SUMMARY

• MonumenTAL-1 (MMY1001) is an ongoing, open-label, 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
  • Schinke et al (2023)¹ presented (at the American Society of Clinical Oncology [ASCO] Annual Meeting) the updated efficacy and safety results from the MonumenTAL-1 study at a median follow-up of 18.8 months for the 0.4 mg/kg subcutaneous (SC) weekly (QW) cohort, 12.7 months for the 0.8 mg/kg SC once every other week (Q2W) cohort, and 14.8 months for the prior T-cell redirection therapy (TCR)-exposed cohort.
  • Jakubowiak et al (2023)⁴ presented (at the 65th American Society of Hematology [ASH] Annual Meeting) the updated efficacy and safety results in patients with prior TCR, including an additional 19 patients enrolled in the MonumenTAL-1 study since the prior analysis. A total of 70 patients with prior TCR were enrolled; 67 patients (95.7%) were exposed to B-cell maturation antigen (BCMA)-targeting TCR.
  • Chari et al (2023)⁵ presented (at the 65th ASH Annual Meeting) efficacy and safety results in patients from MonumenTAL-1 who switched to reduced or less frequent dosing with TALVEY at a data cutoff of October 11, 2023, in the responsive dose intensity reduction cohorts (n=50) and October 2, 2023, in the prospective dose intensity reduction cohort (n=19).
  • Rodriguez-Otero et al (2023)⁶ presented (at the ASCO Annual Meeting) data on the infection profile and immune function from the MonumenTAL-1 study after median follow-up of 18.8 months, 12.7 months, and 14.8 months in the QW, Q2W, and prior TCR cohorts.
  • Touzeau et al (2022)⁷ presented (at the 64th ASH Annual Meeting) patient-reported outcomes (PROs) of patients in the TALVEY 0.4 mg/kg SC QW cohort of the phase 2 portion of the MonumenTAL-1 study.
  • Chari et al (2022)² published safety and efficacy of TALVEY in the phase 1 portion of the MonumenTAL-1 study in patients with RRMM. Patients received intravenous (IV) TALVEY QW or Q2W ([0.5 to 180 µg/kg] at median follow-up of 4.0 months) and at the first recommended phase 2 dose (RP2D) of 405 µg/kg SC QW cohort (at median follow-up of 11.7 months) and the second RP2D of 800 µg/kg SC Q2W cohort (at median follow-up of 4.2 months). Additional IV and SC doses were evaluated in order to select the recommended phase 2 dose (RP2Ds).
• Shown below is the summary of the study design and results from part 3 of the phase-2 portion of the MonumenTAL-1 study.

CLINICAL DATA - Monumental-1 study - phase 2

MonumenTAL-1 (MMY1001; NCT03399799, NCT04634552) is a phase 1/2 study of TALVEY in patients with RRMM.^8,9

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 RP2Ds and schedule.
• Part 2 (phase 1; dose expansion): to further characterize the safety of TALVEY at the RP2Ds.
• Part 3 (phase 2): to evaluate the efficacy of TALVEY at the RP2Ds.

Study Design/Methods (Phase 2)

Patients were enrolled into 1 of the following 3 cohorts^1,4:

• TCR naive: 0.4 mg/kg SC QW (n=143), not previously exposed to TCR such as chimeric antigen receptor T-cell therapy (CAR-T) or bispecific antibodies (BsAbs; prior BCMA antibody-drug conjugate [ADC] allowed).
• TCR naive: 0.8 mg/kg SC Q2W (n=154), not previously exposed to TCRs (prior BCMA ADC allowed).
• Prior TCR: 0.4 mg/kg SC QW or 0.8 mg/kg SC Q2W (n=70), have been previously exposed to TCRs.
  • Among the prior TCR-exposed cohort (n=70), patients were divided based on type of TCR:
    • CAR-T (n=50).
      • BCMA CAR-T (n=48).
    • BsAb (n=25).
      • BCMA BsAb (n=23).
    • CAR-T and BsAb (n=5; these 5 patients were also counted in each of the respective overall CAR-T and BsAb groups).
      • BCMA CAR-T and BCMA BsAb (n=4).
• Key eligibility criteria (Part 3; Phase 2):
  • Measurable multiple myeloma (MM).⁴
  • ≥3 prior lines of therapy including a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.⁴
  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2.⁴
• Key exclusion criteria (Part 3; Phase 2):
  • Prior grade 3 or higher cytokine release syndrome (CRS; per Lee criteria 2014¹⁰) related to any TCR or any prior G protein-coupled receptor family C group 5 member D (GPRC5D)-targeting therapy.³
  • Received cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within 14 days prior to study drug (not including premedication).³
• Primary endpoint: overall response rate (ORR).¹
• Key secondary endpoints: duration of response (DOR), progression-free survival (PFS), overall survival, safety, immunogenicity and pharmacodynamics.¹
• Dosing
  • TALVEY 0.4 mg/kg SC QW and 0.8 mg/kg SC Q2W treatment dose schedule is based on a 28-day cycle.³
  • Step-up dosing for 0.4 mg/kg SC QW³:
    • Week 1: step-up doses of TALVEY (0.01 mg/kg and 0.06 mg/kg SC).
    • Cycles 1+: TALVEY 0.4 mg/kg SC QW until progressive disease or unacceptable toxicity.
  • Step-up dosing for 0.8 mg/kg SC Q2W³:
    • Week 1: step-up doses of TALVEY (0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg SC).
    • Cycles 1+: TALVEY 0.8 mg/kg SC Q2W until progressive disease or unacceptable toxicity.
  • Premedications: dexamethasone, acetaminophen, and diphenhydramine were required to be administered for each step-up dose, and for the first full treatment dose of TALVEY.³
  • Patients were required to be hospitalized for at least 48 hours from the start of the injection, for each step-up dose and the first full treatment dose of TALVEY.³

Schinke et al (2023)¹ presented the updated efficacy and safety results from the phase 2 portion of the MonumenTAL-1 study.

Results

Patient Characteristics

• Overall, 143 patients were included in the 0.4 mg/kg SC QW cohort, 145 patients in the 0.8 mg/kg SC Q2W cohort, and 51 patients in the prior TCR cohort. The baseline patient and disease characteristics are presented in Table: Baseline Patient and Disease Characteristics.¹
• The median duration of follow-up was 18.8 months for the 0.4 mg/kg SC QW cohort, 12.7 months for the 0.8 mg/kg SC Q2W cohort, and 14.8 months for the prior TCR cohort.¹

Efficacy

• At a data-cut off of January 17, 2023 in the TALVEY 0.8mg/kg Q2W cohort (n=145), ORR was 71.7%; median PFS was 14.2 months (95% CI, 9.6-NE), 12-month PFS rate was 54.4%, and median DOR was NE (95% CI, 13.0-NE).^1,5
• The treatment response and survival outcomes are summarized in Table: Efficacy Outcomes.¹
• In the prior TCR cohort, the ORR was 75.0% (27/36) in patients with prior CAR-T therapy and 44.4% (8/18) in patients with prior BsAb therapy.¹
• The ORR was consistent across prespecified subgroups based on high-risk cytogenetics, International Staging System (ISS) stage, number of prior lines of therapy, prior therapy with ADC, and refractory status, except in the subgroup of patients based on extramedullary plasmacytomas. Additional details are provided in Table: ORR Among Clinically Relevant Subgroups.¹
  • The ORR ranged between 31-49% in patients with ≥1 plasmacytoma and between 80-82% in patients without plasmacytomas.¹

Safety

• Adverse events (AEs; ≥30%, any grade) occurring in any cohort are summarized in Table: Adverse Events (≥30%).¹
• AEs leading to dose reductions and treatment discontinuations are summarized in Table: Dose Reductions and Treatment Discontinuations Due to AEs.¹
  • Five patients discontinued treatment due to skin-related AEs and dysgeusia, none discontinued due to nail-related AEs.¹
• Opportunistic infections were reported in 3.5% of patients in the 0.4 mg/kg SC QW cohort, 5.5% of patients in the 0.8 mg/kg SC Q2W cohort, and 5.9% of patients in the prior TCR cohort.¹
• Immune effector cell-associated neurotoxicity syndrome (ICANS) (graded by American Society for Transplantation and Cellular Therapy criteria) was reported (during phase 2 only) in 10.7% of patients in the 0.4 mg/kg SC QW cohort, 11.0% of patients in the 0.8 mg/kg SC Q2W cohort, and 2.9% of patients in the prior TCR cohort.¹

Immunogenicity

• Antidrug antibodies (ADAs) were reported in 34.1% of patients in the 0.4 mg/kg SC QW cohort, 35.3% in the 0.8 mg/kg SC Q2W cohort, and 19.6% in the prior TCR cohort. ADAs did not affect pharmacokinetics, safety, or efficacy.¹

Jakubowiak et al (2023)⁴ presented the updated efficacy and safety results in patients with prior TCR, including an additional 19 patients enrolled in the MonumenTAL-1 study since the prior analysis.

Study Design/Methods

• As of October 11, 2023, 70 patients with prior exposure to TCR were enrolled, of whom 8 patients were also previously exposed to BCMA ADC.

Results

Patient Characteristics

• A total of 70 patients with prior TCR were enrolled; 67 patients (95.7%) were exposed to BCMA-targeting TCR. Baseline patient characteristics of these 70 patients are presented in Table: Baseline Characteristics (Prior TCR).

Efficacy

• ORR was 72.9% and 56.5% in patients with prior BCMA CAR-T and prior BCMA BsAb respectively. Additional details on efficacy outcomes in patients with prior TCR by prior BCMA groups are presented in Table: Efficacy Outcomes by Prior BCMA Groups (Prior TCR).
• ORR trended higher in patients with <9 months between the last dose of prior BCMA CAR-T and TALVEY and in patients with ≥9 months between the last dose of prior BCMA BsAb and TALVEY. Additional details are provided in Table: ORR and 12-Month DOR Rate by Interval (Prior TCR).
• ORR by prior lines of therapy (LOT) before TALVEY is presented in Table: ORR by Prior LOT Before TALVEY (Prior TCR).

Safety

• A summary of select AEs in patients with prior TCR is presented in Table: Summary of Select AEs (Prior TCR).
  • Patients with prior exposure to CAR-T had similar rates of infections, cytopenias, CRS, and GPRC5D-related AEs (dysgeusia and skin-, nail-, and rash-related AEs) compared to patients with prior exposure to BsAb.

Chari et al (2023)⁵ presented efficacy and safety results in patients in MonumenTAL-1 who switched to reduced or less frequent dosing with TALVEY.

Study Design/Methods

• Patients were treated at the RP2Ds and reduced dose once they achieved a response.
• Patients were divided into the Responsive Dose Intensity Reduction Cohorts and the Prospective Dose Intensity Reduction Cohorts:
  • Responsive Dose Intensity Reduction Cohorts (n=50); after treatment at the RP2Ds, patients received reduced dose or less frequent dose. Patients had ≥partial response (PR), treatment emergent AE (TEAE) mitigation or both:
    • In TCR-naïve TALVEY 0.4 mg/kg QW cohort: 25 patients received a reduced dose or a less frequent dose.
    • In TCR-naïve TALVEY 0.8 mg/kg Q2W cohort: 15 patients received a reduced dose or a less frequent dose.
    • In the prior TCR TALVEY 0.4 mg/kg QW or 0.8 mg/kg Q2W cohort: 10 patients received a reduced dose or less frequent dose.
  • Prospective Dose Intensity Reduction Cohorts (n=19):
    • TALVEY 0.8 mg/kg Q2W was reduced to 0.4 mg/kg Q2W in 9 patients who had ≥PR.
    • TALVEY 0.8 mg/kg Q2W was reduced to 0.8 mg/kg Q4W in 10 patients who had ≥PR.

Results

Efficacy

• Responsive Dose Intensity Reduction Cohorts: At a data cut-off date of October 11, 2023, most patients with dose reductions were in response. Relative to treatment start, dose reduction occurred at a median of 3.2 months (range, 1.8-27.0) in the QW cohort, 4.5 months (range, 1.2-28.9) in the Q2W cohort and 4.7 months (range, 2.3-9.7) in the prior TCR cohort. Full details are provided in Table: Duration of Response (Responsive Dose Intensity Reduction Cohorts).
• Prospective Dose Intensity Reduction Cohorts: At a data cut-off of October 2, 2023, patients with dose reductions had to be in response (n=19). Relative to treatment start, dose reduction occurred at a median of 3.1 months (range, 2.3-4.2).  Full details are provided in Table: Response and Duration of Response (Prospective Dose Intensity Reduction Cohorts).

Safety

• A summary of the onset of TALVEY-associated AEs after switching at a data cut-off of October 2, 2023 is presented in Figure: Prospective Cohorts With Change in AE Status After Switch vs Matched Cohort Without Dose Reduction.

Immune Fitness in Dose-Reduced Cohorts

• As of October 2, 2023, maintenance of CD3+ T-cell recovery was comparable between dose-reduced and non-dose-reduced cohorts between Cycle 3 Day 1 and Cycle 7 Day 1 of TALVEY (12/68 patients from the RP2D group included in the analysis had dose reductions outside the Cycle 3 Day 1 and Cycle 7 Day 1 timeframe).
• Reduction in coinhibitory receptor expression in dose-reduced vs sustained expression in non-dose-reduced cohorts between Cycle 3 and Cycle 7 of TALVEY was observed.

Rodriguez-Otero et al (2023)⁶ presented data on infections and immune function from the MonumenTAL-1 study.

Results

• A total of 339 patients were administered TALVEY. The median duration of follow-up was 18.8 months for the 0.4 mg/kg SC QW cohort, 12.7 months for the 0.8 mg/kg SC Q2W cohort, and 14.8 months for the prior TCR cohort.⁶
• Any-grade infections were reported in 64.0% of patients, of which 18.6% were grade 3/4. In total, 1.5% of infections led to death. See Table: Summary of Infections.⁶
• Hypogammaglobulinemia or postbaseline immunoglobulin G (IgG) <500 mg/dL was reported in 64.3% of patients in the 0.4 mg/kg SC QW cohort, 67.6% in the 0.8 mg/kg SC Q2W cohort, and 72.5% in the prior TCR cohort.⁶
  • IV immunoglobulin was administered to 14.7%, 13.1%, and 15.7% of patients in the QW, Q2W and prior TCR cohorts, respectively.⁶
• New-onset grade 3/4 infections were most prevalent during the first 100 days in all 3 cohorts. Across clinically relevant infections, the most common infections were respiratory infections or coronavirus Disease 2019 (COVID-19; COVID-19 infections were irrespective of causal relation to TALVEY).⁶
• Neutrophil counts decreased during cycle 1 but recovered steadily from cycle 2.
• No reduction in the levels of CD19 B cells was observed over time, with an increasing trend noted at cycle 7.⁶
• No decrease in polyclonal IgG over time was reported across cohorts.⁶

Touzeau et al (2022)⁷ presented PRO assessment of patients in the phase 2 portion of the MonumenTAL-1 study.

Study Design/Methods

• Included all patients who received 0.4 mg/kg of TALVEY SC QW in the phase 2 portion of MonumenTAL-1.⁷
• PROs were assessed using the following questionnaires⁷:
  • European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 item (EORTC QLQ-C30):
    • Includes a subscale to measure health-related quality of life, 5 functional scales, 3 symptom subscales and 6 additional single items.
  • EuroQol 5-dimensional descriptive system (EQ-5D-5L):
    • EQ-5D-5L measures health status by assessing 5 domains.
    • Includes a visual analog scale (VAS) to rate patient health from worst imaginable health to best imaginable health.
• PROs assessments were evaluated at screening, cycle 1, and then every other cycle.⁷
• Compliance rate to the PROs was calculated based on the number of completed assessments divided by the number of patients on study treatment at each assessment time point.⁷
• EORTC QLQ-C30 and EQ-5D-5L scores range from 0 to 100. A higher score indicates better global health scale (GHS) and functioning and greater symptom severity.⁷
• The threshold for meaningful improvement from baseline was defined as a change of ≥10 points.⁷

Results

Patient Characteristics

• A total of 122 patients were included in the PRO analysis population.⁷
• The compliance rates of survey completion for the EORTC QLQ-C30 were 96% at screening and >80% at most posttreatment visits.⁷

Patient-Reported Outcomes

• Improvements were reported in EORTC QLQ-C30 GHS, physical and role functioning compared with baseline.⁷
  • At cycle 9, improvements were reported in GHS (43% of patients), functioning (20-41% of patients), and symptoms (78-92% of patients). Further details are provided in Table: Proportion of Patients With Meaningful Improvement in Select Scales at Cycle 9.
• Improvements were reported in EQ-5D-5L VAS score (least squares mean change was 9.4 [95% CI, 3.5-15.3] at cycle 9).⁷
• Median time to improvement from baseline in the EORTC QLQ-C30 and EQ-5D-5L scores was approximately 2 months; with cognitive functioning, nausea/vomiting, pain, and social functioning in less than 1 month.⁷
• Kaplan-Meier estimates of median time to first worsening (defined as a decrease in score at least half standard deviation from baseline) on the EORTC QLQ-C30 and EQ-5D-5L subscales ranged from 2 months to approximately 9 months.⁷

literature search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 20 December 2023.