SUMMARY  

• Janssen does not recommend the use of TECVAYLI in a manner inconsistent with the approved labeling.
• Additional management recommendations may be available in local/institutional guidelines. Clinicians should use clinical judgement based on local/institutional guidelines, standards of care, and individual patient risk/benefit assessment when considering use of TECVAYLI.
• MajesTEC-1 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
• Per protocol: Dose interruption was the primary method for managing adverse events in the MajesTEC-1 study. Please see below for a summary of prohibited medications, prophylaxis, mitigation, management and dose interruption strategies from the MajesTEC-1 protocol related to infections.^5,6 
• Nooka et al (2023)⁷ published the incidence, timing and management of infections in patients receiving TECVAYLI in the MajesTEC-1 study.

CLINICAL DATA - majestec-1 STUDY

MajesTEC-1 (NCT03145181, NCT04557098) is evaluating the safety and efficacy of TECVAYLI in patients with RRMM.^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 the RP2D; Part 3 (the phase 2 component) to evaluate the efficacy of TECVAYLI at the RP2D.^1,5

• Key eligibility criteria:
  • Cohort A (N=165): ≥3 prior lines of therapy (LOTs), including a proteasome inhibitor (PI), an immunomodulatory drug, and an anti-CD38 monoclonal antibody (mAb); no prior B-cell maturation antigen (BCMA)-targeted therapy use.^1,3
  • Cohort C (N=40): ≥3 prior LOTs including a prior PI, an immunomodulatory drug, and an anti-CD38 mAb, enrolled patients who had prior exposure to BCMA-targeted treatment (chimeric antigen receptor [CAR]-T cell therapy and/or antibody drug conjugate [ADC]).⁴
• Select exclusion criteria:
  • any serious underlying medical conditions such as evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection.⁵
  • live attenuated vaccine within 4 weeks prior to the 1^st dose of TECVAYLI.⁵
  • toxicities from previous anticancer therapies that have not resolved to baseline levels or to Grade ≤1 except for alopecia or peripheral neuropathy.⁵
  • received a cumulative dose of corticosteroids equivalent to ≥140 mg of prednisone within the 14-day period before the 1^st dose of TECVAYLI (does not include pretreatment medication).⁵
  • known active central nervous system (CNS) involvement or exhibit clinical signs of meningeal involvement of multiple myeloma.⁵
  • known to be seropositive for human immunodeficiency virus (HIV) or acquired immune deficiency syndrome.⁵
  • hepatitis B infection or at risk for hepatitis B virus (HBV) reactivation as defined according to the American Society of Clinical Oncology guidelines (in the event the infection is unclear, quantitative levels are necessary to determine the infection status).⁵
  • active hepatitis C infection as measured by positive hepatitis C virus (HCV)-RNA testing. Patients with a history of HCV antibody positivity must undergo HCV-RNA testing.⁵
  • pulmonary compromise requiring supplemental oxygen use to maintain adequate oxygenation.⁵

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

The following medications were prohibited during the study:

• Vaccination with live, attenuated vaccine within 4 weeks prior to the 1^st dose of TECVAYLI during treatment, and for 30 days after the last dose of TECVAYLI unless first discussed with the sponsor. Annual inactivated influenza and inactivated severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) vaccines were allowed.⁵
• 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 should not have been administered as pretreatment medication after Cycle 1 Day 1, except for patients who experienced Grade ≥2 cytokine release syndrome or infusion-related reactions.⁵
• Nonsteroidal anti-inflammatory agents should have been avoided to minimize the risk of exacerbation of potential sub-clinical myeloma-related kidney disease.⁵
• Other immunosuppressant agents unless used as protocol-specified pre- or posttreatment medications to treat an adverse event.⁵

Majestec-1 Study Protocol - Infection Prophylaxis 

Prophylactic measures per institutional guidelines were recommended due to susceptibility of patients with multiple myeloma to infections. New data and guidelines led to more robust recommendations around immunoglobulin replacement. These included:

• Prophylactic immunoglobulin replacement should have been considered with initiation prior to first dose of TECVAYLI (eg, during screening). Alternatively, replacement therapy should have been initiated as early as possible during treatment regardless of immunoglobulin G (IgG) levels and regardless of presence of infections.⁶
• Prophylactic intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients receiving TECVAYLI treatment.⁶
  • Initiation of broad-spectrum antibiotics (eg, levofloxacin) should have been considered at study start and continued throughout the first cycle in which TECVAYLI was administered.⁶
• Pneumocystis carinii/jirovecii pneumonia prophylaxis.⁶
• Prophylaxis for herpes zoster reactivation.⁶
  • Antiviral prophylaxis should have been initiated to prevent herpes zoster reactivation within 1 week after the start of administration of TECVAYLI and continued for 3 months following TECVAYLI treatment. Acceptable antiviral therapy included acyclovir, famciclovir, and valacyclovir.⁶

MajesTEC-1 Study Protocol - Potential Risks Associated with TECVAYLI and Mitigation Strategies Related to Infections

• Infections Mitigation Strategies: frequent monitoring for the presence of infections, with the acquisition of cultures and/or implementation of empiric antibiotic therapy as appropriate, based on best clinical judgement and institutional standards. Screening was to be performed for HBV and HCV, and monitored as clinically indicated, and treatment was to be initiated as appropriate.⁵
• Progressive multifocal leukoencephalopathy (PML) Mitigation Strategies: monitoring for any new onset of or changes in preexisting neurological signs or symptoms. If PML was suspected, treatment with TECVAYLI should have been withheld and appropriate diagnostic testing should have been initiated. TECVAYLI was to be discontinued if PML was confirmed.⁶   
• Hypogammaglobulinemia Mitigation Strategies: immunoglobulin levels were monitored on and after treatment and treated according to local guidelines, including administration of immunoglobulin replacement and monitoring for infection.⁵
• Cytopenia Mitigation Strategies: frequent monitoring of hematological parameters and provide supportive care as outlined by institutional guidelines.⁵

MajesTEC-1 Study Protocol - Infection Management 

• It was recommended that empirical broad-spectrum antibiotics were commenced while performing diagnostic tests in patients with febrile neutropenia or signs/symptoms of infection per institutional guidelines.⁶ 
• Targeted antimicrobial agents were recommended depending on clinical, radiological, and microbiological findings.⁶ 
• For patients with persistent fever with undetermined cause, testing for opportunistic infections including new onset or reactivation of viral infections such as herpes viruses (eg, herpes simplex virus, varicella zoster virus, cytomegalovirus, epstein barr virus), parvovirus B19, and adenovirus should have been considered. Diagnostic imaging should have been considered as clinically indicated.⁶ 

MajesTEC-1 Study Protocol - Management of Hypogammaglobulinemia

The following guidance should have been considered for all patients:

• Prophylactic immunoglobulin replacement should have been considered with initiation prior to first dose of TECVAYLI (eg, during screening). Alternatively, replacement therapy should have been initiated as early as possible during treatment regardless of IgG levels and regardless of presence of infections.⁶ 
  • Due to the potential for reactions from immunoglobulin replacement therapy, it should have been avoided for a minimum of 48 hours after each step-up dose and after the first treatment dose of TECVAYLI, as well as during any event of cytokine release syndrome (CRS).⁶  
• If a patient was not receiving prophylactic immunoglobulin replacement therapy, it should have started as soon as hypogammaglobulinemia was identified (IgG levels <400mg/dL) regardless of active or history of infection and replacement should have been used to maintain serum IgG levels ≥400 mg/dL.⁶
  • If a patient was hypogammaglobulinemic (IgG levels <400 mg/dL) already during screening, immunoglobulin replacement therapy administration should have been considered prior to first dose of TECVAYLI or as early as possible during treatment.⁶
• Where applicable (IgG heavy-chain disease type), assessments to calculate the true IgG level should have been considered by subtracting the monoclonal component IgG from the total IgG as a pragmatic approach to determine the underlying non-paraprotein IgG level.⁶
• It was recommended to administer immunoglobulin (ie, IV immunoglobulin 0.4 g/kg) every 3 to 6 weeks. After reaching a steady-state, IgG levels should have been measured at least every 3 months on treatment and for at least 6 months following last dose of TECVAYLI and as clinically indicated.⁶

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

• Dose interruption was the primary method for management of adverse events. Schedule changes to less frequent dosing could be used for management of recurrent/persistent adverse events with sponsor approval.⁶ 
• Select criteria for a dose interruption in Parts 1, 2, and 3 related to infections were:
  • Grade 4 hematologic toxicity except lymphopenia.⁶ 
  • Grade 3 thrombocytopenia with bleeding.⁶ 
  • Febrile neutropenia⁶ 
  • Grade 3 neutropenia with infection.⁶ 
  • Grade ≥ 3 non-hematologic toxicities (including infections) that are clinically significant (ie, requiring intervention and/or associated with an adverse event) except disease-related pain, unless agreed upon after consultation with the sponsor.⁶ 
  • Grade 1 or 2 infection (not requiring intravenous [IV] antibiotics) per clinical judgement of the investigator⁶ 
  • HBV, HCV, HIV infection/reactivation.⁶ 
  • Suspicion of PML⁶ 

Nooka et al (2023)⁷ published the incidence, timing and management of infections in patients receiving TECVAYLI in the MajesTEC-1 study.

Methods

• This exploratory analysis of infections occurring in patients from MajesTEC-1 (data cutoff date January 4, 2023) included overall infections and selected categories of clinically relevant infections often observed in MM patients (including viral, COVID-19, fungal, Pneumocystis jirovecii pneumonia [PJP], respiratory and gastrointestinal [GI] infections).
• Monitoring for infections occurred frequently; infections were graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.
• TECVAYLI was delayed during febrile neutropenia, grade 3 neutropenia with infection, grade 4 neutropenia, or grade ≥3 nonhematologic toxicities requiring intervention or associated with an AE, and interrupted in patients with HBV reactivation until infection was controlled.
• Prophylaxis and management of infections were conducted per local institutional guidance and investigator discretion.

MajesTEC-1 Study - Preliminary Recommendations for Infections, Neutropenia and Hypogammaglobulinemia

• Preliminary recommendations for the screening, monitoring, prophylaxis, and management of infections and infections-related adverse events during the MajesTEC-1 study are described in the table: MajesTEC-1 Study: Preliminary Recommendations for Screening, Prophylaxis, Management and Monitoring of Infections, Neutropenia, and Hypogammaglobulinemia.

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 09 April 2025.