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.
• Neurotoxicity, including ICANS has been reported as an adverse event (AE) in the MajesTEC-1, MajesTEC-2, MajesTEC-7, RedirecTT-1, and TRIMM-2 studies.^1-10
• 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).^1-3,9,11-13
  • 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.¹
    • At a median follow-up of 14.1 months (range, 0.3-24.4), neurotoxic events assessed by the investigator to be drug related were reported in 14.5% of patients (n=24). A grade 4 neurotoxic event was reported in 1 patient (0.6%). The median time to onset relative to the most recent dose was 3.0 days (range, 1-13). The median duration was 7.0 days (range, 1-291). Headache (8.5%) was the most frequent investigator-identified neurotoxic event. A total of 9 ICANS were reported in 5 patients (3%).^1,14
    • At a longer-term median follow-up of 30.4 months, no new ICANS events were reported. Any grade headache was reported in 40 patients (24.2%), and grade 3/4 headache was reported in 1 patient (0.6%).¹³
  • 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.^9,15 Janssen does not recommend the use of TECVAYLI in a manner inconsistent with the approved labeling.
    • At a median follow-up of follow-up of 28.0 months (range, 0.7-31.1), treatment-emergent neurotoxic events were reported in 27.5% of patients (n=11) overall. The most common neurotoxic event was headache (12.5%). ICANS events were reported in 4 patients (10%); all events were concurrent with cytokine release syndrome (CRS).⁹
  • The prophylactic tocilizumab cohort is evaluating the administration of intravenous (IV) tocilizumab (8 mg/kg) prior to TECVAYLI dosing for the reduction of CRS in 24 patients with RRMM.^3,16 Janssen does not recommend the use of TECVAYLI in a manner inconsistent with the approved labeling.
    • At a median follow-up of 8.1 months (range, 0.9-13.2), 10 events (all grade 1-2) related to neurotoxicity were reported in 5 patients. The events included headache, ICANS, myoclonus, dizziness, and insomnia. All events resolved except for grade 2 headache.¹⁶
• MajesTEC-2 (MMY1004) is an ongoing, phase 1b, multicohort study evaluating the safety and efficacy of TECVAYLI in combination with other anticancer therapies in patients with multiple myeloma (MM).^4-6,17 Janssen does not recommend the use of TECVAYLI or DARZALEX FASPRO^® (daratumumab and hyaluronidase) in a manner that is inconsistent with the approved labeling.
  • Cohort C is assessing the safety and efficacy of TECVAYLI in combination with nirogacestat in 28 patients with RRMM.⁴
    • At a median follow-up of 14.7 months (range, 0.5-22.9), 2 ICANS events occurred; one at dose level 1 (grade 3) and one at dose level 2 (grade 2).⁴
  • Cohort D is assessing the safety and efficacy of TECVAYLI in combination with lenalidomide in 31 patients with triple-class exposed MM.⁵
    • At a median follow-up of 10.8 months (range, 1.1-16.8), 2 patients (6.5%) reported grade 1 ICANS events.⁵
  • Cohort E is evaluating the safety and efficacy of the combination of TECVAYLI with DARZALEX FASPRO and lenalidomide in 32 patients.⁶
    • At a median follow-up of 8.4 months (range, 1.1-12.9), no ICANS events were reported.⁶
• MajesTEC-7 (MMY3005) is a randomized, phase 3, open-label, multicenter study comparing the efficacy and safety of TECVAYLI in combination with DARZALEX FASPRO and lenalidomide (Tec-DR) and TALVEY^® (talquetamab-tgvs) in combination with DARZALEX FASPRO and lenalidomide (Tal-DR) vs DARZALEX FASPRO in combination with lenalidomide and dexamethasone (DRd) in patients with newly diagnosed multiple myeloma (NDMM) who are ineligible or not intended for transplant as initial therapy.^8,18 Janssen does not recommend the use of TECVAYLI, TALVEY, or DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
  • Safety run-in Cohort 1 is evaluating the initial safety results of Tec-DR in 26 patients.¹⁸
    • At a median follow-up of 13.8 months (range, 2.0-15.4), 1 grade 1 ICANS event was noted in 1 patient during cycle 1, which subsequently resolved.¹⁸
• RedirecTT-1 (MMY1003) is an ongoing, open-label, phase 1b/2 study evaluating the safety, and efficacy of TALVEY and TECVAYLI combination in patients with RRMM.^10,19,20 Janssen does not recommend the use of TALVEY and TECVAYLI in a manner inconsistent with the approved labeling.
  • The TALVEY and TECVAYLI cohort is evaluating the safety and efficacy of the combination in 94 patients at all dose levels (median follow-up: 20.3 months) and 44 patients at the recommended phase 2 regimen (RP2R; median follow-up: 18.2 months [range, 0.7-27.0]), including in patients with extramedullary disease (EMD).¹⁰
    • ICANS events occurred in 3 patients (3.2%), including 1 grade 3 ICANS event; 2 events were concurrent with CRS. All ICANS events occurred during step-up dosing (SUD). All ICANS events recovered.¹⁰
• TRIMM-2 (MMY1002) is an ongoing, phase 1b, multicohort study evaluating DARZALEX FASPRO in combination with bispecific T-cell redirecting antibodies in patients with RRMM.^7,21 Janssen does not recommend the use of TECVAYLI or DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
  • The TECVAYLI + DARZALEX FASPRO cohort is evaluating the safety and efficacy of the combination in 65 patients.⁷
    • At a median follow-up of 8.6 months (range, 0.3-19.6), 1 patient had a grade 1 ICANS event during SUD that fully resolved in 1 day. Headache was reported in 20% of patients.⁷

PRODUCT LABELING

• TECVAYLI (teclistamab-cqyv) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.;  https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/TECVAYLI-pi.pdf.
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf.
• TALVEY (talquetamab-tgvs) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/TALVEY-pi.pdf.

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.^1-3,9,11-13

Study Design/Methods

• The main objectives of MajesTEC-1 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 (the phase 2 component) to evaluate the efficacy of TECVAYLI at the RP2D.^1,22
• Key eligibility criteria:
  • Cohort A: ≥3 prior lines of therapy including a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody, no prior BCMA-targeted therapy use.^1,2
  • 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]).⁹
  • Prophylactic tocilizumab cohort: ≥3 prior lines of therapy including a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.³
• Primary endpoint for Cohort A and Cohort C: overall response rate (ORR).^1,2,9
• Key secondary endpoint for Cohort A and Cohort C: safety.^1,2,9
• Endpoint for prophylactic tocilizumab cohort: incidence of CRS.³
• Safety assessments related to neurotoxicities:
  • Neurotoxicities were identified as AEs under either the ‘nervous system disorder’ or ‘psychiatric disorder’ system organ classes that were judged by the investigator to be related to TECVAYLI, including ICANS events. Grouped terms were used for aphasia, delirium, encephalopathy, and tremor.¹⁴
  • As ICANS events were graded by American Society for Transplantation and Cellular Therapy (ASTCT) criteria in phase 2, immune effector cell encephalopathy (ICE) scores were not collected for patients in phase 1. For patients treated at the RP2D in phase 1, all neurotoxicity events and any neurologic AEs that occurred within 28 days after the first dose of TECVAYLI were evaluated for consistency with ICANS.¹⁴

Results

Treatment Disposition, Baseline Demographics, and Disease Characteristics

Cohort A

• 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).^1,13

Cohort C

• 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).⁹
• 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.⁹
• 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.⁹

Prophylactic Tocilizumab Cohort

• At a median follow-up of 2.6 months (range, 0.1-7.0), 23 patients received prophylactic tocilizumab prior to the first TECVAYLI SUD.¹⁶
• At a longer median follow-up of 8.1 months (range, 0.9-13.2), 24 patients received prophylactic tocilizumab prior to the first TECVAYLI SUD.¹⁶
• Patients received a median of 4 prior lines of therapy (range, 2-9).¹⁶

Safety - Adverse Event - Neurotoxicity

Cohort A

Median Follow-up: 14.1 Months

• At a median follow-up of 14.1 months (range, 0.3-24.4), headache (any grade) was reported in 23.6% of patients (n=39) with grade 3/4 headache reported in 0.6% of patients (n=1). Headache (8.5%; n=14) was the most frequent neurotoxic event deemed by the investigator to be related to TECVAYLI. See Table: MajesTEC-1 (Cohort A): Characteristics and Management of Investigator-Identified Neurotoxic Events for additional details on events judged by the investigator to be related to TECVAYLI and supportive measures used for the neurotoxic events.^1,14
  • A total of 9 ICANS events were reported in 5 patients (3%), all either grade 1 or 2. Of these, 7 ICANS events were reported with concurrent CRS. All 9 ICANS events resolved without discontinuation or dose reduction.¹
  • One grade 4 seizure was reported in a patient with bacterial meningitis.One death (progressive multifocal leukoencephalopathy) was reported as an AE-related to TECVAYLI.¹

Median Follow-up: 30.4 Months

• At a longer median follow-up of 30.4 months, no new ICANS events were reported. Any grade headache was reported in 40 patients (24.2%), and grade 3/4 headache was reported in 1 patient (0.6%).¹³

Cohort C

• At a median follow-up of follow-up of 28.0 months (range, 0.7-31.1), treatment-emergent neurotoxic events were reported in 27.5% of patients (n=11) overall; 9 patients experienced 1 event, and 2 patients experienced 2 events. See Table: MajesTEC-1 Study (Cohort C): Characteristics and Management of Neurotoxic Events for additional details.⁹
  • The most common neurotoxic event was headache (12.5%; n=5).⁹
  • ICANS events were reported in 4 patients (10%); all events were concurrent with CRS. ICANS events were grade 1/2 in 3 patients and grade 3 in 1 patient. All ICANS events resolved.⁹
• Of 13 neurotoxicity events, 8 events (61.5%) were resolved or recovered; 1 event was recovering or resolving at data cutoff, and 4 events did not resolve (2 dysgeusia events, 1 insomnia event and 1 peripheral sensory neuropathy event).⁹
  • Two events (5.0%; ICANS and peripheral sensory neuropathy) led to TECVAYLI dose interruption, but no patients had dose reductions or treatment discontinuation.⁹

Prophylactic Tocilizumab Cohort

• At a median follow-up of 8.1 months (range, 0.9-13.2), 10 events related to neurotoxicity (defined as a neurological AE considered related by the investigator) were reported in 5 patients. The events included headache, ICANS, myoclonus, dizziness, and insomnia. All events were grade 1-2 and all events resolved except for grade 2 headache.¹⁶

CLINICAL DATA - MajestEC-2 STudy

MajesTEC-2 (MMY1004; clinicaltrials.gov identifier: NCT04722146) is an ongoing, phase 1b, multicohort study evaluating the safety and efficacy of TECVAYLI in combination with other anticancer treatments in patients with MM.^4-6,17

Study Design/Methods

Key Eligibility Criteria

• Cohort C (TECVAYLI and nirogacestat): disease progression within 12 months of last line of therapy; ≥3 prior lines of treatment or double refractory to a PI, and an immunomodulatory drug and triple-class exposed to a PI, an immunomodulatory drug and an anti-CD38 monoclonal antibody. Patients with prior exposure to BCMA-targeted therapy were permitted.^4,17
• Cohort D (TECVAYLI and lenalidomide): received ≥2 prior lines of treatment including a PI, an immunomodulatory drug and an anti-CD38 monoclonal antibody, no prior BCMA-targeted therapy.⁵
• Cohort E (TECVAYLI and DARZALEX FASPRO and lenalidomide): 1-3 prior lines of treatment including a PI, and an immunomodulatory drug, no prior BCMA-targeted therapy.⁶

Primary Endpoints

• Cohort C: safety, tolerability, and optimal doses.⁴
• Cohort D: safety.⁵
• Cohort E: safety, dose-limiting toxicities, and laboratory abnormalities.⁶

Results

Treatment Disposition, Baseline Demographics, and Disease Characteristics

Cohort C

• Patients received a median of 4 prior lines of therapy (range, 2-12), 92.9% of patients (n=26) were refractory to the last line of therapy, 71.4% of patients (n=20) were triple-class refractory, and 21.4% of patients (n=6) were penta-drug refractory.⁴

Cohort D

• A total of 31 patients were administered TECVAYLI and lenalidomide. Twelve patients received TECVAYLI 0.72 mg/kg with lenalidomide 25 mg and 19 patients received TECVAYLI 1.5 mg/kg with lenalidomide 15 mg.⁵
• Patients received a median of 4 prior lines of therapy (range, 2-9). All patients were exposed to prior lenalidomide, 41.9% of patients (n=13) were refractory to lenalidomide, 41.9% of patients (n=13) were triple-class refractory, and 12.9% of patients (n=4) were penta-drug refractory.⁵

Cohort E

• All patients in the cohort were treated with DARZALEX FASPRO and lenalidomide; 19 patients received TECVAYLI 1.5 mg/kg, and 13 patients received TECVAYLI 0.72 mg/kg.⁶
• Patients received a median of 2 prior lines of therapy (range, 1-3). All patients were exposed to prior PI and immunomodulatory drug therapy; 5 patients in each TECVAYLI dose group received prior anti-CD38 antibody therapy.⁶

Safety - Adverse Event - Neurotoxicity

Cohort C

At a median follow-up of 14.7 months (range, 0.5-22.9), 2 ICANS events occurred; one at dose level 1 (grade 3) and one at dose level 2 (grade 2).⁴

• Headache (any grade) was reported in 25% of patients (n=7), with no reports of grade 3/4 headache.⁴
• Treatment discontinuations related to neurotoxicity:
  • TECVAYLI: One patient discontinued due to an AE of confusional state.⁴
  • Nirogacestat: AEs leading to discontinuation were confusional state, malaise, meningitis, mental disorder, and muscular weakness (n=1 each). A patient could have >1 AE leading to discontinuation.⁴
• A dose-limiting toxicity of grade 3 ICANS was reported in 1 patient at dose level 1.⁴

Cohort D

At a median follow-up of 10.8 months (range, 1.1-16.8), grade 1 ICANS events were reported in 2 patients (6.5%).⁶

Cohort E

At a median follow-up of 8.4 months (range, 1.1-12.9), no ICANS events were reported.⁶

• Any grade insomnia was reported in 37.5% of patients (n=12) with grade 3/4 insomnia reported in 3.1% of patients (n=1).⁶

CLINICAL DATA - MajesTEC-7 study

MajesTEC-7 (MMY3005; clinicaltrials.gov identifier NCT05552222) is a randomized, phase 3, open-label, multicenter study comparing the efficacy and safety of Tec-DR and Tal-DR vs DRd in patients with NDMM who are ineligible or not intended for transplant as initial therapy.^8,18

Study Design/Methods

Safety Run-in Cohort 1 (Tec-DR)

• A safety run-in period was used to establish safety prior to enrolling the randomized phase of the study.¹⁸
• Key eligibility criteria: NDMM either ineligible or not intended for autologous stem cell transplant; (ASCT).^8,18
• Primary endpoints: PFS, 12-month minimal residual disease (MRD)-negative CR.^8,18
• Key secondary endpoint: safety.^8,18

Results

Treatment Disposition, Baseline Demographics, and Disease Characteristics

Safety Run-in Cohort 1

• At a median follow-up of 13.8 months (range, 2.0-15.4), 26 patients received a median of 15 cycles (range, 2-17) of Tec-DR.¹⁸
• Median relative dose intensity was 97% for TECVAYLI, 95.8% for DARZALEX FASPRO, and 58.6% for lenalidomide, with 17 patients undergoing dose reduction.¹⁸

Safety - Adverse Event - Neurotoxicity

Safety Run-in Cohort 1

• At a median follow-up of 13.8 months (range, 2.0-15.4), 1 grade 1 ICANS event was reported in 1 patient during cycle 1, which subsequently resolved.¹⁸

CLINICAL DATA - Redirectt-1 study - TALVEY + TECVAYLI Cohort

RedirecTT-1 (MMY1003; clinicaltrials.gov identifier: NCT04586426) is an ongoing, open-label, phase 1b/2 study evaluating the safety and effectiveness of the combination of TALVEY and TECVAYLI in patients with RRMM.^10,19,20

Study Design/Methods

• Key eligibility criteria: relapsed or refractory or intolerant to established therapies including the last line of therapy, prior exposure to a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.¹⁹
• Primary endpoints: safety, identify RP2R(s), and schedule.¹⁹

Results

Treatment Disposition, Baseline Demographics, and Disease Characteristics

• The median duration of follow-up was 20.3 months in the all dose levels cohort and 18.2 months (range, 0.7-27.0) in the RP2R cohort.¹⁰
• All dose levels (N=94): Patients received a median of 4 prior lines of therapy (range, 1-11), 92.6% of patients (n=87) were refractory to the last line of therapy, and 86.2% of patients (n=81) were triple-class refractory.¹⁰
• RP2R (n=44): Patients received a median of 4 prior lines of therapy (range, 2-10), 88.6% of patients (n=39) were refractory to the last line of therapy, and 84.1% of patients (n=37) were triple-class refractory.¹⁰

Safety - Adverse Event - Neurotoxicity

• ICANS events occurred in 3 patients (3.2%), including 1 grade 3 ICANS event; 2 events were concurrent with CRS. All ICANS events occurred during SUD.¹⁰
• The median time to onset of ICANS was 2-2.5 days; the median duration of ICANS was 3 days. All events recovered.¹⁰

clinical data - Trimm-2 study - tecvayli + Darzalex faspro cohort

TRIMM-2 (MMY1002; clinicaltrials.gov identifier: NCT04108195) is an ongoing, phase 1b, 2-part, multicohort, open-label study evaluating DARZALEX FASPRO regimens in combination with bispecific T-cell redirection antibodies in patients with RRMM.^7,21

Study Design/Methods

• Key eligibility criteria: ≥3 prior lines of therapy including a PI, immunomodulatory drug or were double refractory to PI and immunomodulatory drug; prior anti-CD38 therapy was permitted with a 90-day washout, prior BCMA-targeted therapies were also permitted.^7,21
• Select exclusion criteria: active central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of MM. If either is suspected, brain magnetic resonance imaging (MRI), and lumbar cytology are required.²¹
• Key primary endpoints:
  • Part 1: identify the RP2D for each treatment combination.⁷
  • Part 2: safety and tolerability at the selected RP2D of each treatment combination.⁷

Results

Treatment Disposition, Baseline Demographics, and Disease Characteristics

• A total of 65 patients were administered the DARZALEX FASPRO + TECVAYLI combination.⁷
• Patients received a median of 5 prior lines of therapy (range, 1-15), 80% of patients were refractory to the last line of therapy, 58.5% of patients were triple-class refractory and 30.8% of patients were penta-drug refractory.⁷

Safety - Adverse Event - Neurotoxicity

• At a median follow-up of 8.6 months (range, 0.3-19.6), headache (any grade) was reported in 13 patients (20%). Grade 3/4 headache was reported in 1 patient (1.5%).⁷
• Grade 1 ICANS event was reported in 1 patient during SUD. The event was fully resolved in 1 day.⁷

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 04 November 2024.