SUMMARY  

• This information is provided only in response to your unsolicited request and is not intended as medical advice or recommendation.
• Janssen does not recommend any practices, procedures or practice guidelines that deviate from the product labeling or are not approved by the regulatory guidelines.
• Clinicians should use clinical judgement based on local/guidelines, standards 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 that are 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
  • In the MajesTEC-1 study protocol, patients who experienced neurotoxicity Grade ≥2 (ie, immune effector cell-associated neurotoxicity syndrome [ICANS], symptoms of ICANS, and non-ICANS neurotoxicity) were hospitalized for at least the next 2 subsequent treatment doses. Patients who experienced recurrent Grade 3 or Grade 4 neurotoxicity events must discontinue treatment.²
• Per protocol: Dose delays were the primary method for managing adverse events in Part 3 of the MajesTEC-1 Study. Please see below for a summary of mitigation, prohibited medications, and dose delay strategies for neurotoxic events from the MajesTEC-1 protocol.²

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.^1,3

Study Design/Methods

The main objectives are as follows: Part 1 (dose escalation) to determine the 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

• Cohort A (triple-class exposed) is evaluating the efficacy and safety of TECVAYLI in 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 is evaluating the efficacy and safety of TECVAYLI in 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 antigen (BCMA)-targeted therapies.³ Janssen does not recommend the use of TECVAYLI in a manner inconsistent with the approved labeling.
• 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]).³
• Select exclusion criteria²
  • received a cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within the 14-day period before the first dose of TECVAYLI (does not include pretreatment medication).
  • toxicities from previous anticancer therapies that have not resolved to baseline levels or to Grade 1 or less except for alopecia or peripheral neuropathy.
  • known active central nervous system (CNS) involvement or exhibit clinical signs of meningeal involvement of multiple myeloma.
  • any serious underlying medical conditions such as:
    • evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection.
    • active autoimmune disease or a documented history of autoimmune disease with the exception of vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently euthyroid based on clinical symptoms and laboratory testing.
    • psychiatric conditions (eg, alcohol or drug abuse), dementia, or altered mental status.
    • stroke or seizure within 6 months.
• Primary endpoint: phase 2: overall response rate.^1,3
• Key secondary endpoint: safety.^1,3
• Dosing¹
  • Step-up doses of TECVAYLI (0.06 mg/kg and 0.3 mg/kg SC) followed by first treatment dose of TECVAYLI 1.5 mg/kg SC.
  • Subsequent treatment doses: TECVAYLI 1.5 mg/kg SC QW until progressive disease or unacceptable toxicity.
• Pretreatment Medications: In Part 3 of the study, as per the study protocol, all patients received pretreatment medications (glucocorticoid, antihistamine, and antipyretic) prior to each step-up dose and the first treatment dose of TECVAYLI.²
• Hospitalization for at least 48 hours from the start of injection was required for all patients as follows²:
  • For each step-up dose and the first full treatment dose of TECVAYLI.
  • For two subsequent doses following Grade ≥2 neurotoxicity during the preceding dose.

MajesTEC-1 Study Part 3 - Management and Prevention of Neurotoxic Events

Per protocol, the following guidelines were to be followed for the management and prevention of neurotoxic events²:

• Based on the specific mode-of-action of TECVAYLI, severe or serious neurological toxicities (including ICANS) may occur. Patients should have been monitored for neurological toxicities including, but not restricted to, speech disorders, convulsions, and disturbances in consciousness, confusion, disorientation, or coordination and balance disorders. The investigator should have also excluded other causes of neurological symptomatology, including infarction/bleeding or infection (bacterial and neurotrophic viruses), and considered a cerebral spinal fluid analysis and CT/MRI. If these or other neurological toxicities were observed, the sponsor medical monitor must have been consulted.
• A basic neurologic examination including the immune effector cell encephalopathy (ICE) Assessment Tool was performed at baseline (within 48 hours prior to the administration of TECVAYLI) and repeated as clinically indicated after the first symptoms of ICANS were suspected until resolution.
• Neurological treatment-emergent adverse events that were not assessed as ICANS should have been managed by per institutional guidelines.
• Recommendations for the management of patients who experienced ICANS and raised intracranial pressure (ICP)/cerebral edema are provided in table: MajesTEC-1 Study Protocol: Guidelines for the Management of ICANS and in text below, MajesTEC-1 Study Protocol: Guidelines for the Management of Raised ICP/Cerebral Edema.
• Per protocol: Hospitalization requirements were defined as:
  • Patients who experienced neurotoxicity Grade ≥2 (ie, ICANS, symptoms of ICANS, and non-ICANS neurotoxicity) were to be hospitalized for at least the next 2 subsequent treatment doses for at least 48 hours from the start of injection. Patients who experienced recurrent Grade 3 or Grade 4 neurotoxicity events must have discontinued treatment.
• Per protocol: neurotoxicity (ie, ICANS, symptoms of ICANS, and non-ICANS neurotoxicity) was captured as an adverse event of special interest as follows:
  • Neurotoxicity of any Grade during Part 3 were to be followed as part of standard safety monitoring activities by the sponsor.
  • If these events were Grade ≥2, they were reported to the sponsor within 24 hours of awareness of the event irrespective of seriousness (ie, serious and nonserious adverse events) and required enhanced data collection.
  • Events of neurotoxicity of any Grade for patients in Part 3 were to be followed until recovery or until there was no further improvement.

MajesTEC-1 Study Protocol - Guidelines for the Management of Raised ICP/Cerebral Edema

In case of raised ICP/cerebral edema, guidelines for management were as follows²:

• Elevate head of patient’s bed to an angle of 30 degrees.
• If patient has ommaya reservoir, drain cerebrospinal fluid (CSF) to target opening pressure of <20 mm Hg.
• Hyperventilation to achieve target partial pressure of carbon dioxide (PaCO₂) of 28 to 30 mm Hg but maintained for no longer than 24 hours.
• Consider neurology and/or neurosurgery consultation.
• Use high-dose corticosteroids with methylprednisolone IV 1 g/day, as recommended above.
• Hyperosmolar therapy with either mannitol (20 g/dL solution) or hypertonic saline (3% or 23.4%, as detailed below):
  • Mannitol: initial dose 0.5 to 1 g/kg; maintenance at 0.25 to 1 g/kg every 6 hours while monitoring metabolic profile and serum osmolality every 6 hours and withhold mannitol if serum osmolality is ≥320 mOsm/kg, or the osmolality gap is ≥40.
  • Hypertonic saline: initial 250 mL of 3% hypertonic saline; maintenance at 50 to 75 mL/hr while monitoring electrolytes every 4 hours, and withhold infusion if serum Na levels reach ≥155 mEq/L.
  • For patients with imminent herniation: initial 30 ml of 23.4% hypertonic saline; repeat after 15 min, if needed.
• Consider IV anesthetics for burst-suppression pattern on electroencephalography.

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

Per protocol, the following medications related to neurotoxicity were prohibited²:

• 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 in consultation with the sponsor. Dexamethasone was not to be administered as a pretreatment medication after Cycle 1 Day 1, except for patients who experienced Grade ≥2 cytokine release syndrome (CRS).
• Other immunosuppressant agents unless used as protocol-specified pre- or posttreatment medications to treat an adverse event (eg, CRS).

MajesTEC-1 Study Protocol Part 3 - Dose Modification Guidance

Dose delays were the primary method for managing adverse events in Part 3 (phase 2) of the MajesTEC-1 study.²

• If a dose interruption was >28 days, treatment was to be permanently discontinued unless continuation was agreed in consultation with the sponsor after a review of safety and efficacy. Repeat of step-up dose(s) and pretreatment medication may have been required. In the event of prolonged treatment interruption, disease evaluations should have continued every 4 weeks if possible.
• Select criteria for a dose delay in Part 3 related to neurotoxicity were:
  • Grade 1, 2, and 3 neurotoxicity: treatment with TECVAYLI must have been withheld until the resolution of ICANS neurotoxicity. For non-ICANS neurotoxicity, symptoms should have improved to at least Grade 1 or if highest Grade was 1, must have been stabilized and the sponsor was to be consulted prior to resuming TECVAYLI.
  • Per protocol, CRS (fever, hypoxia and hypotension) and ICANS must have fully resolved 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.
    • Minimum of 24 hours since last administration of tocilizumab.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 10 April 2024.