New TALVEY® (talquetamab) plus daratumumab data demonstrate the potential strength of a novel bispecific combination in earlier-line relapsed or refractory multiple myeloma

Johnson & Johnson's TALVEY Plus Daratumumab Shows Superior PFS in RRMM

Johnson & Johnson announced positive Phase 3 MonumenTAL-3 study results for TALVEY (talquetamab) in combination with daratumumab, with or without pomalidomide, for relapsed or refractory multiple myeloma (RRMM). The regimen significantly reduced the risk of disease progression or death by up to 72.0% and the risk of death by up to 53.0% compared to daratumumab, pomalidomide, and dexamethasone (DPd). At 24 months, progression-free survival (PFS) rates were up to 81.3% and overall survival (OS) rates up to 89.2% with the combination, demonstrating superior PFS and clinically meaningful OS improvements, supporting its use earlier in the treatment paradigm.

• The MonumenTAL-3 study demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS). At 24 months, the Tal-DP arm achieved an 81.3% PFS rate and an 89.2% OS rate, while the Tal-D arm showed 77.6% PFS and 87.9% OS. These results represent a substantial reduction in the risk of disease progression or death (up to 72.0%) and death (up to 53.0%) compared to the standard DPd regimen, highlighting the combination's strong clinical benefit.
• Beyond PFS and OS, the study also showed statistically significant improvements in key secondary endpoints, including overall response rate (ORR), complete response or better (≥CR), and minimal residual disease (MRD)-negative ≥CR. ORRs were 88.2% (Tal-DP) and 88.5% (Tal-D) versus 77.6% (DPd). The study included 864 patients with RRMM who had received at least one prior line of therapy, with most being refractory to lenalidomide (85.1%) and their last line of therapy (93.4%).
• The safety profile of the talquetamab plus daratumumab SC treatment arms was consistent with known monotherapy profiles, with a reduced risk of severe infections observed in the Tal-D arm compared to standard of care. Grade 3/4 infections were lowest in Tal-D (29.2%). Johnson & Johnson has submitted a Type II variation to the EMA on March 31, 2026, for the combination's use in adult RRMM patients who have received at least one prior therapy, aiming to bring this novel regimen to patients quickly.

The Critical Need for Earlier Bispecifics in RRMM

Recent research has identified several critical unmet medical needs in multiple myeloma despite significant therapeutic advances. The disease remains incurable for most patients, with 5-year survival rates below 50% and inevitable development of treatment resistance requiring new therapeutic approaches and targets.

High-Risk and Treatment-Refractory Populations:

• Patients with high-risk cytogenetics who show no improvement in overall survival with current anti-CD38 monoclonal antibodies and require focused clinical trial development for specialized therapies

• Triple-refractory and heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients with limited treatment options, particularly those refractory to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies

• Lenalidomide-refractory patients who demonstrate inferior progression-free survival with subsequent treatments, with overall survival after lenalidomide failure of only 14.7 months and PFS to further lines under 7 months

• Patients progressing after anti-BCMA CAR-T cell therapy, representing an emerging unmet clinical need as these therapies become more widely used

Special Patient Populations:

• Frail and older multiple myeloma patients requiring geriatric assessment and treatment modifications, identified through International Myeloma Working Group Frailty Index and Revised Myeloma Comorbidity Index scores

• Black populations who experience twice the diagnosis rate compared to White patients but face significant disparities in access to advanced therapies like CAR-T cell treatments

• Patients with monoclonal gammopathy of undetermined significance (MGUS), particularly in Black populations where both MGUS and multiple myeloma are more prevalent, requiring prevention strategies to delay or prevent progression

Treatment Resistance and Access Challenges:

• Double-refractory patients to lenalidomide and anti-CD38 agents who have exhausted standard therapeutic options and face very poor outcomes without access to clinical trials incorporating novel agents (8.8 months vs 30 months overall survival)

• Patients with continued disease progression who require durable responses, sustained minimal residual disease negativity, and earlier integration of immunotherapies into treatment protocols

• Underserved populations with limited global accessibility to advanced treatments including CAR-T therapies and bispecific antibodies, highlighting the need for addressing healthcare disparities and improving treatment availability

MonumenTAL-3: Talquetamab Combination's Efficacy and Safety Profile

Recent clinical studies have demonstrated significant advances in multiple myeloma treatment across various patient populations and disease stages. These studies encompass real-world data analyses, randomized controlled trials, and meta-analyses evaluating both established and emerging therapeutic combinations.

GPRC5D Bispecifics: Talquetamab's Place in the Evolving Landscape

Multiple therapeutic agents are being investigated for multiple myeloma using similar mechanisms of action to talquetamab and daratumumab. These include additional CD38-targeting antibodies, BCMA-directed therapies, and other monoclonal antibodies with comparable cytotoxic mechanisms.

MonumenTAL-3: Elevating Talquetamab's Role in Myeloma Treatment

The MonumenTAL-3 study results mark a pivotal moment for talquetamab, a novel bispecific antibody, in the treatment of relapsed or refractory multiple myeloma (RRMM). By targeting GPRC5D on malignant plasma cells and CD3 on T cells, talquetamab activates a potent immune response. The Phase 3 data, demonstrating significant reductions in the risk of disease progression or death by up to 72.0% and death by up to 53.0% when combined with daratumumab (with or without pomalidomide), underscores its profound clinical impact. These impressive outcomes, including 24-month progression-free survival rates up to 81.3% and overall survival rates up to 89.2%, strongly advocate for its integration into earlier lines of therapy.

This strategic shift could significantly expand talquetamab's market presence, positioning it as a cornerstone therapy in combination regimens for RRMM. As a first-in-class GPRC5D/CD3 bispecific antibody, its robust efficacy offers a distinct competitive advantage in a crowded therapeutic landscape. The success of this combination approach also validates the strategy of pairing novel immune-engaging agents with established backbone therapies to achieve superior patient outcomes.

However, several considerations warrant attention. The 'up to' phrasing for risk reduction and survival rates, while indicative of strong efficacy, suggests that the full spectrum of patient responses and median benefits across the entire study population will be crucial for understanding real-world applicability. Furthermore, while daratumumab, pomalidomide, and dexamethasone (DPd) serve as a relevant comparator, the rapidly evolving RRMM treatment paradigm means ongoing evaluation against other emerging novel agents will be essential for sustained differentiation. Finally, earlier clinical data indicated that approximately a quarter of patients may not experience significant anticancer effects, highlighting the importance of patient selection and identifying predictors of response to optimize treatment strategies. This data positions talquetamab to redefine treatment expectations for many patients with RRMM, but careful consideration of its precise role and comparative benefits will be key to its long-term success.