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Introduction: Novel agents are needed for multiple myeloma (MM), which remains incurable with most patients (pts) relapsing or becoming refractory to standard therapies. Talquetamab (Tal) is a bispecific antibody that binds to G protein-coupled receptor family C group 5 member D (GPRC5D), a receptor highly expressed on plasma cells with limited expression in healthy tissue, and CD3 to redirect T cells to GPRC5D-expressing MM cells. Tal monotherapy at the recommended phase 2 dose (RP2D) was well tolerated and yielded an overall response rate of 70% after 6.3 months of follow-up in pts with relapsed/refractory MM (RRMM) in the phase 1 MonumenTAL-1 study; responses were durable and continued to deepen over time. Daratumumab (Dara) is a monoclonal antibody approved for MM treatment that targets CD38 on MM cells, resulting in direct cytotoxicity of MM cells. Dara also impacts immune cell populations, ie, increasing helper and cytotoxic T cells and decreasing suppressive CD38+ immunoregulatory cells. Preclinical studies showed addition of Dara enhanced Tal-mediated lysis of MM cells, suggesting the combination may also increase clinical activity in pts with RRMM. We report initial findings for pts with RRMM who received Tal + Dara in a phase 1b multicohort study (TRIMM-2; NCT04108195). Methods: Eligible pts (aged ≥18 years) were diagnosed with MM and had received ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and an IMiD. Pts were excluded if they had received an anti-CD38 therapy ≤90 days. Subcutaneous (SC) Tal and Dara were administered in 28-day cycles in different dosing cohorts (with step-up dosing for Tal). The primary objectives were to identify the RP2D of Tal in combination with Dara and to characterize the safety of Tal + Dara at the RP2D. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] graded per ASTCT guidelines). Results: As of Jul 23, 2021, 23 pts were administered SC Tal + Dara in separate cohorts: Dara 1800 mg + Tal 400 µg/kg weekly (n=8), + Tal 400 µg/kg biweekly (n=5), and + Tal 800 µg/kg biweekly (n=10). Median follow-up across the Tal + Dara cohorts was 2.9 months (range 0.3-11.2). Median age of pts treated with Tal + Dara was 68 years (range 44-81), and 52.2% were male. Pts had received a median of 6 prior lines of therapy (range 3-18); 82.6% were triple-class exposed (82.6% received prior Dara and 8.7% received prior isatuximab) and 73.9% were penta-drug exposed. Any grade AEs were reported in 95.7% of pts and grade 3/4 AEs in 78.3%. The most frequently reported AEs (≥30% across Tal + Dara cohorts) were dysgeusia (52.2%; all grade 1/2), neutropenia (39.1%; grade 3/4 30.4%), thrombocytopenia (39.1%; grade 3/4 21.7%), anemia (34.8%; grade 3/4 21.7%), CRS (34.8%; all grade 1/2), and skin exfoliation (30.4%; all grade 1/2). The median time to CRS onset was 2.5 days (range 2-4), and the median duration was 2 days (range 1-3). Infections occurred in 34.8% of pts (grade 3/4 17.4%). Skin disorders were reported in 65.2% of pts (grade 3/4 13.0%), including nail disorders in 17.4% (all grade 1/2); these events were manageable and did not lead to treatment discontinuation. Two events of ICANS were reported (a grade 1 event [concurrent with CRS] and a grade 3 event), both of which resolved and did not recur. One pt in the Dara 1800 mg + Tal 400 μg/kg biweekly cohort died due to disease progression. Responses in different dosing cohorts are shown in the Table. The median time to first response across Tal + Dara cohorts was 1.0 month (range 0.9-2.4), and median duration of response was not reached. The pharmacokinetic profile of Tal was similar to that observed in the phase 1 monotherapy study. Tal + Dara treatment resulted in proinflammatory cytokine production and T-cell activation, evidenced by interferon-γ and tumor necrosis factor-α induction and PD-1 and CD38 upregulation on peripheral T cells, respectively. Updated data with longer follow-up will be presented at the congress. Conclusions: Tal in combination with Dara was well tolerated, with a safety profile comparable to the monotherapies, and showed promising efficacy in pts with RRMM. These findings support further clinical development of Tal + Dara combination therapy. Figure 1 Figure 1. Disclosures Chari: BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Consultancy, Research Funding; Genentech: 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; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hari: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Bahlis: Janssen: Consultancy, Honoraria; Genentech: Consultancy; BMS/Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Mateos: Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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; Regeneron: 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; Adaptive Biotechnologies: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. van de Donk: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; Takeda: 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; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding. Dholaria: Janssen: Research Funding; Takeda: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau; Pfizer: Research Funding. Garfall: Janssen: Honoraria, Research Funding; GSK: Honoraria; Novartis: Research Funding; Tmunity Therapeutics: Research Funding; Amgen: Honoraria. Goldschmidt: Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Molecular Partners: Research Funding; Johns Hopkins University: Other: Grant; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. Krishnan: City of Hope Cancer Center: Current Employment; JANSSEN: Consultancy, Research Funding; BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; MAGENTA: Consultancy; REGENERON: Consultancy; SANOFI: Consultancy; GSK: Consultancy; Amgen: Speakers Bureau. Martin: Janssen: Research Funding; Amgen: Research Funding; Oncopeptides: Consultancy; Sanofi: Research Funding; GlaxoSmithKline: Consultancy. Morillo Giles: Janssen: Honoraria; Takeda: Honoraria; Abbvie: Honoraria. Oriol: 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; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, 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. Reece: BMS: Honoraria, Research Funding; GSK: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Millennium: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria. Rodriguez: Takeda: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; BMS: Consultancy, Speakers Bureau. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria; Clínica Universidad de Navarra: Current Employment. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board. Usmani: Array BioPharma: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; Merck: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding. Verona: Janssen: Current Employment. Wang Lin: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Prior: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Wade: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Weiss: Janssen: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Askari: Janssen: Research Funding.

Introduction: Teclistamab (Tec) is a B-cell maturation antigen × CD3 T-cell redirecting bispecific antibody. In the phase 1 MajesTEC-1 trial in patients (pts) with heavily pretreated relapsed/refractory multiple myeloma (RRMM), Tec monotherapy was well tolerated and yielded an overall response rate of 65% and very good partial response or better rate of 58% at the recommended phase 2 dose (RP2D) with 6.1 months' median follow-up; responses were durable and deepened over time. Daratumumab (Dara) is a monoclonal antibody that targets CD38 and is approved for the treatment of MM. In addition to direct cytotoxicity, Dara has immunomodulatory effects, including promotion of T-cell expansion and depletion of suppressive CD38+ immunoregulatory cells, making it a rational partner for T-cell redirection. In preclinical studies, the lytic activity of Tec against MM cell lines was enhanced by pretreatment and combination treatment with Dara. By targeting discrete yet complementary antigens, combination of Tec and Dara may improve efficacy in pts with RRMM. We present data for pts with RRMM who received Tec + Dara in a phase 1b multicohort study (TRIMM-2; NCT04108195). Methods: Eligible pts were ≥18 years of age with an MM diagnosis and had received ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and IMiD. Pts who had received anti-CD38 therapy ≤90 days were excluded. In Tec + Dara cohorts, treatment was administered in 28-d cycles (with step-up dosing for Tec). The primary objectives were to identify the RP2D for the Tec + Dara combination and evaluate its safety. This analysis focuses on subcutaneous (SC) cohorts in the study. Responses were assessed by IMWG criteria and adverse events (AEs) by CTCAE v5.0, except for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which were graded per ASTCT guidelines. Results: A total of 33 pts received SC Tec + Dara in different dosing cohorts: Dara 1800 mg + Tec 1500 µg/kg weekly (n=21), + Tec 3000 µg/kg weekly (n=5), + Tec 300 mg biweekly starting Cycle 3 Day 1 (Tec 150 mg weekly in Cycles 1-2; n=2), and + Tec 3000 µg/kg biweekly (n=5). Nine pts in the Dara 1800 mg + Tec 1500 µg/kg weekly cohort switched to Tec 3000 μg/kg biweekly dosing after Cycle 3 Day 1. As of the data cutoff (Jun 22, 2021), median follow-up across Tec + Dara cohorts was 3.6 months (range 0.1-10.4). Median pt age was 67 years (range 51-78) and 57.6% were female. Median number of lines of prior therapy was 5 (range 2-16); 69.7% of pts were triple-class exposed (prior anti-CD38 therapy was Dara in all 69.7%) and 60.6% were penta-drug exposed. Overall, 97.0% of pts had ≥1 AE of any grade; 66.7% had grade 3/4 AEs. The most common AE was CRS (54.5%; all grade 1/2); median time to onset was 2 days (range 1-6), and median duration was 2 days (range 1-7). Other AEs (≥30% across Tec + Dara cohorts) were neutropenia (36.4%; all grade 3/4), thrombocytopenia (36.4%; grade 3/4 33.3%), anemia (36.4%; grade 3/4 24.2%), diarrhea (36.4%; grade 3/4 3.0%), nausea (30.3%; all grade 1/2), and pyrexia (30.3%; all grade 1/2). Infections occurred in 51.5% of pts (grade ≥3 24.2%). No ICANS events were reported. One pt in the Dara 1800 mg + Tec 3000 µg/kg weekly cohort died due to bacterial pneumonia (unrelated to treatment) during Cycle 1, and 1 in the Dara 1800 mg + Tec 1500 µg/kg weekly cohort died due to progressive disease. Responses in different dosing cohorts are shown in the Table. Across Tec + Dara cohorts, median time to first response was 1.0 month (range 0-1.9). Median duration of response was not reached. Tec + Dara treatment led to proinflammatory cytokine production (induction of interferon-γ and tumor necrosis factor-α) and T-cell activation (upregulation of programmed cell death protein-1 and CD38 on peripheral T cells). The Tec pharmacokinetic profile was similar to that in MajesTEC-1. Data will be updated with longer follow-up at the time of the congress. Conclusions: The combination of Tec + Dara had a manageable safety profile, consistent with the monotherapies, and showed preliminary efficacy in pretreated pts with MM; with longer follow-up, responses may continue to deepen, as has been seen with Tec monotherapy. These promising data warrant further investigation; the randomized phase 3 MajesTEC-3 study will evaluate Tec + Dara vs Dara, pomalidomide, and dexamethasone or Dara, bortezomib, and dexamethasone in pts with RRMM. Figure 1 Figure 1. Disclosures Rodriguez-Otero: Amgen: Honoraria; Kite: 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; Pfizer: Consultancy; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Clínica Universidad de Navarra: Current Employment; Regeneron: Honoraria. Dholaria: Takeda: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau. Askari: Janssen: Research Funding. Reece: Karyopharm: Consultancy, Research Funding; GSK: Honoraria; Millennium: Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Research Funding; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. van de Donk: Cellectis: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: 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; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chari: Oncopeptides: 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; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Sanofi Genzyme: 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; Pharmacyclics: Research Funding; Antengene: 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; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldschmidt: MSD: Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; Molecular Partners: Research Funding; Johns Hopkins University: Other: Grant; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. Krishnan: City of Hope Cancer Center: Current Employment; JANSSEN: Consultancy, Research Funding; BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; MAGENTA: Consultancy; REGENERON: Consultancy; SANOFI: Consultancy; GSK: Consultancy; Amgen: Speakers Bureau. Martin: Sanofi: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Consultancy. Mateos: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Roche: 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; Adaptive Biotechnologies: 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; Takeda: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bluebird bio: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Morillo Giles: Janssen: Honoraria; Takeda: Honoraria; Abbvie: Honoraria. Rodriguez: Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Karyopharm: Consultancy, Speakers Bureau. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board. Sureda: Bluebird: Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau. Wäsch: Amgen: Consultancy, Honoraria; Pfizer: Consultancy; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Weisel: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Verona: Janssen: Current Employment. Wang Lin: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Prior: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Weiss: Janssen: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months. Wade: 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. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: 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; 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. Hari: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, 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. Teclistamab clinical starting dose in the first in human (FIH) study in relapsed refractory MM patients began at the minimal anticipated biological effect level (MABEL) of 0.3 µg/kg using the EC20 of the in vitro cytotoxicity assay in the purified T cells model with MM.1R cell line. Since the MABEL dose is usually low, it is important to have guidance on the expected therapeutic range in patients. The therapeutic concentrations of teclistamab were estimated from an ex vivo cytotoxicity assay in which samples from MM patients (frozen purified mononuclear cells from bone marrow) were treated with healthy human purified T cells (1:1 ratio) spiked with teclistamab and incubated for 48 hours. The mean and range of EC50 and EC90 values of the cytotoxicity endpoint were estimated. The pharmacokinetic (PK) data following the first cycle doses in the low dose cohorts in the FIH study in MM patients were modeled using 2-compartment model and simulated to predict the doses that will have average and trough serum teclistamab concentrations in the expected therapeutic range (between EC50 and EC90). The predicted doses with average serum concentrations between the mean EC50 (372 ng/mL) and mean EC90 (2287 ng/mL) range were validated with the observed clinical data showing positive response in 2 out of 4 patients at the 38.4 µg/kg intravenous treatment dose level and their average serum teclistamab concentration overlaid within the estimated therapeutic range. This was also confirmed with the teclistamab concentrations in bone marrow samples (measured in a subset of MM patients in the study) where they were found to superimpose in the estimated therapeutic range. In addition, simulations predicted the dose that will have trough levels above the maximum EC90 (6070 ng/mL), to account for patients with high tumor burden, at which the observed clinical data have shown promising response rate and has been selected to be the recommended subcutaneous phase 2 dose of 1500 µg/kg. In conclusion, ex vivo cytotoxicity assay with MM patients bone marrow samples is an informative tool to predict the efficacious serum concentration of immuno-oncology drugs in MM patients. PK modeling and simulations of MM patients' data in FIH study coupled with the ex vivo cytotoxicity estimates provided guidance on the expected recommended phase 2 dose during the escalation phase of the FIH study. Disclosures Girgis: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Wang Lin:Johnson & Johnson: Current Employment. Pillarisetti:Johnson & Johnson: Current Employment. Banerjee:Janssen: Current Employment. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Shetty:Johnson & Johnson: Current Employment. Stephenson:Johnson & Johnson: Current Employment, Current equity holder in private company. Hilder:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Hanna:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Smit:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Adams III:Genmab: Current Employment. Sun:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Infante:Janssen: Current Employment. Elsayed:Johnson & Johnson: Current Employment. Sharma:Johnson & Johnson: Current Employment.