SUMMARY

• Janssen does not recommend the use of TECVAYLI in a manner inconsistent with the approved labeling.
• Hypogammaglobulinemia has been reported as an adverse event (AE) in the MajesTEC-1, MajesTEC-2, MajesTEC-4, MajesTEC-5, 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).^1,2,6,11-13
  • Cohort A (triple-class exposed) included 165 patients who were previously treated with a proteasome inhibitor (PI), an immunomodulatory agent, and an anti-CD38 monoclonal antibody.^1,14
    • Nooka et al (2023)¹⁵ published the incidence, timing, and management of hypogammaglobulinemia in patients receiving TECVAYLI in the MajesTEC-1 study. At a median follow-up of 22.8 months, hypogammaglobulinemia (as an AE, laboratory immunoglobulin G [IgG] value <400 mg/dL, or both) was reported in 71.5% of patients overall.
    • Garfall et al (2024)¹³ presented the incidence of hypogammaglobulinemia at a median follow-up of 30.4 months. Hypogammaglobulinemia (as an AE, any grade) was reported in 21.8% of patients; grade 3/4 hypogammaglobulinemia was reported in 1.8% of patients.
  • Cohort C included 40 patients, previously treated with a PI, an immunomodulatory agent, an anti-CD38 monoclonal antibody and anti-B-cell maturation antigen (BCMA)-targeted therapies.⁶
    • Touzeau et al (2024)⁶ published the incidence of hypogammaglobulinemia at a median follow-up of 28.0 months. Hypogammaglobulinemia (as an AE, any grade) was reported in 15% of patients.
  • Per protocol: Administration of immunoglobulin replacement for the management of hypogammaglobulinemia should have been considered with initiation prior to first dose of TECVAYLI (eg, during screening) or should have been initiated as early as possible during treatment regardless of IgG levels and regardless of presence of infections.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).^3,10,17
  • Cohort A included 17 patients with RRMM who received TECVAYLI in combination with DARZALEX FASPRO^® (daratumumab and hyaluronidase) and pomalidomide.¹⁰
    • D’Souza et al (2024)¹⁰ presented the incidence of hypogammaglobulinemia at a median follow-up of 16.2 months. Hypogammaglobulinemia (as an AE or postbaseline IgG <400 mg/dL) was reported in 94.1% of patients.
  • Cohort C included 28 patients with RRMM who received TECVAYLI and nirogacestat.³
    • Offner et al (2023)³ presented the incidence of hypogammaglobulinemia at a median follow-up of 14.7 months. Hypogammaglobulinemia (as an AE, any grade) was reported in 28.6% of patients; grade 3/4 hypogammaglobulinemia was reported in 7.1% of patients.
• MajesTEC-4 (EMN30; MMY3003) is an open-label, randomized, multicenter, phase 3 study assessing the safety and efficacy of TECVAYLI in combination with lenalidomide (Tec-Len) and TECVAYLI alone vs lenalidomide alone as maintenance therapy after an autologous stem cell transplant (ASCT) in patients with newly diagnosed multiple myeloma (NDMM).^7,18 
  • Zamagni et al (2024)⁷ presented the incidences of hypogammaglobulinemia (including patients with ≥1 treatment-emergent adverse event [TEAE] of hypogammaglobulinemia or postbaseline IgG <400 mg/dL) from a safety-run in (SRI) consisting of 3 cohorts.
    • Cohort 1 (Tec-Len; TECVAYLI weekly [QW] to once every 4 weeks [Q4W]; N=32): At a median follow-up of 21.1 months, hypogammaglobulinemia was reported in 96.9% of patients.
    • Cohort 2 (Tec-Len; TECVAYLI Q4W; N=32): At a median follow-up of 9.2 months, hypogammaglobulinemia was reported in 78.1% of patients.
    • Cohort 3 (TECVAYLI Q4W; N=30): At a median follow-up of 9.2 months, hypogammaglobulinemia was reported in 93.3% of patients.
• MajesTEC-5 (GMMG-HD10; DSMM-XX; MMY2003) is an open-label, nonrandomized, phase 2 study assessing the safety and efficacy of TECVAYLI- and TALVEY^® (talquetamab-tgvs)-based combination regimens in patients with transplant-eligible newly diagnosed multiple myeloma (TE-NDMM).^8,19
  • Raab et al (2024)⁸ presented the incidence of hypogammaglobulinemia from the 3 induction cohorts of arm A (TECVAYLI QW in combination with DARZALEX FASPROand lenalidomide; Tec [QW]-DR; n=10), arm A1 (Tec [Q4W]-DR; n=20), and arm B (TECVAYLI Q4W in combination with DARZALEX FASPRO, bortezomib, and lenalidomide; Tec [Q4W]-DVR; n=19) in the MajesTEC-5 study.
    • Hypogammaglobulinemia (including patients with ≥1 TEAE of hypogammaglobulinemia or postbaseline IgG <400 mg/dL) was reported in 91.8% of patients overall.
• MajesTEC-7 (MMY3005) is a randomized, phase 3, open-label, multicenter study comparing the safety and efficacy of Tec-DR and TALVEYin combination with DARZALEX FASPRO and lenalidomide (Tal-DR) vs DARZALEX FASPRO in combination with lenalidomide and dexamethasone (DRd) in patients with NDMM who are ineligible or not intended for transplant as initial therapy.^5,20
  • Touzeau et al (2024)²⁰ presented the incidence of hypogammaglobulinemia from SRI Cohort 1 (TEC-DR) at a median follow-up of 13.8 months. Hypogammaglobulinemia (including patients with ≥1 treatment-emergent hypogammaglobulinemia or postbaseline IgG <500 mg/dL) was reported in 80.8% of patients.
• RedirecTT-1 (MMY1003) is an ongoing, open-label, phase 1b study evaluating the safety and efficacy of TECVAYLI and TALVEY combination in patients with RRMM.^4,9,21,22
  • Cohen et al (2025)^9,23 published the incidence of hypogammaglobulinemia from the phase 1 dose-escalation segment of the RedirecTT-1 study.
    • All dose levels (dose levels 1-5; N=94): At a median follow-up of 20.3 months, 56% of patients across all dose levels had non-IgG myeloma at baseline, of which, 70% of patients had hypogammaglobulinemia (defined as IgG <400 mg/dL) at baseline and 57% of patients had post-treatment hypogammaglobulinemia.
• TRIMM-2 (MMY1002) is an ongoing, phase 1b, multicohort study evaluating the safety and efficacy of DARZALEX FASPRO regimens in combination with bispecific T-cell redirecting antibodies in patients with RRMM.^10,24,25
  • D’Souza et al (2024)¹⁰ presented the incidence of hypogammaglobulinemia in the TECVAYLI + DARZALEX FASPRO + pomalidomide cohort (N=10) at a median follow-up of 38.3 months. Hypogammaglobulinemia (as an AE or postbaseline IgG <400 mg/dL) was reported in 100% of patients.

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.^1,2,6,11-13

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 (the phase 2 component) to evaluate the efficacy of TECVAYLI at the RP2D.^1,26

• Key eligibility criteria:
  • Cohort A: ≥3 prior lines of therapy (LOTs) including a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody, no prior BCMA-targeted therapy use.^1,2
  • Cohort C: ≥3 prior LOTs, 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] therapy and/or antibody drug conjugate [ADC]).⁶
• Primary endpoint for Cohort A and Cohort C: overall response rate (ORR).^1,2,6
• Key secondary endpoint for Cohort A and Cohort C: safety.^1,2,6

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.²⁷ 
• 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.²⁷
  • 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.²⁷
• 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.²⁷
• 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.²⁷

Cohort A Safety Results

Nooka et al (2023)¹⁵ published the incidence, timing, and management of hypogammaglobulinemia in patients receiving TECVAYLI in the MajesTEC-1 study at a median follow-up of 22.8 months (range, 0.3-33.6); data cutoff date of January 4, 2023.

• Hypogammaglobulinemia was reported in 71.5% of patients (n=118) overall (hypogammaglobulinemia defined as an AE, laboratory IgG value <400 mg/dL, or both).
• A total of 21.2% of patients (n=35) reported hypogammaglobulinemia as an AE.
• A total of 70.9% of patients (n=117) had ≥1 postbaseline IgG value <400 mg/dL.
  • IgG MM was reported in 60.4% of patients and non-IgG MM was reported in 83.8% of patients.
• No patients discontinued TECVAYLI treatment due to hypogammaglobulinemia.
• Median time to IgG <400 mg/dL was 1.2 months (range, 0.2-19.8).
• A total of 46.1% of patients (n=76) received IgG replacement (prophylaxis and management). Of these, 35.2% of patients received IV only, 3.6% of patients received SC only, 0.6% of patients received intramuscular (IM) only, and 6.7% of patients received ≥1 route of administration.
  • A total of 6.1% of patients started IgG replacement prior to receiving TECVAYLI, including 5.5% of patients who started before TECVAYLI treatment and continued throughout the treatment period.
• Decreased IgG, IgA, and IgM levels were observed in patients across MM subtypes at baseline. See Table: MajesTEC-1 (Cohort A): Proportion of Patients with Immunoglobulin Depletion at Baseline Across IgG, IgA and IgM MM Subtypes.¹⁵

Recommendations for Management of Hypogammaglobulinemia

• IgG levels should be monitored every 4-6 weeks. IgG replacement (0.4 g/kg, IV or SC) should be used to maintain serum IgG levels ≥400 mg/dL every 3-6 weeks. After steady state is reached, measure IgG levels every 3 months.
• IgG replacement should be administered per institutional guidelines for life-threatening infections (especially from encapsulated bacteria), for serious or recurrent/chronic infections, and prophylactically based on physician-assessed clinical benefit.
• Serum IgG testing and/or serum protein electrophoresis during disease status evaluation might be altered due to IgG replacement.

Garfall et al (2024)¹³ presented the incidence of hypogammaglobulinemia (as an AE) at a median follow-up of 30.4 months.

• Hypogammaglobulinemia (as an AE, any grade) was reported in 21.8% of patients (n=36); grade 3/4 hypogammaglobulinemia was reported in 1.8% of patients (n=3).

Cohort C Safety Results

Touzeau et al (2024)⁶ published the incidence of hypogammaglobulinemia in Cohort C of the MajesTEC-1 study at a median follow-up of follow-up of 28.0 months (range, 0.7-31.1).

• Hypogammaglobulinemia (as an AE, any grade) was reported in 15% of patients (n=6).
• 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.

clinical data - Majestec-2 Study

MajesTEC-2 (MMY1004; clinicaltrials.gov identifier: NCT04722146) is an ongoing, phase 1b, multicohort, open-label study evaluating the safety and efficacy of TECVAYLI in combination with other anticancer treatments in patients with MM.^3,10,17

Study Design/Methods

Key Eligibility Criteria

• Cohort A (TECVAYLI and DARZALEX FASPRO and pomalidomide): received 1 to 3 prior LOT, including a PI and lenalidomide.¹⁰
• Cohort C (TECVAYLI and nirogacestat): disease progression within 12 months of last LOT; ≥3 prior LOTs 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.^3,28

Primary Endpoints

• Cohort A: safety and dose-limiting toxicities.¹⁰
• Cohort C: safety, tolerability, and optimal doses.³

Cohort A Safety Results

D’Souza et al (2024)¹⁰ presented the incidence of hypogammaglobulinemia in Cohort A of the MajesTEC-2 study at a median follow-up of 16.2 months (range, 0.5-34.5).

• Hypogammaglobulinemia (reported as an AE or postbaseline IgG <400 mg/dL) was reported in 94.1% of patients (n=16). A total of 70.6% of patients (n=12) received IVIG. Of note, study enrollment began before IVIG was routinely recommended for patients treated with bispecific antibodies (March 2021 to August 2021).

Cohort C Safety Results

Offner et al (2023)³ presented the incidence of hypogammaglobulinemia (as an AE) in Cohort C of the MajesTEC-2 study at a median follow-up of 14.7 months (range, 0.5-22.9).

• Hypogammaglobulinemia (as an AE, any grade) was reported in 8 patients (28.6%); grade 3/4 hypogammaglobulinemia was reported in 2 patients (7.1%).
• A hypogammaglobulinemia TEAE or ≥1 postbaseline IgG value of <500 mg/dL, was reported in 78.6% of patients. Of these, 42.9% of patients were administered IVIG treatment.

CLINICAL DATA - MajesTEC-4 study

MajesTEC-4 (EMN30; MMY3003; clinicaltrials.gov identifier NCT05243797) is an open-label, randomized, multicenter, phase 3 study evaluating the safety and efficacy of Tec-Len and TECVAYLI alone vs lenalidomide alone as maintenance therapy in patients with NDMM.^7,18

Study Design/Methods

SRI Cohorts

• A SRI period consisting of 3 cohorts was used to establish safety prior to enrolling the randomized phase of the study.⁷
• Maintenance regimen (2-year fixed duration): patients who achieved a complete response (CR) on Tec-Len after 1-year discontinued TECVAYLI and continued lenalidomide for an additional year.⁷
• Key eligibility criteria: NDMM, receipt of 4 to 6 cycles of 3- or 4-drug induction therapy (PI and/or immunomodulatory drug ± anti-CD38 antibody), and ASCT (single or tandem ASCT permitted) ± consolidation with partial response (PR) or better.⁷
• Primary endpoints: progression-free survival (PFS) and 12-month minimal residual disease (MRD)-negative CR.⁷
• Key secondary endpoint: safety.⁷

Safety Results

Zamagni et al (2024)⁷ presented the incidence of hypogammaglobulinemia from SRI Cohort 1 (Tec-Len; TECVAYLI QW to Q4W) at a median follow-up of 21.1 months (range, 14.8-23.8), SRI Cohort 2 (Tec-Len; TECVAYLI Q4W) at a median follow-up of 9.2 months (range, 1.2-12.2), and SRI Cohort 3 (TECVAYLI Q4W) at a median follow-up of 9.2 months (range, 3.7-11.5).

• Hypogammaglobulinemia (including patients with ≥1 TEAE of hypogammaglobulinemia or postbaseline IgG <400 mg/dL) was reported in 96.9% of patients (n=31) in Cohort 1, 78.1% of patients (n=25) in Cohort 2, and 93.3% of patients (n=28) in Cohort 3. All patients received ≥1 dose of IVIG or subcutaneous immunoglobulin (SCIg).
• Prophylactic IVIG replacement was advised to maintain serum IgG levels of ≥400 mg/dL.

CLINICAL DATA - MajesTEC-5 study

MajesTEC-5 (GMMG-HD10; DSMM-XX; MMY2003) is an open-label, nonrandomized, phase 2 study assessing the safety and efficacy of TECVAYLI- and TALVEY-based combination regimens in patients with TE-NDMM.^8,19

Study Design/Methods

• Key eligibility criteria: presence of NDMM for which high-dose therapy (HDT) and ASCT were intended as part of the treatment plan, completion of HDT and ASCT within 12 months of induction start and within 6 months of the last ASCT (7 months if consolidation was received), receipt of only 1 prior LOT, and achievement of at least PR as per International Myeloma Working Group (IMWG) 2016 without evidence of progression at the time of enrollment.⁸
• Primary endpoints: safety and tolerability.⁸

Safety Results

Raab et al (2024)⁸ presented the incidence of hypogammaglobulinemia from 3 induction cohorts of the MajesTEC-5 study.

• Hypogammaglobulinemia (including patients with ≥1 TEAE of hypogammaglobulinemia or postbaseline IgG <400 mg/dL) was reported in 91.8% of patients (n=45) overall.
  • Of the total patients, 89.8% (n=44) received ≥1 dose of IVIG,including those who started IVIG prior to receiving TECVAYLI.

clinical data - Majestec-7 Study - TECVAYLI + TALVEY COHORT

MajesTEC-7 (MMY3005; clinicaltrials.gov identifier NCT05552222) is a randomized, phase 3, open-label, multicenter study comparing the safety and efficacy of Tec-DR and Tal-DR vs DRd in patients with NDMM who are ineligible or not intended for transplant as initial therapy.^5,20

Study Design/Methods

SRI Cohort 1 (Tec-DR)

• A SRI period was used to establish safety prior to enrolling in the randomized phase of the study.²⁰
• Key eligibility criteria: NDMM either ineligible or not intended for ASCT.^5,20
• Primary endpoints: PFS, 12-month minimal residual disease (MRD)-negative CR.^5,20
• Key secondary endpoint: Safety.^5,20

Safety Results

Touzeau et al (2024)²⁰ presented the incidence of hypogammaglobulinemia from the SRI of 26 patients in Cohort 1 (Tec-DR) of the MajesTEC-7 study at a median follow-up of 13.8 months (range, 2.0-15.4).

• Hypogammaglobulinemia (including patients with ≥1 treatment-emergent hypogammaglobulinemia or postbaseline IgG <500 mg/dL) was reported in 80.8% of patients (n=21). Overall, 73.1% of patients (n=19) received at least 1 dose of IVIG.

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 efficacy of the combination of TALVEY and TECVAYLI in patients with RRMM.^4,9,21,22

Study Design/Methods

• Key eligibility criteria: relapsed or refractory or intolerant to established therapies including the last LOT, prior exposure to a PI, an immunomodulatory drug, and an anti-CD38 monoclonal antibody.^9,22
• Primary endpoints: dose limiting toxicity and ORR.^9,22

Safety Results

Cohen et al (2025)^9,23 published the incidence of hypogammaglobulinemia from the phase 1 dose-escalation segment of the RedirecTT-1 study at a median follow-up of 20.3 months (range, 0.5-37.1) in the all dose levels (dose levels 1-5) cohort.

• At baseline, 56% of patients (n=53) across all dose levels had non-IgG myeloma.⁹
  • Of these patients, 70% of patients (n=37) had hypogammaglobulinemia (defined as IgG <400 mg/dL) at baseline and 57% of patients (n=30) had post-treatment hypogammaglobulinemia.⁹
• The assessments excluded patients with IgG myeloma and those who received IVIG replacement.⁹
• A total of 57% of patients (n=30) with non-IgG myeloma received IVIG.⁹
• A patient with a baseline IgG value of 248 g/dL and hypogammaglobulinemia, without IVIG administration, experienced intermittent neutropenia prior to AE.²³
  • The patient experienced grade 2 John Cunningham (JC) virus infection on day 163, progressive disease on day 170, when the patient discontinued TALVEY and TECVAYLI, and died on day 217 from grade 5 JC virus infection.²³

clinical data - Trimm-2 study - TECVAYLI + TALVEY COHORT

TRIMM-2 (MMY1002; clinicaltrials.gov identifier: NCT04108195) is an ongoing, phase 1b, 2-part, multicohort, open-label study evaluating the safety and efficacy of DARZALEX FASPRO regimens in combination with bispecific T-cell redirection antibodies in patients with RRMM.^10,24,25

Study Design/Methods

• Key eligibility criteria: ≥3 prior LOTs (including a PI and an immunomodulatory drug) or double refractory to a PI and an immunomodulatory drug, anti-CD38 monoclonal antibody >90 days prior allowed, prior BsAb and CAR-T were allowed.²⁴
• Key primary endpoint: safety.²⁴

Safety Results

D'Souza et al (2024)¹⁰ presented the incidence of hypogammaglobulinemia in the TECVAYLI + DARZALEX FASPRO + pomalidomide cohort at a median follow-up of 38.3 months (range, 1.2-39.6).

• Hypogammaglobulinemia (as an AE, any grade or postbaseline IgG <400 mg/dL) was reported in 100% of patients; 80% of patients (n=8) received IVIG.
• Study enrollment began before IVIG was routinely recommended for patients treated with bispecific antibodies (November 2020 to March 2021).

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 10 February 2025.