Editor's Note: At the recent European Hematology Association (EHA) Annual Congress, Professor Peter Voorhees from the Atrium Health Levine Cancer Institute (Charlotte, USA) was invited to share the preliminary results of the MONUMENTAL-3 study (NCT05455320). This study is the first randomized Phase 3 clinical trial evaluating GPRC5D-targeted therapy in combination with Daratumumab ± Pomalidomide for the treatment of relapsed/refractory multiple myeloma (RRMM).01 Synergistic Mechanism: The Scientific Foundation of GPRC5D Bispecific Combination Regimens
Professor Peter Voorhees first reviewed the evolution of the RRMM treatment landscape. With the advent of T-cell redirecting immunotherapy, the treatment paradigm for myeloma has undergone a fundamental shift. Talquetamab (TAL), as the first and only currently approved GPRC5D×CD3 bispecific antibody, has demonstrated durable responses and a median overall survival (OS) exceeding 3 years in patients who previously received ≥3 lines of therapy.
The rationale for the MONUMENTAL-3 study is based on the immune synergistic effects of the three drugs:
- Talquetamab: Induces T-cell mediated cytotoxicity by targeting GPRC5D, which is highly expressed on plasma cells.
- Daratumumab (DARA): As a CD38 monoclonal antibody, it depletes CD38+ regulatory T cells, enhancing the immune environment.
- Pomalidomide (POM): This immunomodulatory drug (IMiD) inhibits regulatory T cells while concurrently inducing the activation and proliferation of effector T-cell populations.
The combination of these three agents is expected to enhance the anti-tumor activity of the bispecific antibody through multidimensional immune mechanisms, further overcoming resistance.
02 MONUMENTAL-3 Study: Design of the First Phase 3 Randomized Trial for GPRC5D Bispecific Antibody
The study enrolled RRMM patients who had received at least one prior line of therapy (including lenalidomide and a proteasome inhibitor). Enrolled patients were randomly assigned to three groups: • TAL+DARA+POM (Triplet Group): Talquetamab (administered every 2 weeks) combined with DARA and POM. • TAL+DARA (Doublet Group): Talquetamab combined with DARA. • Daratumumab + Pomalidomide + Dexamethasone (DPD Control Group).
The primary endpoint of the study was progression-free survival (PFS). Professor Voorhees noted that the study featured a unique dose adjustment mechanism: patients achieving a very good partial response (VGPR) or better within the first 6 cycles could pivot from dosing every 2 weeks to every 4 weeks to balance long-term treatment toxicity.
03 Outstanding Benefits: Significant PFS Prolongation and Universality Across Subgroups
Data from a median follow-up of approximately 24 months (2 years) showed an overwhelming advantage for the TAL-based experimental arms compared to the control arm: • Triplet Regimen Benefit: The TAL+DARA+POM group reduced the risk of disease progression or death by 72% compared to the DPD group (HR=0.28; P<0.0001). • Doublet Regimen Benefit: The TAL+DARA group reduced that risk by 67% compared to the DPD group (HR=0.33; P<0.0001). • Survival Rates: The 2-year PFS rates for the triplet and doublet groups reached 81.3% and 77.6%, respectively, in contrast to just 51.2% for those receiving DPD.
In subgroup analyses, TAL-based combination regimens showed consistent clinical benefit regardless of patient age, ISS stage (Stage III), presence of extramedullary plasmacytomas, or high-risk cytogenetic profiles. Particularly striking was the PFS benefit observed in patients receiving this regimen at first relapse, where the HR for the triplet group was as low as 0.19, implying a stronger potential for this regimen to break the stalemate for early-relapse patients.
04 Deep Remission: A Leap in Response Rates and MRD Negativity
In terms of depth of response, the experimental arms demonstrated extremely high clinical response rates: • Complete Response (CR) or Better Rate: The CR+ rates for both the TAL+DARA+POM and TAL+DARA groups were approximately 70%, compared to 35% for the DPD control group. • Minimal Residual Disease (MRD) Negativity Rate: At a detection sensitivity level of 10⁻⁶, the MRD negativity rates for the triplet group, doublet group, and control group were 48%, 42%, and 10%, respectively.
Professor Voorhees emphasized that the TAL combination regimens can induce extremely deep and durable molecular remissions, laying a solid foundation for long-term patient survival.
05 Survival Trends: Clinical Insights from Preliminary OS Data
Although the current OS data have not yet crossed the pre-specified statistical significance threshold, positive trends have been observed: • The TAL+DARA+POM group reduced the risk of death from any cause by 53% compared to the control (HR=0.47). • The TAL+DARA group reduced that risk by 49% (HR=0.51). With longer follow-up, this clinical benefit is expected to further translate into a statistically significant survival advantage.
06 Safety Evaluation: Hematologic Toxicity, Infection, and GPRC5D-Specific Adverse Events
Regarding safety, the overall performance of the TAL combination regimens was largely consistent with the known profiles of the individual agents:
- Hematologic Toxicity: Grade 3/4 neutropenia was more common in the Pomalidomide-containing triplet arm, with an incidence of 62%, compared to only 29% in the TAL doublet arm.
- Infection Risk: The risk of Grade 3/4 infections was higher in the triplet arm (56%), while the risk in the TAL doublet arm (29%) was notably superior to previously reported data for BCMA-targeted bispecifics (e.g., the 54% Grade 3/4 infection risk for the Teclistamab plus DARA regimen). This difference reflects the uniqueness of the GPRC5D target in terms of preserving immune protective function, given its limited expression on healthy B cells.
- Cytokine Release Syndrome (CRS): While CRS is common in bispecific antibody therapy, the vast majority were low-grade, with only 2 instances of high-grade CRS in each of the TAL-treated arms.
- GPRC5D-Related Non-Hematologic Toxicities: These included taste changes (dysgeusia), and skin and nail-related changes. Professor Voorhees analyzed the weight loss issue in detail: patient BMI typically decreased over the first 6 months of treatment and subsequently stabilized. Interestingly, weight loss occurred primarily in patients who were overweight or obese, while those who were healthy weight or underweight remained relatively stable.
07 Expert Outlook: Significance of Early-Line Use and Individualized Supportive Care
In the subsequent Q&A session, Professor Voorhees offered important suggestions for clinical practice: • Key of Supportive Care: Due to TAL-specific taste and skin toxicities, early involvement of a dietitian or nutritionist and managing patient expectations from the beginning are crucial. • Dosing Interval Optimization: The study proved that prolonging the dosing interval (from every 2 weeks to every 4 weeks) can effectively mitigate GPRC5D-related side effects without compromising efficacy. • Clinical Positioning: The data from the MONUMENTAL-3 study strongly support TAL+DARA ± POM as a new Standard of Care (SoC) for RRMM patients, especially those as early as their first relapse.
Summary: The MONUMENTAL-3 study provides powerful data demonstrating the exceptional value of the Talquetamab plus Daratumumab combination in the treatment of RRMM. Its significant PFS benefit, deep MRD-negative remission, and relatively manageable infection profile make it a highly competitive new weapon in the myeloma treatment toolbox.
