SUMMARY

• Janssen does not recommend any practices, procedures or practice guidelines that deviate from the product labeling or are not approved by the regulatory agencies.
• The information contained within this letter is limited to management recommendations from the MajesTEC-1 study protocol.
• Additional management recommendations may be available in local/institutional guidelines. Clinicians should use clinical judgement based on local/institutional guidelines, standard of care, and individual patient risk/benefit assessment when considering use of TECVAYLI.
• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• 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
• In the MajesTEC-1 study protocol, patients were immediately hospitalized for evaluation at first sign of cytokine release syndrome (CRS; such as fever).²
• Per protocol: Dose interruption was the primary method for managing adverse events in the MajesTEC-1 study. Please see below for a summary of management and prevention of CRS, dose interruption, and prohibited medications strategies from the MajesTEC-1 protocol related to CRS.^2,3

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.^1,4

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 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 MM, RRMM, ≥3 prior lines of treatment, prior PI, immunomodulatory drug, and anti-CD38 monoclonal antibody, no prior BCMA-targeted therapy use.¹
• Key eligibility criteria for Cohort C: ≥3 prior lines of therapy, prior PI, immunomodulatory drug, and anti-CD38 monoclonal antibody, enrolled patients who had prior exposure to BCMA-targeted treatment (chimeric antigen receptor [CAR]-T cell and/or antibody drug conjugate [ADC]).⁴
• Primary endpoint: overall response rate.^1,4
• Key secondary endpoints: duration of response, very good partial response or better, complete response or better, stringent complete response, time to response, minimal residual disease status, progression-free survival, overall survival, safety, pharmacokinetics, immunogenicity, and patient-reported outcomes.^1,4
• Dosing: week 1: step-up doses of TECVAYLI (0.06 mg/kg, and 0.3 mg/kg  subcutaneously [SC]). The step-up doses were administered 2-4 days apart and completed 2-4 days prior to the 1st full treatment dose of TECVAYLI (1.5 mg/kg SC). Cycles 1+: TECVAYLI 1.5 mg/kg SC weekly until progressive disease, unacceptable toxicity, death, or the end of study.¹
• Premedications: dexamethasone, acetaminophen, and diphenhydramine were required to be administered for each step-up dose, and 1st full treatment dose of TECVAYLI.²
• Hospitalization for at least 48 hours from the start of injection was required for all patients as follows:
  • For each step-up dose and the 1^st full treatment dose of TECVAYLI.^2,5
  • For 1 dose following prior Grade 2 CRS and limited Grade 3 CRS (defined as: resolves to baseline or improves to Grade ≤1 in 48 hours) during the preceding dose.²

MajesTEC-1 Study Protocol Part 3 - Management and Prevention of CRS

• As the specific mode-of-action of TECVAYLI is based on the binding and activation of T cells and the release of cytokines in the tumor environment, adverse events of CRS should be anticipated.²
• At first sign of CRS (such as fever) patients should be immediately hospitalized for evaluation.²
• To reduce the risk of CRS, study patients received step-up doses of TECVAYLI. Per protocol, patients also received premedications (glucocorticoid, antihistamine, and antipyretic) prior to each step-up dose and the first treatment dose of TECVAYLI.²
• Clinical symptoms indicative of CRS may have included but were not limited to fever (with or without rigors), arthralgia, nausea, vomiting, tachycardia, hypotension, headache, confusion, tremor, and delirium.²
• Potentially life-threatening complications of CRS may have included cardiac dysfunction, adult respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).²
• Patients were closely monitored for early signs and symptoms indicative of CRS.
• Patients were monitored before and after the administration of TECVAYLI and as clinically indicated. Monitoring included vital signs (including temperature) and oxygen saturation.²
• Laboratory testing for coagulation was conducted at screening, and as clinically indicated (including at CRS onset and then as clinically indicated) in Part 3 to monitor for DIC, a manifestation of CRS.²
• Trained clinical personnel were prepared to intervene in the event of CRS. Resources necessary for resuscitation (ie, agents such as epinephrine and aerosolized bronchodilator; medical equipment such as oxygen, tracheostomy equipment, and a defibrillator) were made readily available. Vital signs and laboratory parameters were monitored at regular intervals until normalized.²
• In the MajesTEC-1 study Part 3, CRS and CRS symptoms were captured as an adverse event of special interest and graded per the American Society for Transplantation and Cellular Therapy (ASTCT) grading system.²
• Recommendations for the clinical management of CRS were provided in the published protocol (see Table: MajesTEC-1 Study Protocol: Guidelines for the Management of CRS) and were symptom-driven.²³ 
• Per protocol: Hospitalization requirement was defined as:
  • If a patient developed limited grade 3 CRS (defined as: resolved to baseline or improved to grade ≤1 in 48 hours), then the 1^st subsequent dose required hospitalization for at least 48 hours from the start of injection.²

MajesTEC-1 Study Protocol (Parts 1, 2, and 3) - Dose Interruption

• Dose interruption was the primary method for the management adverse events. Schedule changes to less frequent dosing could be used for management of recurrent/persistent adverse events with sponsor approval.³ 
• Select criteria for a dose interruption in Parts 1, 2, and 3 related to CRS were:
  • Any Grade CRS.³
• Per protocol, CRS (fever, hypoxia, and hypotension) must have fully resolved (ie, end date reported) before the next administration of TECVAYLI and the following criteria must have been met:
  • Minimum of 12 hours since last fever without use of antipyretics.²
  • Minimum of 24 hours since last administration of tocilizumab or equivalent (ex. siltuximab, anakinra) for the treatment of CRS.³ 

MajesTEC-1 Study Protocol Part 3 - Discontinuation Related to CRS

• A patient’s study treatment was discontinued if the patient presented with Grade 3 or 4 CRS (exception: first occurrence of limited Grade 3 CRS [eg, recovery to baseline or Grade ≤1 in less than 48 hours]).²

MajesTEC-1 Study Protocol - Key Prohibited Medications Related to CRS

• Corticosteroids in excess of 10 mg daily of prednisone or equivalent was prohibited other than for the management of adverse events where no other treatment options were available and when consulted with the sponsor. Dexamethasone should not have been administered as a pretreatment medication after Cycle 1 Day 1, except for patients who experienced Grade ≥2 CRS.²
• Other immunosuppressant agents unless used as protocol-specified pre- or posttreatment medications to treat an adverse event (eg, CRS).²
• 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 up to 7 days after the first treatment dose of TECVAYLI was administered.³
• 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.³
• Growth factor support should have been avoided during step-up doses, first treatment dose, and during CRS.²

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 02 January 2025.