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-cluster of differentiation 38 (anti-CD38) monoclonal antibody.^1-3
  • Ma et al (2023)⁴ presented (at the American Society of Clinical Oncology [ASCO] annual meeting) the pharmacokinetic (PK), pharmacodynamic, immunogenicity, and exposure-response (E-R) analyses of talquetamab that support the selection of recommended phase 2 doses (RP2D) in the MonumenTAL-1 study. Based on a population PK analysis, the exposure of talquetamab was generally proportional to both intravenous (IV) and subcutaneous (SC) doses, with a mean bioavailability of 61.9% with the SC dose. The overall response rate (ORR) increased with exposure and leveled at or above the RP2Ds, with no increase in response at higher doses. No E-R relationship was observed for grade ≥3 cytopenias and infections, grade ≥2 weight loss, or grade 2 ageusia across the predicted exposure quartiles.
  • Gong et al (2024)⁵ presented (at the American Society for Clinical Pharmacology & Therapeutics [ASCPT]) data on anti-talquetamab antibodies (ADAs) and changes in soluble B-cell maturation antigen (sBCMA) levels at both RP2D regimens (0.4mg/kg once weekly [QW] regimen and 0.8 mg/kg once 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)⁴. 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. 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 talquetamab, respectively. The presence of ADAs had no apparent impact on talquetamab safety or PK in the QW and Q2W RP2D regimens, respectively.
  • Girgis et al (2023)⁶ evaluated serum sBCMA levels in patients treated with talquetamab in phase 1 of the MonumenTAL-1 study. At cycle 3 day 1, 98% of responders (49 of 50) reported a decrease in sBCMA levels from baseline, and 49% of nonresponders (24 of 49) reported an increase in sBCMA levels from baseline.
  • Vishwamitra et al (2023)⁷ presented (at the 65th American Society of Hematology [ASH] Annual Meeting and Exposition) the results of a correlative analysis to understand the mechanisms of response, resistance, and relapse in patients treated with talquetamab in phase 1/2 of the MonumenTAL-1 study. At baseline, G protein-coupled receptor family C group 5 member D (GPRC5D) was highly expressed on multiple myeloma (MM) cells, but no correlation between baseline GPRC5D expression and response was observed. Baseline and longitudinal analyses showed that responders had a less exhausted T-cell phenotype compared with nonresponders in heavily pretreated patients with RRMM. Lower T-cell counts and higher T-cell exhaustion markers vs baseline were observed to be associated with potential mechanism of relapse.
• Vishwamitra et al (2023)⁸ presented (at the Society of Immunotherapy of Cancer [SITC] 2023 annual meeting) pharmacodynamic data from TRIMM-2 (talquetamab and daratumumab cohort) and MonumenTAL-1 (talquetamab monotherapy) studies demonstrating how immune modulation by daratumumab affects T-cell phenotypes observed with talquetamab.
• Other relevant data has been identified in addition to the data summarized above:
  • Vishwamitra et al (2024)⁹ 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.

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; clinicaltrials.gov identifiers: NCT03399799, NCT04634552) is a phase 1/2 study of TALVEY in patients with RRMM.^2,3

The study was conducted in 3 parts; the primary objectives are listed below¹⁰:

• Part 1 (phase 1; dose escalation): to characterize the safety of talquetamab and determine the RP2D and schedule
• Part 2 (phase 1; dose expansion): to further characterize the safety of talquetamab at the RP2D
• Part 3 (phase 2): to evaluate the efficacy of talquetamab 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 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.^1,7,11
• Key Study Objectives:
  • Part 1: characterize the safety of talquetamab and identify RP2Ds³
  • Part 2: further characterize the safety of talquetamab at the RP2Ds³
• Dosage and Administration for Part 1 and Part 2
  • Initial Dosing^1,11,12
    • IV dosing (0.0005-0.0338 mg/kg) Q2W (on days 1 and 15 of 28-day cycles)
  • Modified Dosing^8,10,11 
    • IV dosing (0.0005-0.18 mg/kg) QW on days 1, 8, and 15 in each 21-day cycle
    • SC dosing (0.005-1.6 mg/kg) QW, Q2W or monthly
  • Full doses preceded by 1-3 step-up doses¹
• Primary Endpoints
  • Part 1 (dose escalation): frequency and type of dose-limiting toxicity (DLT).¹
  • Part 2 (dose expansion): frequency and severity of adverse events (AEs), serious AEs and laboratory abnormalities.¹
• Secondary Endpoints: PK parameters, pharmacodynamic markers, presence of ADA, ORR.¹¹

Shown below is a summary of the study design for the phase 2 portion (part 3) of the study.

Study Design/Methods (Phase 2)

Patients were enrolled into 1 of the following 3 cohorts¹³:

• TCR naive: 0.4 mg/kg SC QW (n=143): not previously exposed to prior 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 (n=154): not exposed to prior TCRs (prior BCMA ADC allowed).
• Prior TCR: 0.4 mg/kg SC QW or 0.8 mg/kg SC Q2W (n=70): exposed to prior TCRs (prior BCMA ADC, CAR-T, and/or BsAb allowed).
• Key Eligibility Criteria (Part 3; Phase 2)
  • Measurable MM⁷
  • At least 3 prior lines of therapy, including a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody⁷
  • ECOG PS of 0-2⁷
• Primary Endpoint: ORR¹⁰
• Key Secondary Endpoints: duration of response, progression-free survival, overall survival, safety, immunogenicity, and pharmacodynamic¹⁰
• Dosing: Patients received talquetamab 0.4 mg/kg QW or 0.8 mg/kg Q2W; patients who were exposed to prior T-cell receptor (TCR) were treated with either dosing schedule (prior TCR cohort).⁷

Ma et al (2023)⁴ presented the PK, pharmacodynamic, immunogenicity, and E-R analyses of talquetamab 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 talquetamab 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 talquetamab serum concentration, ADAs, and pharmacodynamics associated with talquetamab.

Results

Pharmacokinetics

• Based on a population PK analysis, the exposure of talquetamab 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: Mean Talquetamab Serum Concentration-Time Profiles at the RP2Ds).
• In a subgroup analysis, the covariates that affected the PK of talquetamab 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 talquetamab exposure were not observed when weight-based dosing was used.
  • With the 0.4 mg/kg QW dose, the predicted average talquetamab 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 talquetamab 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 talquetamab exposure and ORR was observed at the RP2Ds.
• The prognostic factors identified for ORR were myeloma subtype and extramedullary plasmacytomas (see Figure: 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: TEAE Rates in Patients Who Received Talquetamab SC Doses Across the Predicted C_{max, 4weeks} Exposure Quartiles.
• No apparent E-R relationship was observed between all-grade or grade ≥2 cytokine release syndrome (CRS) and peak talquetamab 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: Dysgeusia Rates in Patients Who Received Talquetamab SC Doses Across the Predicted C_{max, 4weeks} Quartiles.

Gong et al (2024)⁵ 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)⁴.

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 talquetamab 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: Immunogenicity and Response in the QW and Q2W RP2D Regimens.

sBCMA and Response to Talquetamab

• Changes in serum sBCMA levels vs response in the QW and Q2W RP2D regimens is presented in Figure: 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 talquetamab.
  • 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 talquetamab compared with non-responders.

ADAs and Talquetamab Safety and PK Profiles

• The presence of ADAs had no apparent impact on talquetamab 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: Immunogenicity vs Safety Analysis.

Girgis et al (2023)⁶ evaluated serum sBCMA levels in patients treated with talquetamab in phase 1 of the MonumenTAL-1 study.

Study Design/Methods

• Adult (≥18 years of age) patients with RRMM were included and received talquetamab per phase 1 dosing schedule.⁶
• 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.⁶
  • In the SC dosing cohorts, additional samples were collected from patients on day 4 of cycles 1 and 3.⁶
• A total of 153 patients had an evaluable sBCMA at baseline. Of those, 99 patients treated with talquetamab had evaluable data on cycle 3, day 1.⁶
• 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.⁶

Results

sBCMA Levels, Tumor Burden, and Cytogenetic Risk

• Baseline sBCMA levels correlated with the percentage of BMPCs.⁶
• Patients with extramedullary plasmacytomas with low levels of BMPCs (<10%) tended to have high levels of sBCMA (≥400 ng/mL).⁶
• 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).⁶
• 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.^6,14

sBCMA Levels and Response to Talquetamab

• Overall, 98% of responders (49 of 50) to talquetamab had a decrease in sBCMA levels from baseline to cycle 3 day 1.⁶
• Overall, 49% nonresponders (24 of 49) to talquetamab had an increase in sBCMA levels from baseline to cycle 3 day 1.⁶
• 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 talquetamab.⁶ See Table: Change in sBCMA Levels on Cycle 3 Day 1 Compared With Baseline According to the Depth of Response to Talquetamab Treatment.
• Patients with baseline sBCMA levels of ≥200 ng/mL appeared to respond to active doses of talquetamab (IV: 0.06-0.18 mg/kg; SC: 0.405-0.8 mg/kg).⁶

Vishwamitra et al (2023)⁷presented the results of baseline and longitudinal correlative analyses of immune profiles to evaluate the mechanisms of response, resistance, and relapse in patients treated with talquetamab 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.⁷
• Whole blood samples and bone marrow aspirates were analyzed by flow cytometry for⁷:
  • 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.⁷

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.⁷
• 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.⁷

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.⁷ 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.⁷
• 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.⁷
• 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.⁷

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.⁷
• 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.⁷
• 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.⁷

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

Vishwamitra et al (2023)⁸ presented the pharmacodynamic results with talquetamab and daratumumab in the TRIMM-2 study, and talquetamab 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 monoclonal antibody (anti-CD38 monoclonal antibody 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 (talquetamab + daratumumab), and June 20, 2023 (talquetamab 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 Talquetamab 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: Peripheral CD+3 T cells in Patients Treated with Talquetamab + Daratumumab and Talquetamab 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: Clonal Expansion Data in Patients from C1D1 to C3D1.

T-cell Activation with Talquetamab 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 Talquetamab + Daratumumab

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

Effect on NK cells and B cells with Talquetamab and Daratumumab

• Sustained reduction in NK cells was observed after administration of talquetamab + daratumumab (consistent with observed effects of daratumumab) but was not observed after talquetamab administration.
• There was no change observed in total CD19+ B cells following treatment with talquetamab + daratumumab or with talquetamab monotherapy, consistent with the Bcell sparing MOA of the combination. See Figure: B cells in Patients Treated with Talquetamab + Daratumumab and Talquetamab 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 15 January 2025.