurred over the first 6 months of treatment and subsequently stabilized,” Voorhees said. “Patients who were obese or overweight were the ones that lost weight, whereas those at healthy weight or underweight were pretty stable over the course of the trial.”

Wilson I. Gonsalves, MD, professor of medicine at Mayo Clinic, Rochester, Minnesota, who was not involved in the research, called the findings “phenomenal.”

However, he cautioned that none of the patients were daratumumab-refractory, and few (11.6%) were daratumumab-exposed, “which is quite different than the US population.”

As for side effects, he noted that taste disruptions often didn’t resolve, and ataxia and balance side effects led some patients to discontinue treatment.

As for access for patients at earlier stages, he said “unless this combination is designated on the NCCN [National Comprehensive Cancer Network] compendium, without an FDA label, I would find it very difficult to get access to these drugs.” For now, he said, patients will need to get to four lines of therapy or access the drug via a clinical trial to receive it earlier.

Johnson & Johnson funded the study. Voorhees disclosed having relationships with AbbVie, Ascentage Pharma, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen Biotech, Johnson & Johnson, Legend Biotech, Pfizer, Predicta Biosciences, Regeneron, and Sanofi. Other authors reported having various and multiple disclosures.