SUMMARY

• Janssen does not recommend any practices, procedures or practice guidelines that deviate from the product labeling or are not approved the by regulatory agencies.
• MajesTEC-1 (MMY1001) is an ongoing, phase 1/2, multicohort study evaluating the safety and efficacy of TECVAYLI in patients with relapsed or refractory multiple myeloma (RRMM).^1,2 
  • Cohort A (triple-class exposed) included 165 patients with RRMM who were triple-class exposed to a proteasome inhibitor (PI), an immunomodulatory drug and an anti-CD38 monoclonal antibody.¹ 
  • Cohort C included 40 patients with RRMM, previously treated with a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. All patients enrolled in Cohort C had prior exposure to B-cell maturation (BCMA)-targeted therapies. Janssen does not recommend the use of TECVAYLI in a manner inconsistent with the approved labeling.²
• Willemin et al (2024)³ conducted a physiologically based pharmacokinetic (PBPK) analysis to evaluate potential drug-drug interactions due to cytochrome P450 (CYP450) enzyme inhibition by cytokine interleukin-6 (IL-6) in patients administered TECVAYLI at the recommended phase 2 dose (RP2D) in the MajesTEC-1 study.
  • The PBPK model suggested the risk of a drug-drug interaction was highest during step-up dosing up until about 7 days after the first treatment dose, and during/after CRS.
  • At high IL-6 levels, a modest CYP450 inhibition for omeprazole and simvastatin, weak inhibition for midazolam and cyclosporine, and minimal inhibition for caffeine and s-warfarin was observed.

CLINICAL DATA - MAJESTEC-1 STUDY

MajesTEC-1 (MMY1001; clinicaltrials.gov identifiers: NCT03145181; NCT04557098) is evaluating the safety and efficacy results of TECVAYLI in patients with RRMM after ≥3 prior lines of therapy, including triple-class exposure to a PI, an immunomodulatory drug and an anti-CD38 monoclonal antibody.^1,2

Study Design/Methods

The main objectives are as follows: Part 1 (dose escalation) to determine the recommended phase 2 dose (RP2D) for TECVAYLI; Part 2 (dose expansion) to distinguish safety and tolerability of TECVAYLI at the RP2D; Part 3 (the phase 2 component) to evaluate the efficacy of TECVAYLI at the RP2D.^1,2

• Key eligibility criteria for Cohort A (triple-class exposed): measurable multiple myeloma, RRMM, ≥3 prior lines of treatment including a PI, an immunomodulatory drug, and anti-CD38 monoclonal antibody, no prior B-cell maturation antigen (BCMA)-targeted therapy use.¹
• Key eligibility criteria for Cohort C: ≥3 prior lines of therapy, prior PI, immunomodulatory drug, and anti-CD38 antibody, enrolled patients who had prior exposure to BCMA-targeted treatment (chimeric antigen receptor [CAR]-T cell and/or antibody drug conjugate [ADC]).²
• Dosing: week 1: step-up doses of TECVAYLI (0.06 mg/kg and 0.3mg/kg subcutaneously [SC]). The step-up doses were administered 2-4 days apart and completed 2-4 days prior to the 1^st full treatment dose of TECVAYLI (1.5 mg/kg SC). Cycle 1+: TECVAYLI 1.5mg/kg SC weekly until progressive disease, unacceptable toxicity, death or the end of study.^1,2
• Primary endpoint: overall response rate.^1,2

MajesTEC-1 Study Protocol - Key Prohibited Medications Related to Drug Interactions

The following medications were prohibited during the study:

• Cytochrome P450 substrates with a narrow therapeutic index should have been used with caution during a CRS event and from the start of step-up doses to 7 days after the first treatment dose of TECVAYLI was administered.⁴
• For patients who received warfarin (or other vitamin K antagonists), investigators should have considered switching from warfarin (or other vitamin K antagonists) to a different anticoagulant. For patients who could not be switched to a different anticoagulant and who experienced CRS, coagulation parameters should have been monitored closely during a CRS event and until CRS symptoms resolved.⁴

physiologically based pharmacokinetic model - Majestec-1 STUDY

Willemin et al (2024)³ applied PBPK modelling and simulations to analyze drug-drug interactions between TECVAYLI and other drugs that were substrates of CYP450.

Methods

• A literature-based PBPK model was developed using observed IL-6 plasma concentrations (C_max). Prospective simulations were performed using observed IL-6 data from 112 patients administered TECVAYLI at the RP2D in the MajesTEC-1 study either without or prior to administration of tocilizumab (an anti-IL-6 agent).
• The exposure of substrates of CYP450 enzymes were predicted for 2 IL-6 kinetic profiles by the model: one with a mean IL-6 concentration per time event up to cycle 1 day 15 with mean Cmax=21 pg/mL, and the second with the highest individual observed concentration of IL-6 (288 pg/mL) among all patients occurring during cycle 1 before administration of any tocilizumab. Simulations for both scenarios included 10 trials of 75 subjects (aged 20-50 years, 50% female).
• The following CYP450 substrates were evaluated for the potential of drug-drug interactions:
  • CYP1A2: caffeine
  • CYP2C9: s-warfarin
  • CYP2C19: omeprazole
  • CYP3A4/CYP3A5: midazolam and cyclosporine
  • CYP3A4: simvastatin
• Additionally, the time to reach maximum change in CYP450 activity (due to IL-6) and return to 80% of baseline enzymatic activity was estimated, with the start of step-up dosing in cycle 1 as the reference. A cut-off of 80% was chosen, since the impact on exposures was considered low.

Results

PBPK Model Verification

• The model captured the peak and steady state (50 pg/mL) plasma concentrations of IL-6. Drug-drug interactions of substrates were calculated at 50 pg/mL of IL-6 using data derived from literature. The predicted Cmax and AUC ratios for each of CYP substrates that were studied met the predefined success criteria.

PBPK Model Application to TECVAYLI RP2D

• Of the 112 patients who experienced CRS after administration of TECVAYLI at RP2D, the mean IL-6 C_max was 21 pg/mL, with a highest IL-6 C_max of 288 pg/mL before any administration of tocilizumab.
• Predicted exposures of CYP450 substrates at mean and maximum IL-6 levels are presented in the table: Simulated Change in CYP450 Substrate Exposure After Single Dose Administration of CYP450 Substrate in Presence of IL-6 Kinetics in MajesTEC-1.
  • Using scenario 1 with the mean C_max of 21 pg/mL, the model predicted limited changes in exposure for caffeine, s-warfarin, omeprazole, midazolam, cyclosporine, and simvastatin (mean area under the curve [AUC] ratio, 0.87-1.20) at the IL-6 C_max of 21 pg/mL.
  • Using scenario 2 with the highest IL-6 C_max of 288 pg/mL, the impact on exposure was predicted to be moderate for omeprazole and simvastatin (mean AUC ratio= 2.23 and 2.09 respectively), weak for midazolam and cyclosporine (mean AUC ratio=1.90), and minimal for caffeine and s-warfarin (mean AUC ratio=0.82 and 1.25, respectively).
• Predicted enzyme activity for 2 IL-6 kinetic profiles are shown in the Table: Predicted Enzyme Activity for Two IL-6 Kinetic Profiles in MajesTEC-1 and Corresponding Time with Start of Cycle 1.
  • Using scenario 1 (mean IL-6 profile), the highest maximum level of CYP activity was for caffeine (CYP1A2) at 118%, and the lowest was for omeprazole (CYP2C19) at 87%. After the start of cycle 1, the maximum difference was seen at 65-82 hours (3 days).
  • Using scenario 2 (highest IL-6 profile), the highest maximum was for caffeine (CYP1A2) at 128% and the lowest was for omeprazole (CYP2C19) at 56%. After the start of cycle 1, the maximum difference was seen at 75-105 hours (3-4 days).
• In the profile with the highest IL-6 C_max (288 pg/mL) CYP450 activity returned to 80% of the baseline enzymatic activity approximately 7-8 days after the start of cycle 1.

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 07 January 2025.