SUMMARY

• 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.
• Routine pharmacovigilance surveillance activities in Johnson and Johnson (J&J) are in place to detect safety signals, both clinical and spontaneous events as a standard part of our processes. Confirmed signals are communicated as appropriate with health authorities and investigators/healthcare professionals (HCPs) in a timely manner.
• Cardiovascular adverse events (CVAEs) have been reported in the MajesTEC-1 study.^1,2
• MajesTEC-1 (MMY1001) is a phase 1/2, multicohort study evaluating the efficacy and safety of TECVAYLI in patients with relapsed/refractory multiple myeloma (RRMM).^3-5
  • Cohort A (triple-class exposed) included 165 patients with RRMM who were previously treated with a proteasome inhibitor (PI), an immunomodulatory agent, and an anti-CD38 monoclonal antibody.⁴
    • Details on cardiovascular treatment-emergent adverse events (TEAEs) are presented in the table: MajesTEC-1 Study (Cohort A): Incidence of Cardiovascular TEAEs.¹
  • Cohort C included 40 patients with RRMM, previously treated with a PI, an immunomodulatory agent, an anti-CD38 monoclonal antibody and anti-B-cell maturation antigen (BCMA)-targeted therapies.^3,6 Janssen does not recommend the use of TECVAYLI in a manner inconsistent with the approved labeling.
    • Details on cardiovascular TEAEs are presented in the table: MajesTEC-1 Study (Cohort C): Incidence of Cardiovascular TEAEs.²
• Sayed et al (2024)⁷ published a postmarketing surveillance study that reported the frequency and association of CVAEs with bispecific T-cell engagers (BTEs), their prognostic implications on patients receiving BTEs, and the extent of their overlap with cytokine release syndrome (CRS). TECVAYLI was associated with fatal CVAEs (reporting overall response [ROR], 2.44; 95% confidence interval [CI], 1.653.60) as well as with a disproportionate risk of myocarditis (ROR, 25.70; 95% CI, 9.54-69.23) and shock (ROR, 3.63; 95% CI, 2.30-5.74).
• Stepanovic et al (2023)⁸ presented results from a single-center, retrospective study that evaluated real-world treatment outcomes in patients with RRMM who received TECVAYLI. One unexplained sudden cardiac death was reported.

PRODUCT LABELING

Cardiac and vascular AEs are reported within the United States Prescribing Information for TECVAYLI.⁹

clinical data - majestec-1 study

MajesTEC-1 (MMY1001; clinicaltrials.gov identifiers: NCT03145181; NCT04557098) is evaluating the safety and efficacy of TECVAYLI in patients with RRMM.^4,6,10,11

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 at the RP2D; and Part 3 (phase 2 component), to evaluate the efficacy of TECVAYLI at the RP2D.^4,12
• Key eligibility criteria:
  • Cohort A: ≥3 prior lines of therapy, including a PI, an immunomodulatory drug, and an anti-CD38 mAb, and no prior BCMA-targeted therapy use.⁴
  • Cohort C: ≥3 prior lines of therapy, a prior PI, an immunomodulatory drug, and an 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]).⁶
• Primary endpoint for Cohort A and Cohort C: overall response rate (ORR).^4,6
• Key secondary endpoint for Cohort A and Cohort C: safety.^4,6

Cohort A

Results

Treatment Disposition, Baseline Demographics, and Disease Characteristics

• A total of 165 patients were enrolled in the RP2D cohort; 40 patients were enrolled in phase 1 and 125 patients were enrolled in phase 2. At a median follow-up of 30.4 months, 65 patients had transitioned to less frequent dosing (e.g., every other week [Q2W]). At the data cutoff of August 22, 2023, 38 patients remained on treatment (37 remained on less frequent dosing schedule).^4,13

Safety

• Cardiovascular TEAEs reported at a median follow-up of 30.4 months (range, 0.3 - 41.5), are shown in Table: MajesTEC-1 Study (Cohort A): Incidence of Cardiovascular TEAEs.¹

Cohort C

Results

Treatment Disposition, Baseline Demographics, and Disease Characteristics

• At a median follow-up of 28.0 months (range, 0.7-31.1), 40 patients had received TECVAYLI with a median duration of treatment of 6.0 months (range, 0.2-29.8).³
• All patients in Cohort C were triple-class exposed (PI, immunomodulatory drug, anti-CD38 monoclonal antibody). All patients were exposed to BCMA-targeted treatment (72.5% of patients [n=29] were exposed to ADC therapy and 37.5% of patients [n=15] were exposed to CAR-T therapy). There were 4 patients who previously received both BCMA-targeted therapies.⁶
• At baseline, patients received a median of 6 prior lines of therapy (range, 3-14), 85.0% of patients (n=34) were refractory to the last line of therapy, 85.0% of patients (n=34) were triple-class refractory and 35.0% of patients (n=14) were penta-drug refractory.³

Safety

• Cardiovascular TEAEs reported at a median follow-up of 28.0 months (range, 0.7 – 31.1) are shown in Table: MajesTEC-1 Study (Cohort C): Incidence of Cardiovascular TEAEs.²

REAL-WORLD studies

Sayed et al (2024)⁷ published a postmarketing surveillance study that reported the frequency and association of CVAEs with BTEs, their prognostic implications on patients receiving BTEs, and the extent of their overlap with CRS.

Study Design/Methods

• Adverse event (AE) reports between October 2014 and September 2023 from the United States Food and Drug Administration’s Adverse Event Reporting System (FAERS) were included in this analysis.
• The 5 BTE products included in this analysis were blinatumomab, TECVAYLI, mosunetuzumab, glofitamab, and epcoritamab.
• CVAEs of interest (bleeding, hypotension or shock, thromboembolic disease [including overall thromboembolic events, arterial and venous thromboembolic events, and disseminated intravascular coagulation [DIC]], coronary disease, myocardial infarction, heart failure, conduction abnormalities [including tachyarrhythmia, bradycardia, QT prolongation, and premature contractions], myocarditis, pericardial disease [including both pericardial effusion and pericarditis], vasculitis, and sudden death) corresponding to each case were coded using the Medical Dictionary for Regulatory Activities (MedDRA).
• Association between different CVAEs and BTE was assessed using multivariable logistic regression models with CVAEs as the dependent variable to yield adjusted ROR (aROR).
• Time to onset of CVAEs (vs non-CVAEs) and the time to onset of specific CVAEs was assessed using graphical displays of the empirical cumulative distribution function of each AE.
• Statistical significance was assessed using the Wilcoxon two-sample test.

Results

• A total of 1,437,817 FAERS cases were included in this analysis.
  • Of these, 3668 cases of BTE-related AEs were reported, of which 409 (11.2%) were listed with TECVAYLI as the primary suspected drug.
• Of the 3668 cases, 747 (20.4%) were CVAE related; 65 were reported with TECVAYLI.
• The median age of patients was 52.0 years (interquartile range, 41.0 years), and 44.4% of BTE recipients were female. Most reports came from the United States (43.2%).

Safety

• The association between CVAEs and TECVAYLI is presented in Table: Association Between CVAEs and the Use of TECVAYLI.

Frequency and associations of CVAEs reported with BTE

• A total of 3668 cases of BTE-related AEs were reported, of which 747 (20.4%) involved a CVAE.
• The median time to onset of CVAEs vs non-CVAEs following BTE therapy was 6 days vs 17 days (P<0.001).
• CVAEs were associated with a significantly higher risk of mortality compared with non-CVAEs (30.1% vs 16.8%; P<0.001).
  • CVAEs were associated with significantly higher mortality rates compared with non-CVAEs (RR, 1.76; 95% CI, 1.54-2.03).
  • The CVAEs with the highest mortality rates were myocarditis (50%), shock (57.7%), heart failure (44.2%), DIC (42.4%), and bleeding (40.9%).
• A total of 16.7% of CVAEs and 18.7% of fatal-CVAEs overlapped with CRS, respectively.

Limitations

The limitations to this study were as follows:

• The FAERS database included only reports of BTE-associated AEs from users who experienced them, not all BTE users, which precludes determination of the risk of incident CVAEs.
• The decision to report CVAEs was at the discretion of treating clinicians, potentially introducing reporting bias.
• Users of FAERS might have been incentivized to submit reports of serious AEs, which could inflate the fatality rates of AEs submitted to FAERS.
• Because BTEs have been approved relatively recently, there is a need for more (larger) pharmacovigilance analyses as more data accumulates, especially for newer BTE products, which have limited available data.
• The diagnostic criteria for the reported AEs could not be ascertained, which is particularly important for diagnoses such as myocarditis, where in-depth verification would have been helpful.
• The presence of comorbidities was inferred through the use of medications with a recorded cardiovascular indication, which might’ve underestimated the proportion of cardiovascular comorbidities and the proportion of fatal CVAEs occurring in patients with cardiovascular comorbidities.
• Causality cannot be inferred from the analyses, and confirmation of the causal nature of these signals would require further corroboration by independent sources of data as well as possibly mechanistic insight into BTE-related toxicity.

Stepanovic et al (2023)⁸ presented results from a single-center, retrospective study that evaluated real-world treatment outcomes in patients with RRMM who received TECVAYLI at Indiana University.

Study Design/Methods

• Patients who received TECVAYLI per standard of care dosing and schedule between October 25, 2022, and July 1, 2023 were included in this study.
• Patients were hospitalized during TECVAYLI step-up dosing.
• Response was assessed after each cycle based on the International Myeloma Working Group (IMWG) Uniform Response Criteria.
• AEs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.

Results

Patient Characteristics

• A total of 33 patients (median age, 75 years [range, 39-85]), who received 5 (range, 2-21) median prior lines of therapy were included in this study.

Safety

• Within a median follow-up duration of 17.6 weeks, 1 unexplained sudden cardiac death was reported.

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 19 November 2024.