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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.

Background: Heavily pretreated relapsed and refractory multiple myeloma (RR MM) constitutes a specific and unmet medical need. Median survival ranges from as little as 6 to 9 months, and responses to treatment are characteristically short (Richardson et al. 2007). Belantamab Mafodotin (BM), a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin F, showed single-agent activity in the phase 1 DREAMM-1 and phase 2 DREAMM-2 studies in heavily pre-treated patients with RRMM (Lonial et al, 2019 & 2021). We aim to assess efficacy and safety of BM treatment administered via the expanded access compassionate care program for triple class MMRR patients in the region of Madrid (Spain). Methods: An observational, retrospective and multicenter study has been performed including all patients who received at least one dose of BM under the expanded access program in the region of Madrid (Spain) from Nov 2019 to Jun 2021. Hematology centers provided data from the medical records and entered them in a case report form distributed to the sites. Primary endpoint was overall response rate (ORR). Secondary endpoints were progression free survival (PFS), overall survival (OS) and the incidence of treatment emergent adverse events (TEAEs), with a major focus on ocular and hematologic toxicity. Results: A total of 33 patients (pts), from 14 different centers, were included from February 2020 till May 2021. Median age was 70 (46-79) years. 55% of the pts were women. Median time from diagnosis was 71 (10-858) months. 30.3% were high-risk cytogenetic features. Median of prior therapy lines was 5 (3-8) and at least 88% of the pts were triple class refractory. The median number of BM doses per patient was 3 (1-16) and the median follow-up was 11 months (95%CI 6.34-15.66). ORR was 42.2%, and 18.2% achieved ≥VGPR. Median PFS was 3 months (95%CI 0.92-5.08). Median PFS for patients who achieved ≥PR was 11 months (HR 0,26; 95% CI 0,10-0,68). No significant differences were found in PFS according to age, cytogenetic risk and prior therapy lines. OS was 424 days (95% CI 107-740). The incidence of non-hematological TEAEs was 57.6% and the most common of which was ocular toxicity (45.5%). The incidence of ≥G3 non-hematological TEAEs was 30.3%. 51.5% of the pts were diagnosed of keratopathy and 21.2% was ≥G3. 30.3% of the pts showed a reduced visual acuity, but this event was resolved in 92.9% of the pts. The most common symptoms were blurry vision (30.3%, n=10) and dry eye (24.2%, n=8). The incidence of ≥G3 hematological TEAEs was 18.2% and thrombocytopenia was the most frequent (21.2%). Dose reductions of BM were required in 30.3% of the pts and delayed in 36.4% due to TEAEs. Main causes for treatment discontinuation (81%, n=27) were disease progression (54.5%, n=18), toxicity (15.2%, n=5), death (6.1%, n=3) and due to patient's decision (3%, n=1). Conclusion: Compassionate use of BM in heavily pretreated RR MM pts showed a relevant anti-myeloma activity with a manageable safety profile.These results are similar to those observed in the DREAMM-1 and DREAMM-2 clinical trials. Disclosures No relevant conflicts of interest to declare.

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.

Introduction: Despite recent advances in treatment, patients with multiple myeloma (MM) continue to relapse. G protein-coupled receptor family C group 5 member D (GPRC5D) is a promising target for immunotherapy in patients with MM due to its high expression in malignant plasma cells and limited expression in normal human tissue; unlike other antigens targeted by MM therapies, there is no indication that GPRC5D sheds into the periphery. Talquetamab (JNJ-64407564) is a first-in-class bispecific IgG4 antibody that redirects T cells to kill MM cells by binding to both GPRC5D and CD3 receptors. Here we report updated and new results of talquetamab at the recommended phase 2 doses (RP2Ds) from a phase 1 trial in relapsed/refractory MM (RRMM; NCT03399799). Methods: Eligible patients with MM had relapsed or refractory disease or were intolerant to standard therapies; patients previously treated with B-cell maturation antigen (BCMA)-directed therapies were eligible. This analysis focuses on patients who received talquetamab subcutaneously (SC; range 5.0-800 µg/kg) weekly or biweekly. Step-up dosing was used as a patient management strategy to minimize the severity of cytokine release syndrome (CRS). The primary objectives were to identify the RP2D (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Adverse events (AEs) were graded by CTCAE v4.03 with CRS events graded per Lee et al 2014 criteria. Responses were investigator-assessed per International Myeloma Working Group criteria. Results: As of July 19, 2021, 95 patients have received SC talquetamab. The RP2D was originally identified as a weekly SC dose of 405 µg/kg talquetamab with step-up doses. However, alternative dosing schedules that require less frequent administration continue to be investigated. A biweekly RP2D was also identified as an SC dose of 800 µg/kg talquetamab with step-up doses. 30 patients received the 405 µg/kg weekly dosing schedule (median age: 61.5 years [range 46-80]; 63% male; 100% triple-class exposed; 80% penta-drug exposed; 77% triple-class refractory, 20% penta-drug refractory; 30% prior BCMA-directed therapy; median follow-up: 7.5 mo [range 0.9-15.2]). 23 patients received the 800 µg/kg biweekly dosing schedule (median age: 60.0 years [range 47-84]; 48% male; 96% triple-class exposed; 70% penta-drug exposed; 65% triple-class refractory, 22% penta-drug refractory; 17% prior BCMA-directed therapy; median follow-up 3.7 mo [range 0.0-12.0]). There were no treatment discontinuations due to AEs at either of the RP2Ds. The most common AEs at the 405 µg/kg weekly dose were CRS (73%; 1 patient had grade 3 CRS), neutropenia (67%; grade 3/4: 60%), and dysgeusia (60%; grade 2: 29%); skin-related AEs occurred in 77% (all grade 1/2; nail disorders: 30%) of patients, and infections occurred in 37% of patients (1 patient had grade 3 COVID-19 pneumonia). The most common AEs at the 800 µg/kg biweekly dose were CRS (78%; all grade 1/2), dry mouth (44%; all grade 1/2), and neutropenia (44%; grade 3/4: 35%); skin-related AEs occurred in 65% of patients (grade 3: 13%; nail disorders: 17%) and infections occurred in 13% of patients (1 patient had grade 3 pneumococcal sepsis). In 30 response-evaluable patients treated with the 405 µg/kg weekly dose, the overall response rate (ORR) was 70% (very good partial response or better [≥VGPR] rate: 57%). In 17 response-evaluable patients treated with the 800 µg/kg biweekly dose, the ORR was 71% (≥VGPR rate: 53%). Responses were durable and deepened over time in both cohorts (Figure). Median duration of response (DOR) was not reached at either RP2D; the 6-month DOR rate for patients who received the 405 µg/kg weekly dose was 67% [95% CI: 41-84]. Serum trough levels of talquetamab were comparable at both RP2Ds. Consistent with the mechanism of action for talquetamab, pharmacodynamic data from cohorts treated at both dose levels showed peripheral T-cell activation and induction of cytokines. Conclusions: These findings indicate that SC talquetamab is well tolerated and highly effective at both RP2Ds. Preliminary data from the 800 µg/kg biweekly cohorts indicate that less frequent, higher doses of SC talquetamab do not have a negative impact on the previously described safety profile. Further investigation of talquetamab as monotherapy (phase 2; NCT04634552) and in combination with other therapies in patients with RRMM is underway. Figure 1 Figure 1. Disclosures 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. Minnema: Celgene: Other: Travel expenses; Alnylam: Consultancy; Cilag: Consultancy; BMS: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy. Berdeja: Lilly, Novartis: Research Funding; Abbvie, Acetylon, Amgen: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; EMD Sorono, Genentech: Research Funding; Poseida, Sanofi, Teva: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; GSK, Ichnos Sciences, Incyte: Research Funding. Oriol: 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; 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. van de Donk: Roche: Consultancy; Takeda: Consultancy; Cellectis: Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS/Celgene: Consultancy, Honoraria; Novartis /bayer/servier: Consultancy. Rodriguez-Otero: Clínica Universidad de Navarra: Current Employment; 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. Askari: Janssen: Research Funding. Mateos: Sanofi: 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; 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; Amgen: 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; 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; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Bluebird bio: Honoraria; AbbVie: Honoraria; GSK: Honoraria; Oncopeptides: 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. Costa: BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau. Verona: Janssen: Current Employment. Ma: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Girgis: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Yang: Janssen: Current Employment. Hilder: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Russell: Janssen: Ended employment in the past 24 months. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Chari: Shattuck Labs: 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; Millenium/Takeda: Consultancy, Research Funding; Sanofi Genzyme: 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; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Secura Bio: 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; AbbVie: 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; Novartis: Consultancy, Research Funding; Genentech: 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.

Despite improved outcomes with current MM treatments, most patients (pts) will develop refractory disease, highlighting the need for novel treatments. GPRC5D is an orphan receptor whose transcript is highly expressed in primary MM cells but has generally limited expression elsewhere, making it an attractive therapeutic target. Talquetamab (JNJ-64407564) is a first-in-class bispecific antibody that binds to GPRC5D and CD3 to induce T cell-mediated killing of GPRC5D-expressing MM cells through the recruitment and activation of T cells. In preclinical models, talquetamab induced cell killing of primary MM cells and inhibited tumor formation and growth in MM mouse models. We present initial results from an ongoing phase 1 dose escalation study of talquetamab (NCT03399799). Eligible pts have measurable MM and progressed on or could not tolerate established therapies. Primary objectives are to characterize the safety of talquetamab and to identify a recommended phase 2 dose (RP2D). Escalating doses of intravenous (IV) or subcutaneous (SC) talquetamab ± step-up doses were assessed. Secondary objectives include characterizing the pharmacokinetics, pharmacodynamics, and preliminary efficacy. Adverse events (AEs) were graded per CTCAE, cytokine release syndrome (CRS) per Lee 2014. Response was assessed by the investigator according to IMWG criteria. As of 20 Jul 2020, 137 pts had received talquetamab; 102 by IV (0.5 - 180 µg/kg) and 35 by SC (5 - 800 µg/kg) dosing. Median age was 64 years (33 - 80; 31% were ≥70) and 22% had ISS stage III disease at study entry. Median number of prior therapies was 6 (2 - 20) over a median of 6.5 years (0.9 - 27) since diagnosis, 85% were refractory to last line of therapy, 79% triple-class refractory, 73% penta-drug exposed, and 31% penta-drug refractory. 13 (10%) pts had received selinexor and 21 (15%) had prior BCMA-directed therapy. Most frequently reported all grade AEs were anemia (50%), CRS (47%), neutropenia (45%), and lymphopenia (40%). Most common grade 3 - 4 AEs were lymphopenia (37%), anemia (27%), and neutropenia (25%). CRS was mostly grade 1 - 2 except for 5 pts with grade 3 CRS (˂8% of pts with CRS) that occurred with IV dosing; only grade 1 - 2 CRS was seen with SC dosing. CRS was generally confined to the first cycle with median time to onset of 1 day (1 - 3) for IV and 2 days (1 - 5) for SC dosing. Treatment-related neurotoxicity was reported in 7 (5%) pts (all resolved/resolving; median duration of 2 days [1 - 9]): 4 had grade 1 - 2 events and 3 had grade 3 events of delirium (n=1), decreased level of consciousness (n=1), or confusion (n=1). Six of 7 pts had neurotoxicity that occurred in the context of CRS, including all 3 grade 3 events. Infections were reported in 37% of pts (8% grade 3 - 4). Infusion related reactions (IV; 15%) and injection site reactions (SC; 14%) were grade 1 - 2 and generally occurred in cycle 1. Two dose-limiting toxicities were observed: clinically asymptomatic grade 4 increased lipase in the setting of a pancreatic plasmacytoma (7.5 µg/kg IV) and grade 3 maculopapular rash (135 µg/kg SC). The maximum tolerated dose (MTD) has not been defined. The half-life of talquetamab supports weekly IV dosing. Exposure increased in an approximately dose-proportional manner following the first IV dose (1.5 - 60 µg/kg). SC dosing resulted in lower Cmax with trough levels comparable to IV dosing at a similar dose. IV and SC dosing of talquetamab led to comparable increases in T cell activation and cytokines (e.g., IL-10, IL-2Rα, IL-6). Cytokine production was modulated with step-up dosing while T cell activation was maintained. Overall response rate (ORR) for IV doses of 20 - 180 µg/kg was 78% (14/18; 2 pending confirmation); 6/6 responded at the 60 µg/kg IV dose. ORR for SC doses of 135 - 405 µg/kg was 67% (8/12); 3/4 responded at the 405 µg/kg SC dose. Responses were noted starting at 1.0 µg/kg, were rapid at a median of 1 month (0.2 - 3), and durable with median not reached in 36/46 (4 pts with response 15+ months; longest at 23+ months). Data at higher doses are immature, and results will be updated at the meeting. GPRC5D is a novel target for MM and in the first clinical report of this first-in-class agent, encouraging clinical activity with manageable safety was observed with talquetamab in heavily pretreated pts with RRMM. A MTD has not been defined and dose escalation continues, with the study nearing a RP2D. The encouraging clinical activity supports monotherapy development and combination approaches. Disclosures Chari: Novartis: Honoraria; Array BioPharma: Honoraria; The Binding Site: Honoraria; Bristol Myers Squibb: Consultancy; Adaptive Biotechnology: Honoraria; Pharmacyclics: Research Funding; Karyopharm: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Glaxo Smith Kline: Consultancy; Secura Bio: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Berdeja:Takeda: Consultancy, Research Funding; Servier: Consultancy; Teva: Research Funding; Prothena: Consultancy; Poseida: Research Funding; Lilly: Research Funding; Novartis: Research Funding; Acetylon: Research Funding; BMS: Consultancy, Research Funding; CURIS: Research Funding; Karyopharm: Consultancy; Bluebird: Research Funding; EMD Sorono: Research Funding; Bioclinica: Consultancy; Kesios: Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Abbvie: Research Funding; Constellation: Research Funding; Cellularity: Research Funding; Vivolux: Research Funding; Legend: Consultancy; Glenmark: Research Funding; Celgene: Consultancy, Research Funding. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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, Speakers Bureau. van de Donk:BMS: 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, Research Funding; TAKEDA: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; ROCHE: 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; 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. Rodriguez:Oncopeptides: Consultancy; Sanofi: Consultancy; Abbvie: Consultancy; Kite: Consultancy; GSK: Consultancy; Janssen: Consultancy, Honoraria; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees. Askari:Hospital Universitario Fundacion Jimenez Diaz: Consultancy, Current Employment. Mateos: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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Pharmamar: Consultancy; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; EDOMundipharma: Consultancy; Roche: 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; Oncopeptides: 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. Minnema:Janssen Cilag: Honoraria; Celgene Corporation: Honoraria, Research Funding; Gilead: Honoraria; Amgen: Honoraria; Servier: Honoraria. Verona:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Girgis:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Prior:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Hilder:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Russell:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Goldberg:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Krishnan:Takeda: Speakers Bureau; Sanofi: Consultancy; Sutro: Membership on an entity's Board of Directors or advisory committees; Z Predicta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Regeneron: Consultancy; Amgen: Speakers Bureau; BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau.

Introduction The comprehensive geriatric assessment (CGA) in older patients with cancer is the gold standard to identify robust, frail or poor prognosis patients according Balducci classification. In Spain, a new proposal of a specific Geriatric Assessment in Hematology (GAH) scale has been designed and validated in patients with hematologic malignancies such as MDS/AML, multiple myeloma and CLL. The GAH scale has not been explored in patients with lymphoma. In this study, we have analyzed the utility of using the GAH scales in patients with hematologic malignancies, mostly lymphoma patients. Patients and methods. From March 2016 and September 2017, patients with hematologic malignancies were prospectively referred to the Geriatric Oncology clinic after a frailty screening test using G8 scale and with score Results Of the 96 patients referred aged 70 years or over, 41 were males (42.7%) and 55 females (57.3%), the median age was 79 years (range, 70-89), and with the diagnosis of lymphoma in 53 patients (55.2%), multiple myeloma in 23 patients (24.0%), CLL in 13 patients (13.6%), MDS/AML in 5 patients (5.2%) and CML in 2 patients (2.0%). Seventy-five patients (78.1%) had good performance status with ECOG score 0-1. Regarding frailty, 20 patients (20.8%) had a score of 15 points or over at G8 scale and 76 patients (79.2%) were identified as frail because of a score of 14 points or below. Regarding comorbidities, the median CIRS-G score was 9 (range, 4-20). After the GAH scale assessment, the median number of domains affected in robust patients was 2 (1-4) and in frail patients was 4 (3-5) (p=0.0001). In the ROC curve, with an AUC of 0.7595 and a likelyhood ratio of 9, the cut-off in this series was 2 domains with impairment, with a sentivity of 13.79% and a specificity of 92.5% (p= 0.0003). Using a correlation factor for each domain, the mean score at GAH scale in robust patients was 26 points and in frail patients was 42.5 points (p=0.0038). In the ROC curve, with an area under the curve of 0.7026 and a likelihood ratio of 2.04, the cut-off value to identify robust vs frail patients was 33 points in the GAH scale, with a sensitivity of 77.5% and a specificity of 62.07% (p=0.0043). Analyzing the eight domains explored in the GAH scale, robust patients according CGA had less risk of polypharmacy of 31.25% vs 81.48% in frail patients (OR 0.1033, 95% CI 0.0472-0.2541) (p Mean G8 score were similar between robust (11.68) and frail (11.04) patients (p=n.s.) among all patients with score below 14 points. Robust patients had less comorbidities according to CIRS-G scale, with a median of 9 vs 11 points (p=0.0001). There was correlation between CIRS-G and ECOG with G8 score, not found in previous studies. There is a correlation between the brief comorbidity assessment in the GAH scale with CIRS-G score. Among patients identified as not having comorbidities, the median CIRS-G score was 9 vs 13.5 among patients with comorbidities according the GAH scale (p Conclusions. The GAH scale is a valid tool for patients with hematologic malignancies, including patients with lymphoma, in order to classify patients according frailty phenotype. All domains explored in GAH scale were impaired with higher frequency in frail patients. Robust patients had less comorbidities and better performance status. The brief comorbidities assessment in the GAH scale correlates well with the CIRS-G. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Introduction: Ibrutinib is a covalent inhibitor of Bruton Tyrosine Kinase (BTK), approved for the treatment of Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL) and Waldenstrom's Macroglobulinemia (WM). BTK is expressed in platelets and is believed to have a central role in platelet activation through GPIb and GPIV pathway. However, the clinical significance of inhibition of BTK is unclear in terms of bleeding and it is known that patients with congenitally deficient BTK do not exhibit increased risk of bleeding. Objectives: The main objectives were: (1) identify possible alterations in hemostasis induced by Ibrutinib in patients who start taking the drug, and (2) to monitor the development of hemorrhagic adverse effects in patients who start taking Ibrutinib. Methods: From August 31, 2015 and January 31, 2016 we conducted a prospective study including all consecutive patients with the diagnosis of MCL, CLL or WM treated in 2nd line or more, with Ibrutinib as single-drug therapy. The following parameters were analyzed on day 0 (baseline), 10 and 28 after starting treatment with Ibrutinib: APTT, PT, platelet count, PFA-100 Collagen/Epinephrine and Collagen/ADP, aggregometry impedance in whole blood by multiplate assay with AA, ADP, Ristocetin and TRAP as agonists. Von Willebrand factor antigen (vWF:Ag), Ristocetin cofactor (vWF:RCo) and coagulant factor VIII were also analyzed. We collected prospectively bleeding adverse events. Results: In the period of study, we enrolled 11 patients, 7 were males and 4 females, with a median age of 63 years old (range, 53-88). Five patients had the diagnosis of CLL, 5 patients had MCL and 1 patient had WM. After a median follow-up of 6 months, 3 out of 11 (27.3%) developed grade 1 bleeding adverse events. Of these, 1 patient was under anticoagulant treatment with intermediate dose of enoxaparin, and another patient had low levels of vWF:Ag and vWF:RCo, suggesting a possible acquired von Willebrand disease. Five out of 11 (45.5%) of patients had a prolonged shutter speed Collagen/Epinephrine at baseline, with a median of 175 sec (range, 94-270). After Ibrutinib exposure, median shutter speed Collagen/epinephrine at 10 days was 231 sec (range, 108-287), p=0.02; and at 30 days was 142 sec (range, 79-300), p=n.s. Four out of 11 patients (36.4%) had a prolonged shutter speed Collagen/ADP at base line, with a median of 105 sec (range, 63-190). After Ibrutinib exposure, median shutter speed Collagen/ADP at 10 days was 107 sec (range, 66-192), p=n.s; and at 30 days was 78 sec (range, 75-149), p=n.s. Regarding platelet aggregometry impedance, 2 patients had abnormal platelet aggregation baseline at TRAP assay, 6 at ADP assay, 3 at AA assay and 4 at Ristocetin assay. After Ibrutinib exposure, there was a worsening of platelet aggregation in ADP analysis at 10 days of treatment but became normal after 30 days of treatment. There was an improvement with TRAP at both 10 and 30 days of treatment. Of notice, all 3 patients with minor bleeding had abnormal hemostasis studies baseline before starting with Ibrutinib. Conclusions: Almost half of patients showed an altered haemostasis baseline studies before starting with Ibrutinib. The biology of the disease appears to cause in subjects primary hemostasis changes that result in a basal bleeding risk regardless of the treatment used. Only minor bleeding complications were observed under Ibrutinib treatment, all with baseline altered platelet function; 2 of the three patients who developed bleeding complications had other bleeding risk factors associated. PFA-100 Collagen/Epinephrine is prolonged in almost 50% of patients after Ibrutinib is started compared with baseline study. Aggregometry impedance only worsened with ADP at 10 days, but went into normal level at 30 days. There is an interindividual variability in alterations of haemostasis and hemorrhagic clinical signs. Disclosures Cordoba: Janssen: Research Funding, Speakers Bureau.

Abstract 1486 Poster Board I-509 Hematopoietic differentiation has to be tightly regulated since uncontrolled or exaggerated development of blood cells may lead to the development of leukemia or autoimmune diseases. Many mechanisms exist to control hematopoiesis on a molecular level, including the regulation of transcription, which has been intensely studied. However, new evidence suggests the process of alternative splicing to be an important regulator of the maturation and activation of blood- and immune effector cells. One of the factors that has been identified as a potential regulator of the immune response and controls alternative splicing is “heterogenous nuclear ribonucleoprotein L” (hnRNP L). This factor affects among others the alternative splicing of the CD45 gene, which encodes the major tyrosine phosphatase expressed on all hematopoietic cells. To investigate the biological role of hnRNP L as a regulator of alternative splicing in hematopoiesis, we have generated conditional hnRNP L knockout (KO) mice carrying floxed alleles that can be deleted by co expression of Cre recombinase. Both the inducible MxCre transgene or Vav-Cre transgene, which is active in all hematopoietic cells were introduced into hnRNP Lfl/fl mice. We found that the conditional deletion of hnRNP L by the Vav Cre transgene led to early mortality before birth (at stage E17.5) and flow cytometric analysis of fetal liver of hnRNP Lfl/fl, Vav-Cre mice or bone marrow from pIpC induced hnRNP Lfl/fl Mx-Cre mice showed a deficit in erythrocyte maturation. In addition, fetal thymi from hnRNP Lfl/fl X Vav-Cre mice were severely reduced in cellularity and showed disturbed T cell maturation. Moreover, the deletion of hnRNP L results in reduced numbers of Lin−Sca1+ckit+ (LSK) cells, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte-monocyte progenitors (GMPs) and megakaryocyte-erythrocyte progenitors (MEPs). Strikingly, while most of the progenitors and the short-term hematopoietic stem cells (HSCs) were affected by the deletion of hnRNP L, the population of long term HSCs was not reduced. We found a high percentage of Annexin V positive cells in the LSK population suggesting that the loss of progenitors and short term HSCs in hnRNP L deficient mice is due to an accelerated cell death. To test whether stem cells lacking hnRNP L were still functional, we sorted Lin−Sca1+ckit+ (LSK) cells and cultured them on either methylcellulose or the feeder cell lines OP9 and OP9-DL1. The co-culture with OP9 or OP9-DL1 cells demonstrated that hnRNP L−/− LSK cells had lost their potential to differentiate into B and T lymphocytes. Similarly, hnRNP L deficient LSK cells were unable to give rise to lymphoid, myeloid or erythroid colonies on methylcellulose. This suggests that hnRNP L is required to maintain not only the numbers of hematopoietic stem cells, but also their ability for multilineage differentiation. We conclude that the regulation of alternative splicing is an essential component of the regulatory network required to maintain hematopoietic differentiation and the functional integrity of hematopoietic stem cells. Disclosures: No relevant conflicts of interest to declare.

Inflammatory responses are complex and comprise multiple mediators including cytokines such as TNF-alpha (TNF-α) and IL-1beta. These cytokines are synthesized and secreted in response to signaling by plasma membrane receptors of the Toll-like receptor (TLR) family. A central downstream element of TLR-dependent signaling is the transcription factor NF-kappaB (NF-κB), which plays a pivotal role in controlling the proper sequence of events during an inflammatory response. In unstimulated cells, NF-κB is bound to inhibitory IkappaB (IκB) proteins and remains sequestered in the cytoplasm. Stimulation of TLRs triggers a signaling cascade that leads to phosphorylation and proteasomal degradation of IκB, resulting in the translocation of NF-κB to the nucleus, where it acts as a transcriptional activator of target genes. To keep the innate immune system under control, the TLR signaling cascade is under a tight control of many positive and negative regulators. We have previously shown that the transcription factor Growth Factor Independence 1 (Gfi1) represents a novel factor limiting the inflammatory immune response including TNF-α. Gfi1-deficient (Gfi1−/−) mice show a very strong systemic response to the TLR4 ligand and endotoxin LPS and die rapidly within 36 h with symptoms of septic shock. Here, we investigated the molecular mechanism of this exaggerated TNF-α production in the absence of Gfi1. It is known that endotoxin stimulation results in the activation of the transcription factor NF-κB through TLR4, leading to TNF-α production. This activation also resulted in rapid and de novo expression of Gfi1 in the nucleus in a time- and dose-dependent manner. The expression of Gfi1 was not due to feedback regulation from secreted TNF, since TNF-deficient macrophages were also able to upregulate Gfi1 mRNA following LPS stimulation. As expected, LPS stimulation of Gfi1−/− macrophages resulted in significantly higher levels of TNF-α mRNA, and secreted TNF-α cytokine. Strikingly and in contrast to most known negative regulators of TLRs, Gfi1 did not affect the activity or the expression levels of the cytoplasmic components of TLR signaling pathway. Additionally, NF-κB phosphorylation and nuclear translocation post- LPS treatment were intact in both Gfi1−/− and Gfi1+/+ macrophages. Immunoprecipitation analysis from cells endogenously expressing Gfi1 and NF-κB or over-expressing these two proteins post transfection, clearly revealed a direct interaction between Gfi1 and the p65 subunit of NF-κB. Immunofluorescence staining of macrophages post-LPS treatment confirmed direct interaction of these two proteins in the nucleus at the endogenous level. Gfi1 represses transcription by binding to DNA recognition sequences in target gene promoters. Thus, aiming to investigate the effect of Gfi1 expression on NF-κB nuclear signaling, we found that LPS treatment enhances NF-κB DNA binding activity in Gfi1−/− macrophages as compared to Gfi1+/+ cells. Furthermore, over expression of Gfi1 protein resulted in negative regulation of NF-κB mediated gene activation in a dose-dependent manner. Chromatin immune precipitation with anti-p65 antibodies from LPS stimulated Gfi1+/+ and Gfi1−/− macrophages revealed enhanced NF-κB promoter occupancy at the TNF gene in Gfi1−/− macrophages as compared to Gfi1+/+ cells. In conclusion, our findings reveal a novel function for Gfi1 in the innate immune response by directly antagonizing NF-κB function. This molecular perceptive of TNF-α regulation during inflammation may provide an attractive strategy for therapeutic intervention in chronic inflammatory diseases and certain cancers.

Hematopoietic differentiation is controlled to a large extent by a network of transcription factors and chromatin modifiers and disruption of this system can lead to leukemia or lymphoma. One of the transcription factor genes, which is aberrantly expressed in human T-cell lymphoma is Growth Factor Independence 1 (Gfi1). Since over expression of Gfi1 can accelerate experimentally induced T-cell tumors in mice, it is likely that Gfi1 plays a crucial role in establishing or maintaining lymphoid neoplasms. To test this hypothesis we have used, N-ethyl-N-nitrosourea (ENU) to induce T-cell tumors in WT mice ( Gfi1 +/+ ), Gfi1 -deficient mice ( Gfi1 −/− ) or mice transgenically over expressing Gfi1 under the control of the pan-hematopoietic vav-promoter (vav- Gfi1 ). As expected, most of Gfi1 +/+ mice (25/27) developed T-cell tumors and acute myeloid leukemia within 118 days. Similarly, vav-Gfi1 mice (10/10) developed T-cell lymphoma, but within a shorter latency period (88 days). In contrast, only 3/14 Gfi1 −/− mice developed hematopoietic neoplasia with a prolonged median latency period of 126 days. Other approaches using infection of newborn mice with Moloney Murine leukemia virus (MoMuLV) to induce T-cell lymphoma or co expression of an Eμ-myc transgene to induce B-cell lymphoma showed a similar dependency of tumor formation on the presence and expression of Gfi1. Closer analysis of tumors forming in Gfi1 −/− mice demonstrated that Gfi1 deficiency correlated with a smaller size of the tumors and a noticeably increased rate of cell death within the tumor samples. This pointed to a potential role of Gfi1 in the regulation of apoptosis. To explore this hypothesis, we exposed both thymocytes and hematopoietic stem cells (Lin - , Sca1 + , c-kit + , LSK) to ENU or gamma-irradiation in vitro . We could observe that Gfi1 −/− thymocytes and stem cells (LSK cells) have a higher rate of cell death following exposure to these DNA damage inducing agents in vitro than the WT controls. To validate these results, we recapitulated these experiments in vivo. Gfi1 −/− mice exhibited severe bone marrow failure and a more pronounced loss of hematopoietic stem cells (LSK) than Gfi1 +/+ mice after ENU treatment or gamma irradiation in vivo . To explore this mechanism on the molecular basis we evaluated expression of the different pro and antiapoptotic components in Gfi1 +/+ and Gfi1 −/− thymocytes after irradiation. Strikingly, Gfi1 −/− thymocytes expressed higher levels of the pro-apoptotic proteins such as Bax and Noxa and lower levels of the CDK inhibitor p21 WAF than WT thymocytes following induction of DNA damage. Our model would be that Gfi1 represents a new regulator in the cellular response to DNA damage in the hematopoietic system by inhibiting different proapoptotic factors. We propose that Gfi1 is essential for the development of lymphoid and potentially myeloid neoplasms by inhibiting apoptosis. We suggest that Gfi1 could represent a possible new target structure for therapeutic intervention.

Chronic myelomonocytic leukaemia (CMML) is an entity with a heterogeneous clinical evolution, initially included among myelodysplastic syndromes (MDS) according to the FAB classification. The recent WHO classification brings CMML closer to myeloproliferative disorders, and moved it into a new category termed myelodysplastic/myeloproliferative diseases (MDS/MPD). Aim: To describe the immunophenotypic profile of CMML and to compare it with the phenotype described in MDS and MPD. Patients: 76 patients: 20 CMML (15 CMML I, 5 CMML II), 38 MDS (refractory cytopenia with multilineage dysplasia), and 18 MPD (11 essential thrombocytemia, 2 chronic idiopathic myelofibrosis, and 5 polycythemia vera). Material and Methods: Flow cytometry immunophenotyping (FCI) in bone marrow samples. Data studied: 1 In the myeloid lineage: abnormalities in granularity and CD45 distribution, abnormalities in the phenotypic pattern of myeloid development (CD16/CD11b/CD13), and the absence of CD10 expression on mature granulocytes (CD10−). 2 In the monocytic lineage: CD2 and CD56 expression. 3 In the red cells: abnormalities in CD71 and glycophorin A distribution. 4 In B-cells, detection of a low percentage of CD10+ B-cell precursors (less than 1% of bone marrow B-cells). 5 In myeloblasts, identification of more than >5% CD34+ cells, and evaluation of aberrant expression of CD7 and TdT in these cells (positive expression was described when >10% of CD34+ cells were positive for any of these antigens). Results: Abnormal cases among those studied for each parameter analysed is specified in the table. Patients with CMML and MDS showed statistically significant differences (p Immunophenotypic data in patients with MDS (row1), CMML (row2), and MPD (row3). Abnormal SSC/CD45 Abnormal myeloid CD16/CD11b/CD13 CD10− neutrophils CD2+ monocytes CD56+ monocytes Abnormal erythroid CD71/GlyA 5% CD34+ MDS: myelodysplastic syndromes; CMML: chronic myelomonocytic leukemia; MPD: myeloproliferative disorders. 33/38 35/38 15/30 5/27 5/31 27/38 16/31 2/38 20/20 20/20 4/17 8/17 9/16 16/19 14/17 0/20 4/18 5/18 1/18 1/18 0/16 12/17 4/18 0/18 Conclusions: With the number of cases studied, higher similarities can be found between CMML and MDS immunophenotypic profiles. The antibody panel selected, including several abnormalities previously described in patients with MDS, might justify the differences found between CMML and MPD. However, it does not explain the relationship between the immunophenotypic profile of CMML and MDS. Abnormalities in B-cell development and aberrant expression of CD56 on monocytes were the most useful data to distinguish CMML and MPD. Although the number of patients studied is still low, quantification of CD34+ cells did not help to identify CMML with an aggressive clinical course.