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•Teclistamab induces severe defects in humoral immunity with decreased polyclonal immunoglobulin levels and impaired vaccination responses.•IVIG use was associated with a significantly lower risk of serious infections among patients receiving teclistamab treatment.

There is a need for novel therapies for relapsed or refractory multiple myeloma, and B-cell maturation antigen (BCMA) is a validated target. Teclistamab is a bispecific antibody that binds BCMA and CD3 to redirect T cells to multiple myeloma cells. The aim of the MajesTEC-1 study was to evaluate the safety, tolerability, and preliminary efficacy of teclistamab in patients with relapsed or refractory multiple myeloma.

•Better clinical responses to teclistamab correlate with a more functional initial immune T-cell repertoire in the periphery and tumor site.•More durable responses to teclistamab associate with lower Tregs and lower expression of inhibitory receptors on T cells at baseline.

Introduction:Teclistamab (tec) is the only approved B-cell maturation antigen (BCMA) × CD3 bispecific antibody with a personalized, weight-based dosing schedule for the treatment of triple-class exposed relapsed/refractory multiple myeloma (RRMM). In the phase 1/2 MajesTEC-1 study (NCT03145181/NCT04557098), tec demonstrated deep and durable responses. To better understand mechanisms of resistance and relapse in MajesTEC-1, we assessed longitudinal BCMA expression and immune profiles.

Introduction:Teclistamab is the only approved B-cell maturation antigen (BCMA) × CD3 bispecific antibody (BsAb) with personalized, weight-based dosing for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM).In the MajesTEC-1 study (NCT03145181 and NCT04557098), the incidence of all grade (mostly grade 1 or 2) cytokine release syndrome (CRS) was 72.1% (Moreau et al. 2022). The cytokine interleukin-6 (IL-6) is found to be increased in the serum of patients with CRS (Shimabukuro-Vornhagen et al. 2018). Tocilizumab is a humanized IL-6 receptor-inhibiting monoclonal antibody. As a competitive antagonist, tocilizumab inhibits the IL-6 pathway by competing with IL-6 for binding to IL-6 receptor (IL-6R), resulting in lower IL-6R receptor occupancy (RO) by IL-6, thereby blocking IL-6 signaling. By blocking IL-6R, tocilizumab also reduces IL-6R-mediated IL-6 clearance, which leads to an increase in serum IL-6 levels (Uchiyama et al. 2008). It has been published previously that a single dose of prophylactic tocilizumab reduced the overall incidence of CRS to 26% after teclistamab administration, which represents a 64% reduction compared to the CRS incidence observed in MajesTEC-1 (van de Donk et al. 2023). A mechanism-based PK/PD model was used to evaluate the impact of tocilizumab prophylactic treatment on the soluble IL-6R (sIL-6R), IL-6 and the duration of the blockade of IL-6 signaling pathway in the patients following teclistamab treatment.

Introduction:Teclistamab (JNJ-64007957) is a T-cell redirecting, bispecific IgG4 antibody that targets both B-cell maturation antigen (BCMA) and CD3 receptors to induce T-cell mediated cytotoxicity of BCMA-expressing myeloma cells. Teclistamab is under investigation in MajesTEC-1, an ongoing phase 1/2 study in patients (pts) with heavily pretreated relapsed/refractory multiple myeloma (RRMM). Results from the phase 1 study (parts 1 and 2; NCT03145181) indicated that teclistamab is well tolerated at the recommended phase 2 dose (RP2D) and has encouraging efficacy, with an overall response rate (ORR) of 65% and very good partial response or better (≥VGPR) rate of 58% in 40 pts after a median of 6.1 mo of follow-up. Here we report for the first time initial data from the phase 2 portion of MajesTEC-1 (part 3; NCT04557098) and updated results for phase 1 pts treated at the RP2D.

Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria. Usmani: Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; Abbvie: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding. Garfall: Amgen: Honoraria; Tmunity Therapeutics: Research Funding; Novartis: Research Funding; GSK: Honoraria; Janssen: Honoraria, Research Funding. van de Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy. Nahi: XNK Therapeutics AB: Consultancy. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Oriol: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Nooka: GlaxoSmithKline: Consultancy, Other: Travel expenses; Bristol-Myers Squibb: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy; Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive technologies: Consultancy; Karyopharm Therapeutics: Consultancy. Martin: Amgen: Research Funding; Sanofi: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Consultancy; Oncopeptides: Consultancy. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Chari: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Karlin: Abbvie: Honoraria; Amgen: Honoraria, Other: travel support and advisory board ; GSK: Honoraria, Other: member of advisory board; Janssen: Honoraria, Other: member of advisory board, travel support; Takeda: Honoraria, Other: member of advisory board; Celgene-BMS: Honoraria, Other: member of advisory board; Sanofi: Honoraria; oncopeptide: Honoraria. Mateos: Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Bahlis: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Genentech: Consultancy; Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Popat: Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Janssen and BMS: Other: travel expenses. Besemer: GSK: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Sidana: Allogene: Research Funding; Janssen: Consultancy, Research Funding; Magenta Therapeutics: Consultancy, Research Funding; BMS: Consultancy. Pei: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Trancucci: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Verona: Janssen: Current Employment. Girgis: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Olyslager: Janssen: Current Employment. Jaffe: Janssen: Current Employment. Uhlar: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Stephenson: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Van Rampelbergh: Janssen: Current Employment. Banerjee: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Kobos: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Krishnan: MAGENTA: Consultancy; BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; JANSSEN: Consultancy, Research Funding; City of Hope Cancer Center: Current Employment; REGENERON: Consultancy; SANOFI: Consultancy; GSK: Consultancy; Amgen: Speakers Bureau.

B cell maturation antigen (BCMA; CD269; TNFRSF17) is a surface receptor, expressed on benign and malignant plasma cells. The restricted expression of BCMA on B-cell lineage makes it an ideal target for multiple myeloma (MM) immunotherapy. BCMAxCD3 bispecific antibody (Teclistamab; JNJ-64007957) has been developed to recruit CD3+T-cells to BCMA+MM cells. Teclistamab demonstrated potent cytotoxicity in a murine xenograft model and against ex vivo primary MM cells.

Garfall: Tmunity: Consultancy, Other: Personal fees, Research Funding; Kite Pharma: Other: Personal fees; Amgen: Research Funding; Novartis: Research Funding; GSK: Consultancy; Janssen: Consultancy, Research Funding; Surface Oncology: Consultancy. Usmani:Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Research Funding; SkylineDX: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Celgene: Other; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Array Biopharma: Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Mateos:Adaptive: Consultancy; Amgen: Consultancy; GlaxoSmithKline: Consultancy; Pharmamar: Consultancy; Janssen: Consultancy; Celgene: Consultancy; EDOMundipharma: Consultancy; AbbVie: Consultancy; Takeda: Consultancy. van de Donk:Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ferrer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Oriol Rocafiguera:Amgen: Consultancy, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chari:Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Array BioPharma: Honoraria; The Binding Site: Honoraria; Sanofi Genzyme: Consultancy; Adaptive Biotechnology: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Secura Bio: Consultancy; Glaxo Smith Kline: Consultancy; Oncopeptides: Consultancy. Bhutani:Prothena: Other: Clinical Trial Funding to Institute; Janssen: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Sanofi Genzyme: Consultancy; MedImmune: Other: Clinical Trial Funding to Institute. Pei:J&J: Current Employment, Current equity holder in publicly-traded company. Verona:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Girgis:Johnson & Johnson: Current Employment, Current equity holder in private company. Stephenson:Johnson & Johnson: Current Employment, Current equity holder in private company. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Banerjee:Janssen: Current Employment. Krishnan:BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau; Janssen: Consultancy; Takeda: Speakers Bureau; Z Predicta: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Sanofi: Consultancy; Sutro: Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy.

Background:MM inevitably relapses and becomes refractory to treatment, representing a patient (pt) population with unmet needs. Teclistamab (JNJ-64007957) is a bispecific BCMA x CD3 antibody that induces T cell-mediated cytotoxicity against BCMA-expressing MM cells. Previously presented results from an ongoing study of teclistamab in RRMM (NCT03145181) included a 67% objective response rate [ORR] for the 270 µg/kg dose administered intravenously (iv) (Usmani et al, ASCO 2020 Oral Presentation #100). Here we present updated results and newly available data for subcutaneous (sc) administration.