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.
• MajesTEC-1 (MMY1001) is a 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 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, 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.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 neurotoxic events, prohibited medications, and dose interruption strategies from the MajesTEC-1 protocol related to neurotoxic events.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.^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 safety and efficacy of TECVAYLI at the RP2D.^1,3

• Key eligibility criteria for Cohort A (triple-class exposed): measurable multiple myeloma (MM), RRMM, ≥3 prior lines of treatment (LOTs), prior PI, immunomodulatory drug, and anti-CD38 monoclonal antibody, no prior BCMA-targeted therapy use.¹
• Key eligibility criteria for Cohort C: ≥3 prior LOTs, 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]).²
• Select exclusion criteria
  • 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).³
  • toxicities from previous anticancer therapies that have not resolved to baseline levels or to grade 1 or less except for alopecia or peripheral neuropathy.³
  • known active central nervous system (CNS) involvement or exhibit clinical signs of meningeal involvement of multiple myeloma.³
  • any serious underlying medical conditions such as:
    • evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection.³
    • 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.³
    • psychiatric conditions (eg, alcohol or drug abuse), dementia, or altered mental status.³
    • stroke or seizure within 6 months.³
• Primary endpoint: overall response rate.^1,2
• Key secondary endpoint: 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.^1,2
• Dosing: week 1: step-up doses (SUDs) of TECVAYLI (0.06 mg/kg, and 0.3 mg/kg  subcutaneously [SC]). The SUDs 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 SUD, and 1st full treatment dose of TECVAYLI.³

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

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

• Based on the specific mode-of-action of TECVAYLI, severe or serious neurological toxicities (including immune effector cell-associated neurotoxicity syndrome [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 computed tomography (CT)/ magnetic resonance imaging (MRI). If these or other neurological toxicities were observed, the sponsor medical monitor must have been consulted.³
• 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.³
• Neurological treatment-emergent adverse events that were not assessed as ICANS should have been managed by per institutional guidelines.³
• 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.³
• Per protocol: Hospitalization requirements were defined as:
  • Patients who experienced neurotoxicity grade ≥3 (ie, ICANS, symptoms of ICANS, and non-ICANS neurotoxicity) must be hospitalized for at least the next subsequent treatment dose 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.⁴ 
• 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.³
  • 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.³
  • Events of neurotoxicity of any grade for patients in part 3 were to be followed until recovery or until there was no further improvement.³

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 follows:

• Elevate head of patient’s bed to an angle of 30 degrees.³
• If patient has ommaya reservoir, drain cerebrospinal fluid (CSF) to target opening pressure of <20 mm Hg.³
• Hyperventilation to achieve target partial pressure of carbon dioxide (PaCO₂) of 28 to 30 mm Hg but maintained for no longer than 24 hours.³
• Consider neurology and/or neurosurgery consultation.³
• Use high-dose corticosteroids with methylprednisolone IV 1 g/day, as recommended above.³
• Hyperosmolar therapy with either mannitol (20 g/dL solution) or hypertonic saline (3% or 23.4%, as detailed below):³
  • 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 ≥40.³
  • 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.³
  • For patients with imminent herniation: initial 30 ml of 23.4% hypertonic saline; repeat after 15 min, if needed.³
• Consider IV anesthetics for burst-suppression pattern on electroencephalography.³

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

• 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).³
• Other immunosuppressant agents unless used as protocol-specified pre- or posttreatment medications to treat an adverse event (eg, CRS).³

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.⁴ 
• Select criteria for a dose interruption in parts 1, 2, and 3 related to neurotoxicity were:
  • Any grade ICANS.⁴
  • Grade 1 (except headache not related to ICANS), grade 2, or grade 3 neurotoxicity.⁴
• Per protocol, ICANS 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.⁴
  • For non-ICANS neurotoxicity, symptoms should improve to at least grade 1 or if highest grade is 1, must be stabilized and the sponsor should be consulted.⁴

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) topic was conducted on 10 March 2025.