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

Talquetamab-tgvs (Talvey) plus daratumumab (Darzalex) with (Tal-DP) or without (Tal-D) pomalidomide (Pomalyst) led to a longer progression-free survival (PFS) than daratumumab plus pomalidomide and dexamethasone (DPd) in patients with relapsed or refractory multiple myeloma who had previously received at least 1 line of therapy, according to data from the preplanned interim analysis of the phase 3 MonumenTAL-3 study (NCT05455320) presented during the 2026 EHA Congress.^1,2

The results, which were also published in the New England Journal of Medicine, showed that the median PFS with Tal-DP (n = 287) was not reached (NR) vs 24.4 months with DPd (n = 290), translating to a 72% reduction in the risk of disease progression or death (HR, 0.28; 95% CI, 0.20-0.40; P < .0001). The 24-month PFS rates in the respective arms were 81.3% (95% CI, 75.8%-85.7%) and 51.2% (95% CI, 44.8%-57.1%), respectively. Moreover, the median PFS with Tal-D (n = 287) was also NR, translating to a 67% reduction in the risk of disease progression or death vs DPd (HR, 0.33; 95% CI, 0.24-0.46; P < .0001); the 24-month PFS rate with Tal-D was 77.6% (95% CI, 71.7%-82.5%).

Tal-DP reduced the risk of death from any cause compared to control by 53% (HR, 0.47; 95% CI, 0.30-0.73; P = .0006), and Tal-D did so by 49% (HR, 0.51; 95% CI, 0.33-0.78; P = .0015). This was reported as clinically meaningful, although the P values have not crossed the prespecified boundary for superiority and longer follow-up is needed.

“Synergistic Tal-Dara–based immunotherapy combinations significantly improved PFS with clear benefit across clinically relevant subgroups,” Peter Voorhees, MD, of Levine Cancer Institute of Atrium Health and Wake Forest University School of Medicine, in Charlotte, North Carolina, said in a presentation of the data during a plenary session. “We did see substantial efficacy with just the Tal-D doublet alone. We saw clinically meaningful improvements in overall survival [OS]…In total, our data support talquetamab with daratumumab with or without pomalidomide as a new standard of care for patients with relapsed/refractory multiple myeloma as early as first relapse.”

What was the rationale for the initiation of the MonumenTAL-3 study examining talquetamab plus daratumumab–based regimens in multiple myeloma?

The treatment of patients with relapsed multiple myeloma has significantly changed over recent years, largely due to the advent of T-cell–redirecting immunotherapy, according to Voorhees. He added that phase 3 studies like CARTITUDE-4 (NCT04181827), MajesTEC-3 (NCT05083169), and MajesTEC-9 (NCT05572515) have showcased “unprecedented clinical activity” with BCMA-targeted CAR T-cell therapies and bispecific antibodies. “[They] support T-cell–redirecting immunotherapy use as early as first relapse, when immune function is best preserved.”

In August 2023, the FDA granted accelerated approval to talquetamab for use in adult patients with relapsed or refractory multiple myeloma who have previously received at least 4 lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (iMiD), and an anti-CD38 antibody.³ The decision was based on findings from the phase 2 MonumenTAL-1 trial (NCT04634552), which indicated that when the agent was given subcutaneously at biweekly doses of 0.8 mg/kg, it led to an objective response rate (ORR) of 73.6% (95% CI, 63.0%-82.4%) in patients who had received at least 4 prior lines of treatment and did not have exposure to T-cell redirection therapy (n = 187).

At the time of the approval, Ajai Chari, MD, told OncLive®:^5,6 “What’s really exciting about talquetamab is that its adverse effect [AE] profile is unique and combinable with other drugs. The choices [in relapsed/refractory multiple myeloma] are going to be increasing.” Chari is director of clinical research in the Multiple Myeloma Program at the UCSF Helen Diller Family Comprehensive Cancer Center in California.

“Talquetamab is the first and only GPRC5D/CD3 bispecific antibody that is currently approved for relapsed/refractory multiple myeloma for patients who have had 3 or more prior lines of therapy with single-arm phase 2 data demonstrating deep durable responses and median OS exceeding 3 years,” Voorhees noted in his presentation.¹ “Talquetamab targets plasma cells while largely sparing healthy B-cell populations due to limited B-cell expression of GPRC5D, which leads to a unique infection profile that’s quite distinct from BCMA-directed bispecific antibody therapies, and certainly helps facilitate combination therapy.”

He added that there is a strong rationale for pairing daratumumab and pomalidomide with talquetamab that extends beyond antimyeloma activity. He said that pomalidomide inhibits regulatory T cells and concurrently induces activation and proliferation of effector T-cell populations as daratumumab depletes CD38 regulatory T cells. When paired, this could enhance the T-cell–mediated cytotoxicity of a bispecific antibody like talquetamab, he explained.

What was the design of MonumenTAL-3?

The phase 3 study enrolled patients with measurable relapsed or refractory multiple myeloma who were at least 18 years of age, had received at least 1 previous line of therapy including lenalidomide (Revlimid) and a PI, and had an ECOG performance status ranging from 0 to 2. Exclusion criteria included being refractory to an anti-CD38 monoclonal antibody and prior receipt of GPRC5D-targeted therapy, pomalidomide, or a T-cell–redirecting therapy within 3 months of randomization.

A total of 864 patients were randomly assigned 1:1:1 to Tal-DP, Tal-D, or DPd. “After 4 subcutaneous step-up doses of talquetamab [0.01 mg/kg, 0.06 mg/kg, and 0/4 mg/kg followed by 0.8 mg/kg], the experimental arms went on to receive talquetamab every 2 weeks,” Voorhees explained. “After 4 weeks of therapy, if the patient was in a very good partial response or better, they could pivot to every-4-week dosing. If they were in at least a partial response after 6 cycles of treatment, they had to move from 2-week to 4-week dosing.”

The primary end point of the study was PFS by independent review committee. Secondary end points included ORR, complete response (CR) or better, minimal residual disease (MRD)–negative CR, OS, and safety.

At a median follow-up of 24.6 months, a total of 1104 patients were screened and 864 underwent randomization, comprising the intention-to-treat population. Of the 287, 287, and 290 patients who were randomized to Tal-DP, Tal-D, and DPd, respectively, 276, 274, and 283 received treatment; 70.3%, 69.7%, and 47.3% of patients in the respective arms were still on study treatment at the time of data cutoff, which was November 3, 2025.

The baseline demographic and disease characteristics were balanced at baseline and reflective of patients in real-world practice, according to Voorhees. “Patients had received a median of 2 prior lines of therapy, and nearly 40% of patients received this regimen as first relapse. About 11.5% of patients had previously been exposed to daratumumab, 85% were refractory to lenalidomide, and 93% were refractory to their last line of therapy.”

What additional efficacy data were reported?

Tal-DP outperformed the control in clinically relevant subgroups, including older patients (≥75 years, HR, 0.30; 95% CI, 0.10-0.89), those previously exposed to daratumumab (HR, 0.33; 95% CI, 0.14-0.76), those with stage III disease per International Staging System criteria (HR, 0.28; 95% CI, 0.12-0.67), those with high-risk cytogenetics (HR, 0.39; 95% CI, 0.24-0.65), and those with soft tissue plasmacytomas (HR, 0.41; 95% CI, 0.22-0.76). For those receiving Tal-DP in first relapse, the HR for PFS was 0.19 (95% CI, 0.10-0.35).

“The data with Tal-D doublet look very similar to those that we saw with the Tal-based triplet, with a PFS hazard ratio of 0.23 for those patients receiving this doublet as part of first relapse therapy,” Voorhees noted.

Tal-DP and Tal-D showcased significantly higher ORRs, CR or better rates, and MRD-negative (at 10^-5 sensitivity) CR rates than DPd. Tal-DP (n = 287) elicited an ORR of 88.2% with a CR or better rate of 71.1% vs an ORR of 77.6% and a CR or better rate of 34.5% with DPd (n = 290; OR for ORR, 2.27; 95% CI, 1.42-3.61; OR for ≥ CR, 4.93; 95% CI, 3.44-7.08). Tal-D (n = 287) led to an ORR of 88.5% and a CR or better rate of 68.9% (vs DPd: OR for ORR, 2.34; 95% CI, 1.47-3.74; OR for ≥ CR, 4.40; 95% CI, 3.08-6.28). The likelihood of achieving an MRD-negative CR with Tal-DP was 52.3% vs 15.9% with DPd (OR, 5.84; 95% CI, 3.94-8.64; P < .0001); the MRD-negative CR rate with Tal-D was 46.3% (vs DPd: OR, 4.70; 95% CI, 3.16-6.98; P < .0001).

What were the safety profiles of the regimens on the trial?

All patients in the Tal-DP, Tal-D, and DPd arms experienced treatment-emergent adverse effects (TEAEs); they were grade 3 or 4 for 94.9%, 74.8%, and 91.5% of patients, respectively, and led to discontinuation for 10.5%, 8.0%, and 6.7% of patients, respectively. “Deaths due to AEs were uncommon, occurring in less than 5% of patients across the arms, and were similarly distributed,” Voorhees said.

Higher rates of neutropenia were observed with Tal-DP (any grade, 84.1%; grade 3/4, 76.4%) and DPd (90.1%; 86.2%) vs Tal-D (40.9%; 29.2%), which is “consistent with the known profile of pomalidomide,” Voorhees said. He added that “Not surprisingly, cytokine release syndrome was common in the talquetamab arms [Tal-DP: any grade, 67.8%; Tal-D: 58.4%], but there were only two instances of higher-grade CRS in each of the talquetamab arms of the study. Immune effector cell–associated neurotoxicity syndrome occurred in 2.9% of those given Tal-DP and 1.8% of those given Tal-D; all cases resolved.

“The risk of grade 3 and 4 infections was higher in the pomalidomide-containing arms of the study [Tal-DP: 37.7%; DPd: 42.4%] and was only 29[.2]% for those patients receiving Tal-D,” Voorhees said. “Contrast that with a 54% risk of grade 3/4 infections when the bispecific antibody teclistamab-cqyv [Tecvayli] is combined with daratumumab. Importantly, fatal infections were uncommon, occurring in less than 2% of patients across the arms of the study, and were similarly distributed.”

Moreover, hypogammaglobulinemia occurred in 81.5% of those given Tal-DP vs 70.1% of those who received Tal-D and 62.5% of those given DPd. Opportunistic infections were reported in 16.3%, 17.9%, and 12.0% of patients, respectively.

“We know that GPRC5D is expressed on select epithelial structures in the skin and tongue, and it’s also expressed in the inferior olivary nucleus of the cerebellum, which gives rise to a distinct AE profile of talquetamab, and in that regard, taste changes were quite common in the [talquetamab] arms of the study,” Voorhees noted. “Skin-related AEs were also common, as were nail-related changes, but grade 3 events were rare. Ataxia and balance disorders occurred in 14.5% of those on the Tal-DP arm, 12.4% of those on the Tal-D arm, and 0.4% of those on the DPd arm.

Weight loss occurred in 45.7% of those given Tal-DP, 38.3% of those given Tal-D, and 7.4% of those given DPd. “Weight loss serves as a useful surrogate for the oral AEs of talquetamab, and for those patients that were treated with Tal-DP, mean body mass index decreases over the first 6 months of treatment and subsequently stabilizes,” Voorhees said. He concluded that those who were obese or overweight were the ones who lost weight; those who were a healthy weight or underweight were generally stable over the course of the trial.

References

1. Voorhees PM, Mina R, Rodriguez-Otero P, et al. Phase 3, randomized study of talquetamab plus daratumumab ± pomalidomide vs daratumumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: MonumenTAL-3. Presented at: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. S100.
2. Mina R, Beksac M, Rodriguez-Otero P, et al. Talquetamab–daratumumab in relapsed or refractory myeloma. N Engl J Med. Published online June 13, 2026. doi:10.1056/NEJMoa2604657
3. U.S. FDA approves Talvey (talquetamab-tgvs), a first-in-class bispecific therapy for the treatment of patients with heavily pretreated multiple myeloma. News release. Janssen. August 10, 2023. Accessed June 13, 2025. https://www.janssen.com/us-fda-approves-talveytm-talquetamab-tgvs-first-class-bispecific-therapy-treatment-patients-heavily
4. Flaherty C. Talquetamab helps usher in era of bispecific antibodies in relapsed/refractory myeloma: Q&A with Ajai Chari, MD. OncLive.com. August 18, 2023. Accessed June 13, 2026. https://www.onclive.com/view/talquetamab-helps-usher-in-era-of-bispecific-antibodies-in-relapsed-refractory-myeloma
5. Chari A. Dr Chari on the FDA approval of talquetamab in relapsed/refractory multiple myeloma. OncLive.com. August 14, 2023. Accessed June 13, 2026. https://www.onclive.com/view/dr-chari-on-the-fda-approval-of-talquetamab-in-relapsed-refractory-multiple-myeloma