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). Cohort C included 40 patients with RRMM, previously treated with a proteasome inhibitor (PI), an immunomodulatory agent, an anti-CD38 monoclonal antibody, and anti-B-cell maturation antigen (BCMA) targeted therapies.^1-4
  • Touzeau et al (2022)¹ presented the initial efficacy and safety results from Cohort C of the MajesTEC-1 study. At a median follow-up of 12.5 months (range, 0.7-14.4), the overall response rate (ORR) was 52.5% (95% confidence interval [CI], 36.1-68.5). The most common adverse events (AEs; any grade) were neutropenia (67.5%), cytokine release syndrome (CRS; 65.0%), and anemia (50.0%).
  • Touzeau et al (2024)² published longer-term efficacy and safety results from Cohort C of the MajesTEC-1 study. At a median follow-up of 28.0 months (range, 0.7-31.1), the ORR was 52.5% (95% CI, 36.1-68.5). The most common AEs (any grade) were infections (70.0%), neutropenia (70.0%), and CRS (65.0%).

CLINICAL DATA - majestec-1 study - cohort c

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

• Cohort C is evaluating the efficacy and safety of TECVAYLI in 40 patients with RRMM, previously treated with a PI, an immunomodulatory drug, an anti-CD38 monoclonal antibody, and noncellular and cellular anti-BCMA targeted therapies (antibody-drug conjugate [ADC] and/or chimeric antigen receptor [CAR]-T cell therapy).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 at the RP2D; and Part 3 (the phase 2 component) to evaluate the efficacy of TECVAYLI at the RP2D.⁵
• Key eligibility criteria: documented RRMM per International Myeloma Working Group (IMWG) criteria, ≥3 prior lines of therapy including a PI, an immunomodulatory drug, an anti-CD38 monoclonal antibody and prior exposure to anti-BCMA-targeted therapies (ADC and/or CAR-T), and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.²
• Primary endpoint: ORR (defined as partial response or better [≥PR] according to IMWG criteria).²
• Key secondary endpoints: duration of response (DOR), very good partial response or better (≥VGPR), complete response or better (≥CR), stringent complete response (sCR), time to response, minimal residual disease (MRD) negativity status (at the 10⁵ threshold; evaluated by next-generation sequencing), progression-free survival (PFS), overall survival (OS), safety, pharmacokinetics (PK), and immunogenicity.^2,4
• Exploratory endpoints: assessment of soluble BCMA (scam) and membrane BCMA, and characterization of T-cell subsets and activation and exhaustion markers in peripheral blood and tumor.²
• Dosing: step-up doses (SUD) of TECVAYLI (0.06 mg/kg and 0.3 mg/kg subcutaneous [SC]). Cycles 1+: TECVAYLI 1.5 mg/kg SC weekly (QW) until progressive disease (PD) or unacceptable toxicity.²
  • There was an option to switch to once every other week (Q2W) dosing if patients achieved ≥CR for ≥6 months.²
• Patients received dexamethasone, diphenhydramine, and acetaminophen before treatment to minimize the risk of CRS and were hospitalized for observation during both the SUD and the first full dose of TECVAYLI.²
• Tocilizumab was considered for patients with fever (≥38°C) when no other cause was identified, specifically for those patients with grade 1 CRS, and was recommended for patients with ≥grade 2 CRS.²

Touzeau et al (2022)¹ presented the initial efficacy and safety results from Cohort C of the MajesTEC-1 study at a median follow-up of 12.5 months (range, 0.7-14.4).

Results

Treatment Disposition, Baseline Demographics, and Disease Characteristics

• At a median follow-up of 12.5 months (range, 0.7-14.4), 40 patients were administered TECVAYLI with a median duration of treatment of 5.2 months (range, 0.2-13.6).
• A total of 42.5% of patients (n=17) remained on TECVAYLI. Patient characteristics are detailed in Table: MajesTEC-1 Study (Cohort C): Baseline Characteristics and Demographics.
• Four patients discontinued TECVAYLI due to PD.

Efficacy

Response Rates

• The ORR was 52.5% (95% CI, 36.1-68.5). See Table: MajesTEC-1 Study (Cohort C): Response Rates for additional details.
• Four patients had both previous ADC and CAR-T treatment exposure; 3 of these 4 patients had a response to TECVAYLI.

Duration of Response

• The median time to first response was 1.2 months (range, 0.2-4.9); median time to best response was 2.9 months (range, 1.1-9.5).
• Median DOR was not reached (95% CI, 10.5-not estimable [NE]).
• At a median follow-up of 11.8 months (range, 3.6-13.8), 71.4% of responders (15/21) maintained their response.⁶

MRD Negativity

• The MRD-negativity rate at the 10^-5 threshold was 17.5% (95% CI, 7.3-32.8). The MRD-negativity rate was 63.6% among patients with ≥CR (7/11).

Safety

• The incidence of AEs (≥20%) is summarized in Table: MajesTEC-1 Study (Cohort C): Adverse Events (≥20%).
• Six deaths due to AEs were reported; 1 death was possibly related to TECVAYLI (cardiac arrest), and 2 COVID-19 deaths.
• No dose reductions or discontinuations due to AEs have been reported.
• Infections occurred in 65.0% of patients (n=26); grade 3/4 infections occurred in 30.0% of patients.

Cytokine Release Syndrome

• CRS (any grade) occurred in 65.0% of patients. All CRS events were grade 1/2. No patients discontinued TECVAYLI due to CRS. See Table: MajesTEC-1 Study (Cohort C): Characteristics and Management of CRS for additional details.

Neurotoxicity

• ICANS was reported in 4 patients (10%). A grade 3 ICANS event was reported in one patient, which resolved in 2 days after supportive care. See Table: MajesTEC-1 Study (Cohort C): Characteristics and Management of Neurotoxic Events for additional details.

Touzeau et al (2024)² published longer-term efficacy and safety results from Cohort C of the MajesTEC-1 study at a median follow-up of 28.0 months (range, 0.7-31.1).

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).
• The median age was 64 years (range, 32-82), and 7.5% of patients (n=3) were aged ≥75 years. Patient characteristics are detailed in Table: MajesTEC-1 Study (Cohort C): Baseline Characteristics and Demographics.
• TECVAYLI was administered as the next line of therapy in 10 patients after ADC treatment (median interval between treatments, 1.4 months [range, 0.7-4.8]) and in 8 patients after CAR-T therapy (median interval between treatments, 4.6 months [range, 3.0-10.6]).
• Twenty-two patients did not receive anti-BCMA targeted therapy as the last line of therapy prior to TECVAYLI (median interval between treatments, 1.1 months [range, 0.2-2.9]).
• Overall, 10 patients were switched from QW to Q2W dosing including the following:
  • Six patients who met the prespecified response-related criteria to switch to a less frequent dosing schedule (a response of ≥CR for a minimum of 6 months per investigator assessment).
  • Four additional patients were switched without meeting the protocol-defined criteria.
    • Of these 4 patients, 2 patients switched to Q2W dosing due to physician decision (both patients had achieved ≥CR but did not meet the protocol-defined time to switch; 1 of these patients had PD prior to CR so was not considered a responder) and 2 patients switched to due to AEs of neutropenia (grade 4 at day 322 in 1 patient and grade 3 at day 261 in 1 patient).
• No patient had a dose reduction.
• Patients discontinued treatment due to disease progression (n=21), death (n=9), AE (n=3), physician decision (n=2), or patient refusal of further treatment (n=1).

Efficacy

Response Rates

• At a median follow-up of 28.0 months (range, 0.7-31.1), ORR was 52.5% for all patients. See Table: MajesTEC-1 (Cohort C): Efficacy Outcomes for additional details.
• The ORR was 58.3% in patients with extramedullary disease and 33.3% in patients with high-risk cytogenetics.
  • ORR was consistent across subgroups (elderly; renally impaired [creatinine clearance ≤60 mL/min/1.73 m²]); however, a small sample size limited the interpretation.
• Details on ORR in patients with and without anti-BCMA treatment as the last line of therapy before TECVAYLI are provided in Table: Efficacy Outcomes in Patients With and Without Anti-BCMA as Last Line of Therapy.

Duration of Response

• With a median follow-up of 26.3 months (range, 3.6-31.1), 5 of 21 responders (23.8%) maintained their response to TECVAYLI, and 3 of 21 responders were still on treatment at clinical cutoff.
• The median time from the last BCMA-targeted ADC treatment to the first dose of TECVAYLI was shorter for responders (n=16; 108.5 days [range, 39.0-988.0]) than for non-responders (n=13; 265.0 days [range, 22.0-1144.0]).
• The median time from the last BCMA-targeted CAR-T treatment to the first dose of TECVAYLI was similar among responders (n=8; 306.5 days [range, 92.0-950.0]) and non-responders (n=7; 303.0 days [range, 116.0-579.0]). CAR-T treatment was limited to a 1-day infusion and the persistence of circulating CAR-T from prior therapy was not collected.
• In patients who switched to less frequent TECVAYLI dosing, 7 of 9 patients did not experience PD after the dosing schedule change. At clinical cutoff, 5 of these 7 patients maintained responses.
  • Of these 5 patients, 3 patients remained on treatment and 2 patients discontinued treatment: 1 patient due to a TEAE (memory impairment) and 1 patient refused further study treatment. The other 2 patients died without confirmed disease progression.

MRD Negativity

• Of 8 patients (20%) with MRD-evaluable bone marrow samples, 87.5% (n=7) with ≥CR achieved MRD negativity at a threshold of 10^-5 at any time.

Safety

• All patients in Cohort C experienced 1 or more TEAE. See Table: MajesTEC-1 (Cohort C): Adverse Events ≥10%  for additional details.
• Of the 31 patients (77.5%) with evidence of hypogammaglobulinemia, 16 patients (40.0%) received intravenous immunoglobulin (IVIG) treatment at any time during the study according to institutional guidelines.
• Of 3 patients (7.5%) who discontinued TECVAYLI due to AEs, 1 case was considered treatment-related by the investigator (hepatitis E virus infection). No patients had a dose reduction of TECVAYLI.
• A total of 25 patients (62.5%) died; disease progression was the primary cause of death in 12 patients (30.0%). Two patients (5.0%) died due to events that investigators considered were related to TECVAYLI treatment (coronavirus disease 2019 [COVID-19], n=1; cardiac arrest, n=1). Of the 10 patients with grade 5 TEAEs:
  • A total of 8 patients (20.0%) died due to AEs (COVID-19 [n=4; 10%], and 1 patient each [2.5%] due to cardiac arrest, cardiac failure, coronary artery dissection, and sudden death).
  • The other 2 grade 5 AEs were due to disease progression. The patient who suffered cardiac arrest had pneumonia that began 10 days prior to death.

Cytokine Release Syndrome

• CRS events of any grade were reported in 65% of patients (n=26) overall. See Table: MajesTEC-1 Study (Cohort C): Characteristics and Management of CRS Events for additional details.
• All first events of CRS were confined to the step-up dosing schedule or cycle 1.
• All CRS events resolved without TECVAYLI discontinuation.

Neurotoxicity

• 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.
  • The most common neurotoxic event was headache (12.5%; n=5).
  • Immune effector cell-associated neurotoxicity syndrome (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.
• 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).
  • Two events (5.0%; ICANS and peripheral sensory neuropathy) led to TECVAYLI dose interruption, but no patients had dose reductions or treatment discontinuation.

Infections

• Infections were reported in 70.0% of patients overall (n=28). Of these, 32.5% (n=13) were grade 3/4, and 10% (n=4) were grade 5.
  • All 4 grade 5 infections were due to COVID-19. Three patients had received at least 1 COVID-19 vaccination prior to TECVAYLI treatment, and 1 patient had no record of prior COVID-19 vaccination. Patient recruitment in Cohort C began in October 2020, coinciding with the COVID-19 pandemic and overlapping with peak infection and death rates globally per the World Health Organization data.

Pharmacokinetics and Immunogenicity

• TECVAYLI C_trough values in patients were comparable to those observed in BCMA-treatment-naïve patients, with mean C_trough consistently above the maximal 90% effective concentration (EC₉₀) value from an ex vivo assay.
• TECVAYLI serum concentrations at or within 48 hours of CRS onset (including step-up and treatment doses) ranged from 0.070 μg/mL to 8.99 μg/mL.
  • At a PK data cutoff of June 7, 2023, no clear correlation was observed between CRS events or grade and TECVAYLI concentration; serum levels were comparable in patients with CRS across all grades and in non-CRS patients.
  • No serum samples from CRS events were positive for antibodies to TECVAYLI.
• Antibodies to TECVAYLI were not detected in the serum of any of the 36 antidrug antibody-evaluable patients.

Soluble BCMA and Bone Marrow BCMA Expression

• Serum was collected prior to the first TECVAYLI dose, and samples were analyzed for sBCMA.
• Baseline sBCMA serum levels overlapped between Cohort C patients and BCMA-treatment-naïve patients. See Table: MajesTEC-1 Study (Cohort C): sBCMA Levels for additional details.
• On cycle 4 day 1, a total of 78.6% of responders (11 out of 14) had a decrease in sBCMA, while 75% of non-responders (3 out of 4) had an increase in sBCMA after TECVAYLI administration.
• sBCMA reduction was higher in responders to TECVAYLI, although the sample size was limited.
• BCMA expression on multiple myeloma (MM) cells in the bone marrow showed no significant difference in the percentage or level of BCMA expression between patients who had prior anti-BCMA CAR-T or ADC exposure (last prior line or any prior line).

Immune Cell Effects

• Assessments included the impact of prior anti-BCMA CAR-T therapy on the number of T cells and the activation and inhibitory receptor expression on T cells prior to TECVAYLI treatment. B-cell numbers were also evaluated.
• Baseline CD4 and CD8 T-cell numbers trended lower in patients who had received anti-BCMA CAR-T compared with those who received prior BCMA-ADC therapy.
  • Activation markers (CD25 and CD38) and inhibitory receptors (programmed cell death 1 [PD-1], T-cell immunoglobulin mucin family member 3 [TIM-3]) were not upregulated on CD4+ and CD8+ T cells from patients in the prior anti-BCMA CAR-T cohort.
• Patients with prior anti-BCMA therapy did not have lower baseline B-cell numbers compared with anti-BCMA-naive patients at any point during treatment.

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 26 August 2024.