Phase 3 MonumenTAL-3 Trial Demonstrates Significant Survival Benefit With Talquetamab-Based Regimens in Relapsed/Refractory Multiple Myeloma

Patients with relapsed or refractory multiple myeloma (RRMM) treated with talquetamab (Talvey; Janssen Biotech, Inc) in combination with daratumumab (Darzalex; Janssen Biotech, Inc), with or without pomalidomide (Pomalyst; Bristol Myers Squibb), experienced significantly improved progression-free survival (PFS) and overall survival (OS) compared with daratumumab, pomalidomide, and dexamethasone (DPd), according to findings from the phase 3 MonumenTAL-3 trial (NCT05455320) presented at the European Hematology Association (EHA) 2026 Congress.¹

The research met its primary end point at a preplanned interim analysis, demonstrating substantial reductions in the risk of disease progression or death with both talquetamab-containing regimens. The data concluded that talquetamab plus daratumumab, with or without pomalidomide, may represent a new standard of care for patients with RRMM as early as second-line treatment.¹

Talquetamab in Multiple Myeloma

Multiple myeloma remains an incurable plasma cell malignancy characterized by repeated cycles of remission and relapse despite major advances in treatment.² Current therapeutic strategies include proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, CAR T-cell therapies, and bispecific antibodies; however, most patients eventually experience disease progression and require additional lines of therapy.²

Talquetamab is a first-in-class bispecific antibody that targets G protein-coupled receptor family C group 5 member D (GPRC5D), a cell-surface protein highly expressed on malignant plasma cells.²˒³ Through simultaneously binding GPRC5D on myeloma cells and CD3 on T cells, talquetamab redirects T cells to recognize and eliminate tumor cells through immune-mediated cytotoxicity.²˒³ Unlike B-cell maturation antigen (BCMA)-directed therapies, talquetamab targets an alternative antigen and may offer a favorable infection profile due to its B-cell–sparing mechanism.¹˒³

Researchers of the trial hypothesized that the combination of talquetamab with daratumumab, with or without pomalidomide, could enhance antimyeloma activity while maintaining manageable toxicity.¹

MonumenTAL-3 Trial Design

The global phase 3 MonumenTAL-3 trial had enrolled 864 patients with RRMM who had received at least 1 prior line of therapy that included lenalidomide (Revlimid, Celgene) and a proteasome inhibitor.¹ Participants were randomly assigned to receive talquetamab plus daratumumab and pomalidomide (Tal-DP; n=287), talquetamab plus daratumumab (Tal-D; n=287), or daratumumab, pomalidomide, and dexamethasone (DPd; n=290).¹

The median patient age was 64 years, and patients had received a median of 2 prior lines of therapy.¹ More than 85% were refractory to lenalidomide, 93.4% were refractory to their most recent line of therapy, and approximately one-third had high-risk cytogenetic abnormalities.¹

The primary end point was investigator-independent review committee–assessed PFS. Secondary end points included overall response rate (ORR), complete response (CR) or better, minimal residual disease (MRD)-negative CR, OS, and safety.¹

Significant Improvements in Progression-Free Survival and Overall Survival

After a median follow-up of 24.6 months, both talquetamab-containing regimens demonstrated significant improvements in progression-free survival (PFS) compared with DPd.¹ Treatment with Tal-DP reduced the risk of disease progression or death by 72% (HR, 0.28; 95% CI, 0.20-0.40; P<.0001), while Tal-D reduced the risk by 67% (HR, 0.33; 95% CI, 0.24-0.46; P<.0001).¹

The benefit translated into markedly higher 24-month PFS rates, which were 81.3% for Tal-DP and 77.6% for Tal-D, compared with 51.2% for DPd.¹ Notably, the PFS advantage was observed across clinically relevant patient subgroups.¹

The PFS improvements were accompanied by significant overall survival (OS) benefits. Compared with DPd, Tal-DP was associated with a 53% reduction in the risk of death (HR, 0.47; 95% CI, 0.30-0.73; P=.0006), while Tal-D reduced the risk of death by 49% (HR, 0.51; 95% CI, 0.33-0.78; P=.0015).¹

Deeper Responses and Higher MRD Negativity Rates

Talquetamab-based regimens also produced deeper and more durable responses than DPd.¹ Overall response rates were 88.2% with Tal-DP and 88.5% with Tal-D, compared with 77.6% for DPd.¹

The depth of response similarly favored the talquetamab-containing arms, with complete response or better achieved in 71.1% of patients receiving Tal-DP and 69.0% of those receiving Tal-D, compared with 34.5% in the DPd arm.¹ Minimal residual disease (MRD)-negative complete response rates were more than threefold higher with Tal-DP (52.3%) and nearly threefold higher with Tal-D (46.3%) than with DPd (15.9%).¹

These findings suggest that talquetamab-based combinations not only delay disease progression but also drive deeper disease eradication, potentially translating into more durable long-term outcomes for patients with RRMM.¹

Safety Profile Remains Manageable

The safety profile of talquetamab-based regimens was generally consistent with the known toxicities of the individual agents and did not reveal any new safety signals.¹ Grade 3 or 4 adverse events occurred in 96.7% of patients receiving Tal-DP, 78.8% receiving Tal-D, and 95.8% receiving DPd.¹

Notably, the addition of talquetamab did not appear to increase the risk of severe infections relative to the control regimen. Grade 3 or 4 infections were reported in 37.0% of patients receiving Tal-DP and 27.7% receiving Tal-D, compared with 41.0% of patients receiving DPd.¹

Consistent with the mechanism of GPRC5D-targeted therapy, taste disturbances and weight loss were among the most frequently observed adverse events.¹ Most events were grade 1 or 2 in severity and rarely led to treatment discontinuation.¹

Cytokine release syndrome (CRS), a known toxicity associated with T-cell–redirecting therapies, was primarily low grade, occurring in 67.8% of patients treated with Tal-DP and 58.4% of those treated with Tal-D.¹ Immune effector cell-associated neurotoxicity syndrome (ICANS) was uncommon, occurring in fewer than 3% of patients across the talquetamab-containing arms.¹ Overall, treatment discontinuation rates remained low, supporting the feasibility of incorporating talquetamab-based combinations into earlier lines of therapy.¹

The MonumenTAL-3 findings position talquetamab-based regimens among the most effective treatment options currently available for patients with RRMM following initial therapy.¹ For oncology pharmacists, these data highlight the continued movement of bispecific antibodies into earlier lines of treatment and reinforce the importance of monitoring for CRS, ICANS, cytopenias, infections, taste changes, and treatment-associated weight loss.¹˒²

Taken together, the findings support the use of talquetamab-based combinations as highly effective treatment options in earlier lines of RRMM and may help redefine the standard treatment approach for patients whose disease has progressed after frontline therapy.¹

References

1. Voorhees P, Mina R, Rodríguez-Otero P, et al. Phase 3, randomized study of talquetamab (Tal) plus daratumumab (Dara) ± pomalidomide (Pom) versus Dara plus pomalidomide and dexamethasone (DPd) in relapsed/refractory multiple myeloma (RRMM): MonumenTAL-3. Presented at: European Hematology Association Congress; June 12-15, 2026; Madrid, Spain. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.eha/temp/eha26_abstract/S100.pdf

2. Talvey (talquetamab-tgvs) prescribing information. Janssen Biotech, Inc. Revised 2024. https://www.jnjlabels.com/package-insert/product-monograph/prescribing-information/TALVEY-pi.pdf?utm_source=chatgpt.com

3. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma. N Engl J Med. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591