Summary

• MonumenTAL-1 (MMY1001) is an ongoing, open-label, multicenter, phase 1/2 study evaluating the efficacy and safety of TALVEY in patients with relapsed or refractory multiple myeloma (RRMM) after ≥3 prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug, and an anti-CD38 monoclonal antibody (mAb).^1-3
  • Gong et al (2025)⁴ presented updated immunogenicity results, including data from a revised neutralizing antibody (NAb) assay, and evaluated their impact on the pharmacokinetics (PK), efficacy, and safety of TALVEY in the MonumenTAL-1 study.
  • Ma et al (2023)⁵ presented the PK, pharmacodynamic, immunogenicity, and exposure-response (E-R) analyses of TALVEY that support the selection of recommended phase 2 dose (RP2D) in the MonumenTAL-1 study.
  • Gong et al (2024)⁶ presented data on anti-TALVEY antibodies (anti-drug antibody [ADAs]) and changes in soluble B-cell maturation antigen (sBCMA) levels at both RP2D regimens (0.4 mg/kg weekly [QW] regimen and 0.8 mg/kg every other week [Q2W] regimen) with an additional 8 months of follow-up in the Q2W cohort after the original PK analysis presented by Ma et al (2023)⁵.
  • Girgis et al (2023)⁷ evaluated serum sBCMA levels in patients treated with TALVEY in phase 1 of the MonumenTAL-1 study.
  • Vishwamitra et al (2023)⁸ presented the results of a correlative analysis to understand the mechanisms of response, resistance, and relapse in patients treated with TALVEY in phase 1/2 of the MonumenTAL-1 study.
• Vishwamitra et al (2023)⁹ presented pharmacodynamic data from TRIMM-2 (TALVEY and daratumumab cohort) and MonumenTAL-1 (TALVEY monotherapy) studies demonstrating how immune modulation by daratumumab affects T-cell phenotypes observed with TALVEY.
• Vishwamitra et al (2024)¹⁰ presented an assessment of immunologic pharmacodynamic profiles and correlatives of response in patients from the TRIMM-2 study (TALVEY + DARZALEX FASPRO + pomalidomide cohort) to better understand the potential role of combination regimens in patients with RRMM.
• Perrot et al (2025)¹¹ presented PK data from the TRIMM-3 study (TALVEY and cetrelimab cohort), including the proportion of plasma cell expressing G protein-coupled receptor class C group 5 member D (GPRC5D) or PD-L1 and recovery of T-cells.

PRODUCT LABELING

• TALVEY (talquetamab-tgvs) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/TALVEY-pi.pdf.
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf.

Clinical Data - monumental-1 study

MonumenTAL-1 (MMY1001; NCT03399799, NCT04634552) is a phase 1/2 study of TALVEY in patients with RRMM.^12,13

The study was conducted in 3 parts; the primary objectives are listed below¹:

• Part 1 (phase 1; dose escalation): to characterize the safety of TALVEY and determine the RP2D and schedule
• Part 2 (phase 1; dose expansion): to further characterize the safety of TALVEY at the RP2D
• Part 3 (phase 2): to evaluate the efficacy of TALVEY at the RP2D

Shown below is a summary of the study design for the phase 1 portion (parts 1 and 2) of the study.

Study Design/Method (Phase 1 - Parts 1 and 2)

• Key Eligibility Criteria: adults with measurable multiple myeloma (MM) according to the International Myeloma Working Group (IMWG) criteria, relapsed/refractory or intolerant to established MM treatments, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤1.^2,8,14
• Dosage and Administration for Part 1 and Part 2
  • Initial Dosing^2,14,15
    • Intravenous (IV) dosing (0.0005-0.0338 mg/kg) Q2W (on days 1 and 15 of 28-day cycles)
  • Modified Dosing^1,9,14 
    • IV dosing (0.0005-0.18 mg/kg) QW on days 1, 8, and 15 in each 21-day cycle
    • Subcutaneous (SC) dosing (0.005-1.6 mg/kg) QW, Q2W or monthly
  • Full doses preceded by 1-3 step-up doses²

Study Design/Methods (Phase 2)

Patients were enrolled into 1 of the following 3 cohorts^1,16:

• TCR naive: 0.4 mg/kg SC QW, not previously exposed to TCR such as chimeric antigen receptor T-cell therapy (CAR-T) or bispecific antibodies (BsAbs; prior B-cell maturation antigen (BCMA) antibody-drug conjugate [ADC] allowed).
• TCR naive: 0.8 mg/kg SC Q2W, not previously exposed to TCRs (prior BCMA ADC allowed).
• Prior TCR exposed: 0.4 mg/kg SC QW or 0.8 mg/kg SC Q2W, have been previously exposed to TCRs.
  • Among the prior TCR-exposed cohort, patients were divided based on type of TCR (CAR-T, BsAb, or CAR-T and BsAb).
• Key eligibility criteria³:
  • ≥18 years of age, measurable MM per International Myeloma Working Group (IMWG) criteria.
  • ≥3 prior lines of therapy (LOTs) including a PI, an immunomodulatory drug, and an anti-CD38 mAb.
  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2.
• Dosing
  • Step-up doses (SUDs) of TALVEY were administered as follows³:
    • 0.4 mg/kg SC QW: 0.01 mg/kg, and 0.06 mg/kg.
    • 0.8 mg/kg SC Q2W: 0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg. 
  • Subsequent treatment doses: 0.4 mg/kg SC QW or 0.8 mg/kg SC Q2W until disease progression, unacceptable toxic effects, withdrawal of consent, or end of study.³

Gong et al (2025)⁴ presented updated immunogenicity results (including data from a revised NAb assay) and evaluated their impact on the PK, efficacy, and safety of TALVEY in the MonumenTAL-1 study.

Study Design/Methods

• At the data cutoff of September 2024, data were included from the 0.4 mg/kg SC QW cohort (n=143), the 0.8 mg/kg SC Q2W cohort (n=154), and the prior TCR-exposed cohort (n=78; 0.4 mg/kg SC QW or 0.8 mg/kg SC Q2W) from the MonumenTAL-1 study.
• Blood samples were analyzed for TALVEY serum concentration and presence of ADAs and NAb.

Results

• ADA and NAb were detected in TCR-naïve and prior-TCR exposed patients treated at the RP2D of TALVEY. See Table: MonumenTAL-1 Study: ADA and NAb in Patients With and Without Prior TCR-Exposure Treated at the RP2D of TALVEY.
• The presence of ADA and NAb had no apparent impact on TALVEY serum concentration over time in TCR-naïve patients treated at the RP2D of TALVEY. See Figure: MonumenTAL-1 Study: Effect of ADA and NAb on TALVEY Serum Concentration.
• Efficacy outcomes of TCR-naïve patients with ADA and NAb, treated at the RP2D of TALVEY are presented in Table: MonumenTAL-1 Study: Efficacy Outcomes of TCR-Naïve Patients With ADA and NAb Treated at the RP2D of TALVEY.
• In phase 2 analysis of TCR-naïve patients, median time to treatment-induced ADA onset was approximately 4 months after median time to first response to TALVEY. See Table: MonumenTAL-1 Study: Median Time to First Response and ADA Onset in TCR-Naïve Patients Treated at the RP2D of TALVEY for additional details.
• The incidence of adverse events (AEs) of clinical interest in patients with ADA and/or NAb is shown in Table: MonumenTAL-1 Study: Incidence of AEs of Clinical Interest in Patients With ADA and/or NAb .

Ma et al (2023)⁵ presented the PK, pharmacodynamic, immunogenicity, and E-R analyses of TALVEY that supported the selection of RP2Ds in phase 1 of the MonumenTAL-1 study.

Study Design/Methods

• Adult (≥18 years of age) patients with RRMM were included and received TALVEY per phase 1 dosing schedule.
• The RP2Ds were 0.4 mg/kg SC QW or 0.8 mg/kg SC Q2W.
• Blood samples were collected for measurement of TALVEY serum concentration, ADAs, and pharmacodynamics associated with TALVEY.

Results

Pharmacokinetics

• Based on a population PK analysis, the exposure of TALVEY was generally proportional to both IV and SC doses, with a mean bioavailability of 61.9% with the SC dose.
• In an ex vivo cytotoxic assay, the mean concentration-time profiles were comparable at the RP2Ds and were maintained at or above the concentration associated with the 90% maximal drug effect (EC₉₀) (see Figure: MoumenTAL-1 Study: Mean TALVEY Serum Concentration-Time Profiles at the RP2Ds).
• In a subgroup analysis, the covariates that affected the PK of TALVEY were body weight, immunoglobulin G (IgG) subtype myeloma, and International Staging System (ISS) stage. Age, sex, race, and hepatic or renal impairment did not affect PK.
  • Clinically meaningful (ie, ≥20%) differences in TALVEY exposure were not observed when weight-based dosing was used.
  • With the 0.4 mg/kg QW dose, the predicted average TALVEY exposure was approximately 100% higher in patients with non-IgG vs IgG myeloma and approximately 30% lower in patients with ISS stage II/III vs stage I.
  • No significant impact of PK covariates on efficacy was observed.

Pharmacodynamics

• T-cell activation and redistribution, as well as cytokine induction, were consistent with the mechanism of action of TALVEY and supported both RP2Ds.

Immunogenicity

• ADAs were detected in 29% of patients receiving the 0.4 mg/kg QW dose and in 20% of patients receiving the 0.8 mg/kg Q2W dose. ADAs had no apparent impact on PK, safety, or efficacy.

E-R Analysis for Efficacy

• The ORR increased with exposure and leveled at or above the RP2Ds, with no increase in response at higher doses.
• A near-flat E-R relationship between TALVEY exposure and ORR was observed at the RP2Ds.
• The prognostic factors identified for ORR were myeloma subtype and extramedullary plasmacytomas (see Figure: MoumenTAL-1 Study: Subgroup Analyses of ORR at the RP2Ds).

E-R Analysis for Safety

• No apparent E-R relationship was observed for grade ≥3 cytopenias and infections, grade ≥2 weight loss, or grade 2 ageusia across the predicted exposure quartiles. See Figure: MoumenTAL-1 Study: TEAE Rates in Patients Who Received TALVEY SC Doses Across the Predicted C_{max, 4weeks} Exposure Quartiles.
• No apparent E-R relationship was observed between all-grade or grade ≥2 CRS and peak TALVEY exposure at any step-up dose. No influence was observed with tocilizumab at any step-up dose.
• A trend of increasing occurrence of grade ½ dysgeusia with exposure was observed at the second exposure quartile and beyond. The rates of dysgeusia observed at both RP2Ds were similar (48.3% for the 0.4 mg/kg QW dose and 46.2% for the 0.8 mg/kg Q2W dose). See Figure: MoumenTAL-1 Study: Dysgeusia Rates in Patients Who Received TALVEY SC Doses Across the Predicted C_{max, 4weeks} Quartiles.

Gong et al (2024)⁶ presented data on ADAs and changes in sBCMA levels in the QW and Q2W RP2D regimens, with an additional 8 months of follow-up in the Q2W cohort compared with the original PK analysispresented by Ma et al (2023)⁵.

Study Design/Methods

• At the data cutoff of January 2023, data from 288 patients treated at the RP2D regimens (QW, n=143; Q2W, n=145) in MonumenTAL-1 were included.
• Blood samples were analyzed for TALVEY serum concentration, ADAs, and sBCMA.

Results

Immunogenicity

• Treatment-emergent ADAs were observed in 34.1% (n=47/138) and 35.3% (n=49/139) of patients in the QW and Q2W RP2D regimens, respectively. Immunogenicity and response details in ADA-positive vs ADA-negative patients have been summarized in Table: MoumenTAL-1 Study: Immunogenicity and Response in the QW and Q2W RP2D Regimens.

sBCMA and Response to TALVEY

• Changes in serum sBCMA levels vs response in the QW and Q2W RP2D regimens is presented in Figure: MoumenTAL-1 Study: Changes in Serum sBCMA Levels vs Response in the (A) 0.4 mg/kg QW and (B) 0.8 mg/kg Q2W Regimens.
  • A reduction in sBCMA levels from baseline was observed in 100% and 97% of responders in the QW and Q2W regimens 21 to 28 days after the first full treatment dose of TALVEY.
  • Patients with very good partial response or better (≥VGPR; ie, VGPR, complete response, CR; or stringent complete response, sCR) had the greatest reduction in sBCMA.
  • Responders had deeper reductions in serum sBCMA levels at cycle 2 day 1 after the first full treatment dose of TALVEY compared with nonresponders.

ADAs and TALVEY Safety and PK Profiles

• The presence of ADAs had no apparent impact on TALVEY safety or PK in the QW or Q2W RP2D regimens. Immunogenicity vs safety in ADA-positive and ADA-negative patients has been summarized in Table: MoumenTAL-1 Study: Immunogenicity vs Safety Analysis.

Girgis et al (2023)⁷ evaluated serum sBCMA levels in patients treated with TALVEY in phase 1 of the MonumenTAL-1 study.

Study Design/Methods

• Adult (≥18 years of age) patients with RRMM were included and received TALVEY per phase 1 dosing schedule.⁷
• Blood samples were collected for PK analysis on days 1, 2, 3, 8, and 15 of cycles 1 and 3, on days 1 and 15 of cycle 2, and on day 1 of cycle 4 in biweekly IV dosing cohorts and weekly IV and SC dosing cohorts.⁷
  • In the SC dosing cohorts, additional samples were collected from patients on day 4 of cycles 1 and 3.⁷
• A total of 153 patients had an evaluable sBCMA at baseline. Of those, 99 patients treated with TALVEY had evaluable data on cycle 3, day 1.⁷
• sBCMA data were quantitatively analyzed in relation to patient response, tumor burden or percentage of bone marrow plasma cells (BMPCs), cytogenetic risk, and PK data.⁷

Results

sBCMA Levels, Tumor Burden, and Cytogenetic Risk

• Baseline sBCMA levels correlated with the percentage of BMPCs.⁷
• Patients with extramedullary plasmacytomas with low levels of BMPCs (<10%) tended to have high levels of sBCMA (≥400 ng/mL).⁷
• Baseline sBCMA levels were similar in patients with high-risk cytogenetics (median [range], 226 [21.0-1259] ng/mL) and standard-risk cytogenetics (median [range], 127 [4.5-2586] ng/mL).⁷
• Median (minimum [min], maximum [max]) percentage change in sBCMA levels from baseline to cycle 3 day 1 was -83.5% (-99.0, -41.6) in patients with high-risk cytogenetics and -94.5% (-98.9, 167) in patients with standard-risk cytogenetics.^7,18

sBCMA Levels and Response to TALVEY

• Overall, 98% of responders (49 of 50) to TALVEY had a decrease in sBCMA levels from baseline to cycle 3 day 1.⁷
• Overall, 49% nonresponders (24 of 49) to TALVEY had an increase in sBCMA levels from baseline to cycle 3 day 1.⁷
• The extent of sBCMA level reduction corresponded to the depth of response, with the greatest reductions from baseline observed for patients who achieved a VGPR (median [min, max], -92.3% [-98.7, -48.1]) or partial response (PR; median [min, max], -89.7% [-99.3, -37.3]) after treatment with TALVEY.⁷ See Table: MoumenTAL-1 Study: Change in sBCMA Levels on Cycle 3 Day 1 Compared With Baseline According to the Depth of Response to TALVEY Treatment.
• Patients with baseline sBCMA levels of ≥200 ng/mL appeared to respond to active doses of TALVEY (IV: 0.06-0.18 mg/kg; SC: 0.405-0.8 mg/kg).⁷

Vishwamitra et al (2023)⁸presented the results of baseline and longitudinal correlative analyses of immune profiles to evaluate the mechanisms of response, resistance, and relapse in patients treated with TALVEY in phase 1/2 of the MonumenTAL-1 study.

Study Design/Methods

• Correlative analyses were performed in patients in the phase 1/2 MonumenTAL-1 study who were TCR naïve or those exposed to prior TCR therapies.⁸
• Whole blood samples and bone marrow aspirates were analyzed by flow cytometry for⁸:
  • GPRC5D expression at baseline and relapse
  • T-cell counts and markers of T-cell activation/exhaustion at baseline
  • Differential longitudinal profiles in responders vs nonresponders:
    • Indicative of T-cell activation: peak induction of programmed cell death 1 (PD-1), CD38, lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing protein 3 (TIM-3), PD-1/LAG-3, PD-1/TIM-3 expression on CD8+ T cells in cycle 1
    • Indicative of T-cell exhaustion: sustained expression of PD-1, CD38, LAG-3, TIM-3, PD-1/LAG-3, PD-1/TIM-3 on CD8+ T cells after cycle 2
  • Immune profiles at relapse vs baseline

Results

Efficacy

GPRC5D Expression and Response

• At baseline, GPRC5D was highly expressed on MM cells in each cohort, but no correlation between baseline GPRC5D expression and response was observed. A trend of lower GPRC5D expression in nonresponders (defined as stable disease or worse) vs responders (defined as partial response or better) was observed in the prior TCR cohort.⁸

Immune Profile in Responders vs Nonresponders

• Pharmacodynamic analysis at baseline showed that patients in the prior TCR cohort had a more exhausted immune profile at baseline compared with those in the QW and Q2W cohorts, with higher frequencies of CD8+ T cells expressing PD-1/LAG-3, TIM-3, and CD38 and regulatory T cells.⁸
• Across cohorts, responders had a less exhausted immune profile (indicated by higher T-cell counts and lower frequencies of CD8+ T cells expressing LAG-3 and CD38) compared with nonresponders.⁸

T-cell Activation and Exhaustion in Responders vs Nonresponders

• In cycle 1 following treatment, higher induction of CD8+ T cells expressing PD-1/LAG-3 and PD-1/TIM-3 was observed in responders vs nonresponders in the QW and Q2W cohorts, indicative of greater T-cell activation in responders vs nonresponders.⁸ Details are provided in Table: MonumenTAL-1: Maximum-Fold Induction of T-cell Activation Markers in Cycle 1 in Responders vs Nonresponders in the Periphery.⁸
• In cycle 1 following treatment, trends between improved progression-free survival and higher maximum-fold induction of CD8+ T cells expressing TIM-3 and TIM-3/PD-1 in the QW cohort and CD8+ T cells expressing LAG-3 and PD-1/LAG-3 in the Q2W cohort were observed.⁸
• After cycle 2, sustained expression of PD-1/LAG-3 and PD-1/TIM-3 on CD8+ T cells (indicative of T-cell exhaustion) was observed in nonresponders in the QW cohort only.⁸

Expression of T-cell Exhaustion Markers at Relapse vs Baseline

• GPRC5D expression remained high at relapse, suggesting that downregulation of GPRC5D was not a mechanism of relapse.⁸
• Patients who relapsed showed lower counts of CD3+ T cells and significantly higher frequencies of CD8+ T cells expressing PD-1 compared with baseline across cohorts, indicative of an exhausted T-cell phenotype at relapse.⁸
• Higher frequencies of CD8+ T cells expressing LAG-3, TIM-3, PD-1/LAG-3, and PD-1/TIM-3 were also observed in patients with relapse.⁸

pharmacodynamic results - trimm-2 study and monumental-1 study

Vishwamitra et al (2023)⁹ presented the pharmacodynamic results with TALVEY and daratumumab in the TRIMM-2 study, and TALVEY monotherapy in the MonumenTAL-1 study.

TRIMM-2 Study Design

• Key Eligibility criteria:
  • Measurable MM per IMWG
  • Double refractory to PI and immunomodulatory drug or ≥3 prior lines of treatment (including a PI and an immunomodulatory drug)
  • Refractory to anti-CD38 mAb (anti-CD38 mAb treatment >90 days prior was allowed)
  • Prior BsAb and CAR-T therapy was allowed
• Patients in the TALVEY + DARZALEX FASPRO cohort received the following study treatment:
  • TALVEY: 2-3 step-up doses before receiving the full doses of either 0.4 mg/kg SC QW or 0.8 mg/kg SC Q2W
    • Premedication, including glucocorticoid, antihistamine, and antipyretic was administered at step-up and first full dose of TALVEY.
  • DARZALEX FASPRO: 1800 mg SC QW during cycles 1-2, Q2W during cycles 3-6, and once every 4 weeks (Q4W) during cycles ≥7
    • DARZALEX FASPRO was administered with 2-week corticosteroid taper (steroid-free administration after first full treatment dose)

Methods

• Biomarker data cutoffs were July 26, 2023 (TALVEY + daratumumab), and June 20, 2023 (TALVEY monotherapy).
• Flow cytometry and T-cell receptor sequencing (TRIMM-2 only) were used to assess T-cell redistribution and activation, immunosuppressive CD38+ Tregs, total B cells, and natural killer (NK) cells.

Results

Pharmacodynamics

T-cell Redistribution and Clonal Expansion with TALVEY and Daratumumab

• T-cell redistribution (reduction in peripheral CD3+ T cells) was observed early, followed by T-cell recovery, consistent with the mechanism of action (MOA) of each therapy. See Figure: MoumenTAL-1 Study: Peripheral CD+3 T cells in Patients Treated with TALVEY + Daratumumab and TALVEY Monotherapy.
• In available samples from 6 patients, a high level of clonal expansion at cycle 3 day 1 was observed, which included an increase in the fraction of newly detected clones, thereby indicating antigen-specific T-cell response. See Table: MoumenTAL-1 Study: Clonal Expansion Data in Patients from C1D1 to C3D1.

T-cell Activation with TALVEY and Daratumumab

• Increase in effector memory CD8+ T cells and induction of T-cell activation were observed, evidenced by increase in CD8+ T cells expressing lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and programmed cell death protein-1 (PD-1) in the first cycle.

Effect on CD38+ T-cell Populations with TALVEY + Daratumumab

• Initial reduction of CD38+ CD8+ T cells were observed following daratumumab administration. However, after TALVEY administration, induction of CD38+ CD8+ T cells was observed, indicating T-cell activation. See Figure: MoumenTAL-1 Study: CD38+ CD8+ T Cells in Patients Treated with TALVEY + Daratumumab and TALVEY Monotherapy.
• Consistent with daratumumab’s immunomodulatory properties, there was a reduction in immunosuppressive CD38+ Tregs with TALVEY and daratumumab, compared with no reduction with TALVEY monotherapy.

Effect on NK cells and B cells with TALVEY and Daratumumab

• Sustained reduction in NK cells was observed after administration of TALVEY + daratumumab (consistent with observed effects of daratumumab) but was not observed after TALVEY administration.
• There was no change observed in total CD19+ B cells following treatment with TALVEY + daratumumab or with TALVEY monotherapy, consistent with the Bcell sparing MOA of the combination. See Figure: MoumenTAL-1 Study: B Cells in Patients Treated with TALVEY + Daratumumab and TALVEY Monotherapy.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 07 July 2025.