SUMMARY

• Janssen does not recommend any practices, procedures, or usage that deviate from the product labeling or are not approved by the regulatory agencies.
• 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). The prophylactic tocilizumab cohort is an ongoing prospective, phase 1, exploratory cohort of the MajesTEC-1 study evaluating the administration of intravenous (IV) tocilizumab (8 mg/kg) prior to TECVAYLI dosing for the reduction of cytokine release syndrome (CRS) in 24 patients with RRMM.^1-5
  • van de Donk et al (2023)⁴ evaluated the effects of prophylactic tocilizumab for the reduction of CRS in patients treated with TECVAYLI at a median follow-up of 2.6 months (range, 0.1-7.0). A total of 12.5% of response-evaluable patients had a complete response (CR). Grade 1/2 CRS occurred in 26.1% of patients (n=6). The most frequent AEs of any grade were infections (65.2%, n=15), anemia (56.5%, n=13), and neutropenia (56.5%, n=13).
  • van de Donk et al (2024)³ presented the effects of prophylactic tocilizumab for the reduction of CRS in patients treated with TECVAYLI at a longer median follow-up of8.1 months (range, 0.9-13.2). The overall response rate (ORR) in response-evaluable patients was 72.7%. Grade 1/2 CRS occurred in 25% of patients (n=6). The most frequent adverse events (AEs) of any grade were infections (79.2%, n=19), neutropenia (62.5%, n=15), and anemia (58.3%, n=14).
• Korst et al (2024)⁶ published an evaluation of the efficacy of prophylactic tocilizumab prior to the first step-up dose of TECVAYLI to prevent CRS in 29 patients with RRMM from a single center. The study included 20 patients who received TECVAYLI as part of a compassionate use program (CUP) and 9 consecutive patients who received TECVAYLI in the MajesTEC-1 trial. At a median follow-up of 8.7 months, ORR was 82.8%. Grade 1/2 CRS was reported in 10.3% of patients (n=3).
• Kowalski et al (2023)⁷ presented results from a prospective, single-center, real-world study evaluating single-dose prophylactic tocilizumab before beginning TECVAYLI step-up dosing in patients with RRMM. At a median follow-up of 109 days (range, 9225), ORR was 50%. CRS of grade 1 was reported in 13% of patients, and immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 10% of patients.
• Scott et al (2023)⁸ published an evaluation of the prophylactic use of tocilizumab to prevent CRS in patients administered TECVAYLI in a single center. At a median follow-up of 113 days (range, 3-254), ORR in the prophylactic tocilizumab cohort was 70% in patients with assessable responses. All grade CRS was reported in 26.3% of patients in the prophylactic tocilizumab cohort with concurrent ICANS reported in 5.3% of these patients.
• Zhou et al (2023)⁹ employed a mechanism-based pharmacokinetic (PK)/pharmacodynamic model to evaluate tocilizumab PK parameters and soluble interleukin-6R (sIL-6R) target engagement of prophylactic tocilizumab treatment on sIL-6R levels, interleukin-6 (IL-6) levels, and the duration of IL-6 signaling pathway blockade in patients undergoing TECVAYLI treatment.

CLINICAL DATA - majestec-1 study - prophylactic tocilizumab COHORT

MajesTEC-1 (MMY1001; clinicaltrials.gov identifiers: NCT03145181, NCT04557098) is evaluating the safety and efficacy of TECVAYLI in patients with RRMM after ≥3 prior lines of therapy, including triple-class exposure to a proteasome inhibitor (PI), an immunomodulatory drug, and an anti-CD38 monoclonal antibody (mAb).^1-5

• The prophylactic tocilizumab cohort is an ongoing prospective, phase 1, exploratory cohort of the MajesTEC-1 study evaluating the administration of IV tocilizumab (8 mg/kg) prior to TECVAYLI dosing for the reduction of CRS in 24 patients with RRMM.^3,4

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.^5,10
• Key eligibility criteria: documented RRMM per International Myeloma Working Group (IMWG) criteria; ≥3 prior lines of treatment, including a PI, an immunomodulatory drug, and an anti-CD38 mAb; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.⁵
• Primary endpoint: ORR.⁵
• Endpoint for prophylactic tocilizumab cohort: incidence of CRS.⁴
• Prophylactic tocilizumab cohort dosing:
  • Tocilizumab: single-dose 8 mg/kg IV ≤4 hours before TECVAYLI step-up dose 1.^3,4
  • TECVAYLI: step-up doses (0.06 mg/kg and 0.3 mg/kg subcutaneous [SC]) followed by first treatment dose and subsequent treatment doses of TECVAYLI (1.5 mg/kg) SC once weekly (QW). The step-up doses were administered 2-4 days apart and completed 2-4 days prior to the first full treatment dose of TECVAYLI. Cycles 3-6: TECVAYLI 3.0 mg/kg SC once every other week (Q2W); Cycles 7+: TECVAYLI 3.0 mg/kg SC monthly (Q4W).^3,4
  • Premedications: dexamethasone, acetaminophen, and diphenhydramine were required to be administered for each step-up dose, and first full treatment dose of TECVAYLI.^3,4
• Patients were required to be hospitalized for at least 48 hours from the start of injection for each step-up dose and the first full treatment dose of TECVAYLI.⁴
• CRS as an AE was graded as per the criteria by Lee et al.³
  • CRS management with tocilizumab treatment was permitted for grade 1 CRS and was recommended for grade ≥2 CRS.³

van de Donk et al (2023)⁴ evaluated the effects of prophylactic tocilizumab for the reduction of CRS in patients treated with TECVAYLI in the MajesTEC-1 study at a median follow-up of 2.6 months (range, 0.1-7.0).

Results

Treatment Disposition

• At a median follow-up of 2.6 months (range, 0.1-7.0), 23 patients received prophylactic tocilizumab prior to the first TECVAYLI step-up dose.
• The median prior lines of therapy was 4 (range, 2-9).

Efficacy

• Out of the 23 patients in this cohort, 16 were evaluable for response. Among these patients, 12.5% experienced a CR, 37.5% had a very good partial response (VGPR), and 18.8% had a partial response (PR, which includes both confirmed and unconfirmed responses).

Safety

• Dose-limiting toxicities were reported in 3 patients (grade 4 increased lipase, n=1; grade 4 thrombocytopenia, n=2). All dose-limiting toxicities were transient.⁴
• One death occurred due to an AE (pulmonary embolism).

Cytokine Release Syndrome

• Among the 23 patients who received prophylactic tocilizumab, 6 patients (26.1%) experienced CRS. See Table: MajesTEC-1 (Prophylactic Tocilizumab Cohort): CRS Incidence and Severity for additional details.
  • The median time to CRS onset was 2.0 days (range, 1-3). The median duration of CRS was 2.0 days (range, 2-4).
  • Tocilizumab was used after the first CRS event in 4 patients, with 1 patient also receiving dexamethasone.
  • All CRS events resolved without treatment discontinuation.
  • All CRS events occurred during step-up dosing schedule through cycle 2. See Table: MajesTEC-1 (Prophylactic Tocilizumab Cohort): CRS Incidence and Baseline Characteristics for additional details.
  • An association was not observed between the occurrence of CRS of any grade and patient or disease characteristic. See Table: MajesTEC-1 (Prophylactic Tocilizumab Cohort): CRS by Grade and Baseline Characteristics for additional details.

Neurotoxicity

• A total of 4 patients experienced neurotoxic AEs (grade 1, n=2; grade 2, n=2). Of these patients, 1 experienced grade 2 ICANS with concurrent grade 2 CRS.

Infections

• Grade 3/4 infections were reported in 13% of patients (n=3). See Table: MajesTEC-1 (Prophylactic Tocilizumab Cohort): Observed AEs (Grade 3/4 ≥10%) for additional details.

van de Donk et al (2024)³ presented longer follow-up data on the effects of prophylactic tocilizumab for the reduction of CRS in patients treated with TECVAYLI in the MajesTEC-1 study at a median follow-up of 8.1 months (range, 0.9-13.2).

Results

Treatment Disposition

• At a median follow-up of 8.1 months (range, 0.9-13.2), 24 patients received prophylactic tocilizumab prior to TECVAYLI (median age, 72 years [range, 50-82]).
• A total of 58.3% of patients (n=14) were triple-class refractory to immunomodulatory drugs, PIs, and an anti-CD38 mAb.
• The median prior lines of therapy was 4 (range, 2-9).

Efficacy

• Of the 24 patients in this cohort, 22 were evaluable for response. See Table: MajesTEC1 (Prophylactic Tocilizumab Cohort): Efficacy Outcomes for additional details.

Safety

• No new safety signals were identified with longer follow-up. A summary of TEAEs observed in the prophylactic tocilizumab cohort is presented in Table: MajesTEC-1 (Prophylactic Tocilizumab Cohort): TEAEs.
• One grade 5 AE (pulmonary embolism) event occurred 20 days after the last TECVAYLI dose (previously reported at a 2.6-month follow-up).^3,4

Cytokine Release Syndrome

• Among the 24 patients who received prophylactic tocilizumab, 25% experienced CRS. See Table: MajesTEC-1 (Prophylactic Tocilizumab Cohort): CRS Incidence and Severity for additional details.
  • All initial CRS events occurred during TECVAYLI step-up dosing 1 and 2. The median time to CRS onset was 2 days (range, 1-3). The median duration of CRS was 2 days (range, 2-4).
  • A total of 3 patients each had 1 recurrent CRS event.
  • All CRS events resolved.
  • There was no observed association between CRS and any specific patient disease or patient characteristic. See Table: MajesTEC-1 (Prophylactic Tocilizumab Cohort): CRS by Grade and Baseline Characteristics for additional details.
• The magnitude of IL-6 induction was higher with prophylactic tocilizumab. Based on modeling data, a single tocilizumab dose inhibits IL-6 signaling for approximately 10 days and the duration of IL-6 blockage spans the TECVAYLI dosing schedule.

Neurotoxicity

• Overall, 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.

Infections

• In the prophylactic tocilizumab cohort, 79.2% of patients experienced any grade infections and 25% of patients experienced grade 3-4 infections, while in the MajesTEC-1 pivotal trial, at a median follow-up of 7.2 months, 63% of patients had any grade infections and 30.9% of patients had grade 3-4 infections.
  • Infections reported in the prophylactic tocilizumab cohort were pneumonia (n=4), bacterial infection (n=1), diverticulitis (n=1), cytomegalovirus (CMV) infection (n=1), sepsis (n=1), and septic shock (n=1).

Korst et al (2024)⁶ published an evaluation of the efficacy of prophylactic tocilizumab prior to the first step-up dose of TECVAYLI to prevent CRS in 29 patients with RRMM from a single center. The study included 20 patients who received TECVAYLI as part of a CUP and 9 consecutive patients who received TECVAYLI in the MajesTEC-1 trial.

Study Design/Methods

• Prophylactic tocilizumab was given from October 2022 to March 2024 to RRMM patients who received TECVAYLI as part of a CUP (n=20) and also to 9 consecutive patients who received TECVAYLI in the MajesTEC-1 trial.
• TECVAYLI was administered according to the approved schedule: 2 step-up doses (0.06 mg/kg and 0.3 mg/kg) followed by a full dose of 1.5 mg/kg every week (48-72 hours between the step-up doses and first full dose).
  • TECVAYLI was administered immediately after dialysis sessions in patients undergoing hemodialysis.
• Prophylactic tocilizumab (8 mg/kg IV, maximum dose of 800 mg) was administered 1 hour prior to the first TECVAYLI step-up dose.
• Premedications: dexamethasone 16 mg, clemastine 2 mg, and acetaminophen 1000 mg were administered 1 hour prior to both the step-up doses and first full dose of TECVAYLI.
• Valacyclovir for herpes zoster and co-trimoxazole or pentamidine (in case of co-trimoxazole allergy) for Pneumocystis jirovecii pneumonia were administered as prophylaxis to all the patients.
• Granulocyte colony stimulating factor (G-CSF) was considered for grade ≥3 neutropenia, and immunoglobulin G (IgG) replacement was given for polyclonal IgG <4 g/L (primary or secondary prophylaxis at the physician's discretion).
  • At the current follow-up, 26 patients (89.7%) received IgG replacement.
• No other antibacterial or antifungal prophylaxis was administered.
• CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria.

Results

Baseline Characteristics and Treatment Disposition

• At a median follow-up of 8.7 months, 29 patients had received TECVAYLI. Baseline characteristics of patients and a summary of prior lines of treatments in patients treated with TECVAYLI with prophylactic tocilizumab are presented in Tables: Baseline Characteristics of Patients Treated With TECVALYI With Prophylactic Tocilizumab and Prior Treatments in Patients Treated With TECVALYI With Prophylactic Tocilizumab.
• Ninety percent of CUP patients would not have met the eligibility criteria for MajesTEC-1 due to the presence of oligosecretory disease (n=7), severe cytopenias (n=7), renal impairment (n=3, including hemodialysis in one patient), cardiac conditions (n=2, 1 patient with heart failure [New York Heart Association class III] and 1 with Brugada syndrome), and/or other reasons.

Efficacy

• At a median follow-up of 8.7 months, ORR was 82.8% with ≥VGPR reported in 75.9% of patients.
• The median PFS was not reached. The 12-month PFS rate was 63.5% and the 12-month OS rate was 72.2%.
• All 3 patients with renal impairment responded, including the patient who received hemodialysis (VGPR).

Safety

• Grade ≥3 thrombocytopenia was reported in 13.8% of patients, and grade ≥3 anemia in 6.9% of patients. The frequency of grade ≥3 neutropenia was 72.4%. The median time to onset of grade ≥3 neutropenia was 19 days. with a median duration of 7 days. G-CSF support was used in 62.1% of patients.

Cytokine Release Syndrome

• CRS occurred in 10.3% of patients (n=3; grade 1 CRS after step-up dose 1, n=1; grade 2 CRS after step-up dose 1, n=1; grade 1 CRS after step-up dose 2 and grade 2 CRS after the first full dose, n=1).
• CRS in all 3 patients was treated with additional tocilizumab administration and with dexamethasone (10 mg IV) in the patient with recurrent CRS. IV fluids were administered to both patients with grade 2 CRS due to hypotension.
• The median duration of CRS was 1 day (range, 1-3), and all CRS events were completely resolved.
• Both patients who developed grade 2 CRS despite prophylactic tocilizumab had high tumor burden (70%-80% myeloma cells in bone marrow biopsy) and rapidly progressive disease (light-chain doubling time of approximately 4 weeks prior to TECVAYLI initiation).
  • The patient with grade 1 CRS had 30% myeloma cells in bone marrow biopsy and light-chain level increased by 25% in the 4 weeks prior to the first TECVAYLI dose
• In 1 of the 3 patients who developed CRS (patient with recurrent CRS), peripheral blood smears revealed circulating tumor cells (CTCs). In patients who did not develop CRS, CTCs were not detected in the blood smears.

Neurotoxicity

• ICANS was not observed in any patient.

Infections

• Grade ≥3 infections were reported in 27.6% of patients.

Step-up Dosing

• A total of 25 patients received TECVAYLI step-up dosing in the inpatient setting.
• The median duration of hospitalization for step-up dosing was 8 days (interquartile range; IQR, 6-9 days), with only 1 patient staying 2 days longer than expected because of grade 2 CRS after the first full dose.
• Four patients received TECVAYLI step-up dosing in the outpatient setting with tocilizumab prophylaxis without the development of CRS or the need for hospitalization.
  • These patients lived relatively close to the hospital (<60 min travel time) and were in the company of a competent adult.

CLINICAL DATA - REAL-WORLD STUDIES

Kowalski et al (2023)⁷ presented results from a prospective, single-center, real-world study evaluating single-dose prophylactic tocilizumab prior to the first TECVAYLI step-up dosing in patients with RRMM.

Study Design/Methods

• A total of 31 patients received TECVAYLI treatment per United States Prescribing Information (inpatient step-up dosing followed by outpatient treatment) including the recommended premedications.
• A single dose of tocilizumab 8 mg/kg IV (maximum dose of 800 mg) was given 1 hour prior to receiving the first TECVAYLI step-up dose.
• Patients were prospectively followed up for efficacy and safety outcomes.
• Primary objective: effect on CRS as assessed by standard Lee (ASTCT) criteria.¹²
• Other AEs were graded per Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Results

Treatment Disposition

• Patients were evaluated between the Food and Drug Administration (FDA) approval on October 25, 2022, and a data cutoff of July 21, 2023.
• At a median follow-up of 109 days (range, 9225), 17 patients (55%) were receiving TECVAYLI and 31 patients had received TECVAYLI (median age, 71 years [range, 50-84]; black, n=9 [29%]; Hispanic, n=8 [26%]; extramedullary disease, n=24 [77%]; soft tissue plasmacytomas, n=17 [55%]).
• The median duration of response was not reached.

Efficacy

• Among the 30 patients with secretory disease, best ORR was achieved by 15 patients (50%; range, 31%-69%).
  • Based on the standard response criteria, 9 patients (30%; range, 15%-49%) achieved CR, 4 patients (13%; range, 4%-31%) achieved PR, 11 patients (37%; range, 20%-56%) had stable disease, and 4 patients (13%; range, 4%-31%) had progressive disease (PD).

Safety

• CRS limited to grade 1 was reported in 13% of patients (binomial 95% confidence interval [CI], 4%-30%) and did not cause any treatment delay.
  • CRS events were reported after either step-up dose 2 (6%; range, 1%-21%) or step-up dose 3 (6%; range, 1%-21%), with no recurrent events thereafter.
  • No patient required an additional tocilizumab dose.
• ICANS was reported in 10% of patients (binomial 95% CI, 2%-26%) and delayed treatment in 1 patient.
• Grade 2 neurotoxicity was reported in 1 patient.
• IgG levels of <400 mg/dL were reported in 21 patients (68%).
• Infections were reported in 8 patients (26%).
• Neutropenia was reported in 27 patients (87%), with 20 patients (65%) having grade ≥3 neutropenia.

Scott et al (2023)⁸ published an evaluation of the prophylactic use of tocilizumab to prevent CRS in patients administered TECVAYLI in a single center.

Study Design/Methods

• A total of 53 patients were admitted to the Emory University Hospital between December 2022 and August 2023 for TECVAYLI step-up dosing followed by the first full dose administered at least 48 hours apart (0.06 mg/kg, 0.3 mg/kg, and 1.5 mg/kg).
• Premedications comprising dexamethasone 16 mg, diphenhydramine 2550 mg, and acetaminophen 650 mg, were administered 30 minutes before each dose.
• In the first 15 patients, the median time to CRS from the administration of the first priming dose was 48 hours.
• Prophylactic tocilizumab 8 mg/kg IV (maximum dose of 800 mg) was subsequently administered over 1 hour at 44 hours (4 hours before the second step-up dose level) for the next 38 patients.
• CRS and ICANS were graded per ASTCT criteria and managed according to institutional guidelines.

Results

Treatment Disposition

• A total of 53 patients were included into the prophylactic tocilizumab cohort (n=38; median age, 69 years [range, 43-83]) and nonprophylactic tocilizumab cohort (n=15; median age, 58 years [range, 47-73]).
• All patients were refractory to immunomodulatory drug, PI, and an anti-CD38 mAb.
• The median number of tocilizumab doses was 1 (range, 1-3), including the prophylactic dose.

Efficacy

• At a median follow-up of 113 days (range, 3-254), among the 38 patients in the prophylactic tocilizumab cohort, ORR was 70% in patients with assessable responses and CR, VGPR, PR, stable disease, and PD were achieved in 13.3%, 36.7%, 20%, 13.3%, and 16.7% of patients, respectively.
• A total of 15/30 assessable patients (50%) achieved ≥VGPR.

Safety

• All grade CRS was reported in 21/53 patients (39.6%).
  • CRS was reported in 10 patients (26.3%) in the prophylactic tocilizumab cohort and 11 patients (73.3%) in the nonprophylactic tocilizumab cohort.
    • Of the 10 patients (26.3%) who reported CRS in the prophylactic tocilizumab cohort, 5 experienced CRS after the first step-up TECVAYLI dose and received tocilizumab treatment rather than prophylaxis.
    • Grade 1 CRS was reported in 8 patients (21.1%) in the prophylactic tocilizumab cohort and 10 patients (66.7%) in the nonprophylactic tocilizumab cohort.
    • Grade 2 and 3 CRS were reported in 1 patient each in the prophylactic tocilizumab cohort.
    • The patient with grade 3 CRS had 41% circulating plasma cells at the time of TECVAYLI administration.
  • The median duration of CRS was 1 day (range, 1-3).
  • One dose of steroids (in addition to the steroids given during premedication) was administered for the treatment of CRS in the 1 patient who experienced grade 3 CRS.
• Concurrent ICANS was reported in 5.3% of patients in the prophylactic tocilizumab cohort (all grade 1 and concurrent to CRS) and 20% of patients in the nonprophylactic tocilizumab cohort.
  • The median duration of ICANS was 1 day, which was resolved with CRS resolution.
• No patient in the prophylactic tocilizumab cohort was readmitted to the hospital within 14 days of discharge.
• Compared with the MajesTEC-1 study, the use of tocilizumab in this cohort did not increase the incidence of grade 3/4 neutropenia in this single-center study (64.2% vs 42.1%).

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 03 September 2024.