Talquetamab (TALVEY) is a first-in-class GPRC5D×CD3 bispecific antibody co-developed by Johnson & Johnson and Genmab. Unlike BCMA-targeted therapies, talquetamab targets GPRC5D, a novel antigen highly expressed on malignant plasma cells but with limited expression on normal tissues. The drug received regulatory approvals in major markets for heavily pretreated RRMM following the impressive efficacy demonstrated in the MonumenTAL-1 study. Since its initial approval, Johnson & Johnson has pursued an aggressive lifecycle expansion strategy aimed at moving talquetamab into earlier treatment settings and combination regimens. The Phase III MonumenTAL-3 study represents the first registrational trial evaluating talquetamab-based combinations against an established standard-of-care regimen in patients with early relapsed multiple myeloma. 

MonumenTAL-3 enrolled 864 patients with RRMM who had received at least one prior line of therapy, including lenalidomide and a proteasome inhibitor. Patients were randomized to receive Tal-DP (talquetamab, daratumumab, pomalidomide), Tal-D (talquetamab and daratumumab), or the control regimen DPd (daratumumab, pomalidomide, and dexamethasone).

Safety Outcomes-

• Overall AEs (Grade 3-4, Grade 5): Tal-DP (96.7%, 1.8%), Tal-D (78.8%, 4.0%), DPd (95.8%, 4.6%). 

• AEs leading to discontinuation of study occurred in 10.5% (Tal-DP), 8.0% (Tal-D), and 6.7% (DPd). 

• Rates of cytopenias (any Grade, Grade 3-4) were: Tal-DP (91.7%, 87.7%), Tal-D (68.2%, 51.8%), and DPd (91.9%, 89.0%). 

• Infection rates (any Grade, Grade 3-4, Grade 5) were: Tal-DP (87.3%, 37.0%, 0.7%), Tal-D (84.3%, 27.7%, 1.5%), and DPd (83.0%, 41.0%, 1.8%). 

• With Tal-DP and Tal-D, respectively, CRS (any Grade: 67.8%; 58.4%) and ICANS (any Grade: 2.9%; 1.8%) were mostly Grade 1-2. 

• Any Grade GPRC5D-related AEs with Tal-DP, Tal-D, and DPd, respectively, included taste changes (72.8%; 74.8%; 3.9%) and decreased weight (45.7%; 38.3%; 7.4%); most events were Grade 1-2 and did not lead to Tal discontinuation. 

• Ataxia/balance disorders (Grade 1-2, Grade 3) with Tal-DP (11.6%, 2.9%), Tal-D (10.2%, 2.2%), and DPd (0.4%, 0%) were primarily low Grade (none Grade ≥4); events led to Tal discontinuation in 4.7% (Tal-DP) and 2.2% (Tal-D). 

KOL Insights-

“Daratumumab-based regimens have transformed the treatment of multiple myeloma and remain a foundational therapy across all stages of disease. The MonumenTAL-3 study builds on this legacy, combining daratumumab with talquetamab, the first GPRC5D bispecific antibody, to further expand the effective options available to patients in the relapsed/refractory setting.”– Expert Opinion

“The impressive results from this study point to the promise of talquetamab plus daratumumab as a potential new bispecific combination for patients with relapsed or refractory multiple myeloma. Talquetamab works with daratumumab in earlier lines, a critical time for treating patients with the most effective regimens.”– Expert Opinion

Conclusion-

Multiple myeloma remains the second most common hematologic malignancy worldwide, accounting for approximately 180,000 new cases annually. Despite substantial therapeutic advances, most patients eventually relapse and become refractory to standard treatments, creating a continued need for therapies capable of producing deep and durable remissions earlier in the disease course.

The Phase III MonumenTAL-3 trial represents a major advancement in the treatment of RRMM. Both Tal-DP and Tal-D delivered highly significant improvements in PFS, OSl, CR rates, and MRD negativity compared with DPd. Importantly, these efficacy gains were achieved without an increase in severe infections and with manageable rates of CRS and neurotoxicity. While Tal-DP produced numerically deeper responses, Tal-D offered a favorable balance between efficacy and tolerability. Collectively, these findings establish talquetamab-based regimens as potential new standards of care beginning as early as second-line treatment and support broader adoption of GPRC5D-directed immunotherapy in multiple myeloma.