Abstract: 8014 Background: Elranatamab (PF-06863135) is a bispecific molecule that activates and redirects the T-cell mediated immune response against multiple myeloma (MM), a plasma cell dyscrasia characterized by expression of B-cell maturation antigen (BCMA). MagnetisMM-1 (NCT03269136), the ongoing Phase 1 first-in-human study for elranatamab, was designed to characterize safety, pharmacokinetics (PK), pharmacodynamics, and efficacy for patients (pts) with relapsed or refractory MM. Methods: Elranatamab was given subcutaneously (SC) at doses from 80 to 1000µg/kg either weekly or every 2 weeks (Q2W). Treatment-emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events (v4.03) and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria. PK, cytokine and soluble BCMA profiling, and lymphocyte subset analyses were performed. Response was assessed by International Myeloma Working Group (IMWG) criteria. Minimal residual disease (MRD) was assessed by next generation sequencing at a sensitivity of 1×10 -5 in accordance with IMWG criteria. Results: A total of 55 pts received single-agent elranatamab SC at a dose ≥215μg/kg as of 1-Nov-2021. Median age was 64 (range 42-80) years, and 27% of pts were Black/African American or Asian. Median number of prior regimens was 6 (range 2-15), 91% were triple-class refractory, 56% had prior stem cell transplantation, 27% had high cytogenetic risk, and 22% received prior BCMA-targeted therapy. The most common TEAEs regardless of causality included CRS, neutropenia, anemia, injection site reaction, and lymphopenia. With pre-medication and a single priming dose (600µg/kg or 44mg), the overall incidence of CRS at the recommended dose (1000µg/kg or 76mg) was 67% and limited to Grade 1 (33%) or Grade 2 (33%), with no events Grade 3 or higher. Exposure was dose dependent and Q2W dosing achieved exposure associated with anti-myeloma efficacy. Cytokine increases occurred with the first dose and were reduced by pre-medication. Soluble BCMA decreased with disease response, elranatamab therapy was associated with increased peripheral T cell proliferation, and median time to response was 36 days (range 7-73). With a median follow-up of 8.1 months (range 0.3-21) and including only IMWG confirmed responses, 31% of pts achieved complete response or better and the overall response rate was 64% (95% CI 50-75%). For responders (n = 35), median duration of response was not yet reached, but the probability of being event-free at 6 months was 91% (95% CI 73-97%). Single-agent elranatamab induces durable clinical and molecular responses, and updated data including MRD assessment will be presented. Conclusions: Elranatamab shows a manageable safety profile and achieves durable clinical and molecular responses for pts with relapsed or refractory MM. Clinical trial information: NCT03269136.

Abstract: e20021 Background: Multiple myeloma (MM) is a plasma cell dyscrasia that expresses B-cell maturation antigen (BCMA). Elranatamab (PF-06863135), a BCMA x CD3 bispecific antibody, redirects the T-cell mediated immune response against MM. MagnetisMM-1 (NCT03269136) is the Phase 1 study evaluating safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of elranatamab for patients (pts) with relapsed or refractory MM. Methods: Elranatamab was given subcutaneously at doses 80–1000 µg/kg weekly or every 2 weeks. Treatment-emergent adverse events (TEAEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (v4.03), whereas cytokine release syndrome (CRS) was assessed by criteria of American Society for Transplantation and Cellular Therapy. PK and cytokines were analyzed over time. Bone marrow aspirates were used for cytogenetic analysis, whole exome sequencing, and minimal residual disease (MRD). Clinical response and MRD (with sensitivity of 1×10 -5 by next generation sequencing) were assessed by International Myeloma Working Group criteria. Results: 55 pts received elranatamab at efficacious doses ≥215 μg/kg as of September 30, 2022. Pts had median age of 64 years (range 42-80), median of 5 prior regimens (range 2-14), 91% were triple-class refractory, 29% had high cytogenetic risk, and 24% received prior BCMA-targeted therapy. The most common TEAEs included CRS, injection site reaction, neutropenia, anemia, lymphopenia, and thrombocytopenia. Premedication and 1-step priming mitigated CRS. Elranatamab showed linear PK. Genetic alterations potentially relevant to molecular pathogenesis of MM were identified and included functional mutations in KRAS, NRAS, and TP53. With median follow-up of 12.0 months (range 0.3-32.3), objective response rate (ORR) was 64% (95% CI 50-75%) with 56% of pts (31/55) achieving very good partial response (VGPR) or better and 38% of pts (21/55) achieving complete response (CR) or better. Among 13 pts with prior BCMA-targeted therapy, 54% (7/13) achieved response including 46% (6/13) with VGPR or better. All 13 MRD-evaluable pts with confirmed CR or better and dominant clone sequence at baseline achieved MRD negativity, including 2 patients with ongoing stringent CR beyond 2 years. Median duration of response (DOR) was 17.1 months (n = 35; 95% CI 11.1-NE). Median progression-free survival (PFS) was 11.8 months (n = 55; 95% CI 6.0-19.1), and median overall survival (OS) was 21.2 months (n = 55; 95% CI 10.9-NE). Conclusions: Elranatamab induced durable clinical and molecular responses with an acceptable safety profile for pts with relapsed or refractory MM. The ORR was 64% with more than half of these pts (38%) achieving CR or better, and 100% of evaluable pts achieved MRD negativity. These results, along with emerging evidence for both PFS and OS, support the clinical activity of elranatamab for pts with MM. Clinical trial information: NCT03269136 .

Abstract: 8006 Background: Elranatamab (PF-06863135) is a humanized bispecific monoclonal antibody (IgG2a) that targets BCMA, a member of the tumor necrosis factor receptor superfamily expressed in MM, and CD3 on T cells. We reported results for intravenous (IV) dosing (Raje et al. Blood. 2019;134(S1):1869) and now update for subcutaneous (SC) dosing from the ongoing Phase 1 study (MagnetisMM-1). Methods: Patients (pts) received elranatamab at 80, 130, 215, 360, 600, and 1000μg/kg SC weekly. A modified toxicity probability interval method was used for escalation, with monitoring for dose-limiting toxicity (DLT) to end of the first cycle. Treatment-emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events (v4.03), and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant. 2019;25:625). Response was assessed by International Myeloma Working Group criteria. Pharmacokinetics, cytokine profiling, and T cell immunophenotyping were performed. Results: 30 pts had received elranatamab as of 4-Aug-2020 at 80 (n = 6), 130 (n = 4), 215 (n = 4), 360 (n = 4), 600 (n = 6), or 1000 (n = 6) μg/kg SC weekly. Pts had a median of 8 prior treatments; 87% had triple refractory disease, 97% had prior anti-CD38 therapy, and 23% had prior BCMA-directed antibody drug conjugate or chimeric antigen receptor T cell therapy. The most common all causality TEAEs included lymphopenia (n = 24, 80%; 20% G3, 60% G4), CRS (n = 22, 73%; none 〉 G2), anemia (n = 17, 57%; 43% G3, 3% G4), injection site reaction (n = 16, 53%; none 〉 G2), thrombocytopenia (n = 16, 53%; 23% G3, 17% G4), and neutropenia (n = 12, 40%; 17% G3, 17% G4). Both CRS and immune effector cell-associated neurotoxicity syndrome (n = 6, 20%) were limited to ≤G2 with median durations of 2 and 1.5 days, respectively. No DLT was observed. Exposure increased with dose, and T max ranged from 3–7 days. Cytokine increases occurred with the first dose, and increased T-cell proliferation was observed in peripheral blood. The overall response rate (ORR) for doses ≥215μg/kg was 75% (n = 15/20) including partial response (PR; n = 6), very good PR (VGPR; n = 3), complete response (CR; n = 1), and stringent CR (sCR; n = 5). Median time to response was 22 days, and 3 of 4 pts (75%) with prior BCMA-directed therapy achieved response (VGPR, n = 2 and sCR, n = 1). Updated data, including duration of response, will be presented. Conclusions: Elranatamab demonstrated a manageable safety profile, and SC doses ≥215μg/kg achieved ORR of 75% with CR/sCR rate of 30%. These results demonstrate the safety and efficacy of SC elranatamab in this relapsed/refractory population and support ongoing development of elranatamab for pts with MM, both as monotherapy and in combination with standard or novel therapies. Clinical trial information: NCT03269136.

Abstract: Multiple myeloma (MM) is a plasma cell malignancy expressing B cell maturation antigen (BCMA). Elranatamab, a bispecific antibody, engages BCMA on MM and CD3 on T cells. The MagnetisMM-1 trial evaluated its safety, pharmacokinetics and efficacy. Primary endpoints, including the incidence of dose-limiting toxicities as well as objective response rate (ORR) and duration of response (DOR), were met. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Eighty-eight patients with relapsed or refractory MM received elranatamab monotherapy, and 55 patients received elranatamab at efficacious doses. Patients had received a median of five prior regimens; 90.9% were triple-class refractory, 29.1% had high cytogenetic risk and 23.6% received prior BCMA-directed therapy. No dose-limiting toxicities were observed during dose escalation. Adverse events included cytopenias and cytokine release syndrome. Exposure was dose proportional. With a median follow-up of 12.0 months, the ORR was 63.6% and 38.2% of patients achieving complete response or better. For responders, the median DOR was 17.1 months. All 13 patients evaluable for minimal residual disease achieved negativity. Even after prior BCMA-directed therapy, 53.8% achieved response. For all 55 patients, median PFS was 11.8 months, and median OS was 21.2 months. Elranatamab achieved durable responses, manageable safety and promising survival for patients with MM. ClinicalTrials.gov Identifier: NCT03269136 .

Abstract: Introduction: MagnetisMM-1 (NCT03269136) is a Phase 1 study of elranatamab (PF-06863135), a humanized bispecific molecule that targets BCMA expressed on multiple myeloma (MM) and engages CD3 on T cells, for patients (pts) with relapsed or refractory MM (RRMM). We report results from the subcutaneous (SC) cohorts: dose escalation (Part 1), monotherapy with priming (Part 1.1), lenalidomide (LEN) combination (Part 1C), pomalidomide (POM) combination (Part 1D), and monotherapy expansion with priming (Part 2A). Methods: In Part 1, pts received elranatamab at 80, 130, 215, 360, 600, and 1000μg/kg weekly guided by a modified toxicity probability interval method. For monotherapy at the recommended Phase 2 dose (RP2D; Parts 1.1 and 2A), a single priming dose (600μg/kg or equivalent fixed dose of 44mg) was followed one week later by the full dose (1000μg/kg or equivalent fixed dose of 76mg) weekly (Q1W) or every 2 weeks (Q2W) thereafter. For LEN or POM combination therapy, a single priming dose (32mg) was followed one week later by the full dose (44mg) Q1W thereafter in combination with either LEN (25mg) or POM (4mg) on Days 1 to 21 of a 28-day cycle. Dose-limiting toxicity (DLT) was monitored to the end of the first cycle. Treatment-emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events (v4.03), and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria. Pharmacokinetics, cytokine profiling, and T cell immunophenotyping were performed. Response was assessed by International Myeloma Working Group (IMWG) criteria. Minimal residual disease (MRD) was assessed by next generation sequencing at a sensitivity of 1×10 -5, in accordance with IMWG criteria. Results: 58 pts received elranatamab SC as a single agent (n=50) or in combination with either LEN (n=4) or POM (n=4) as of 4-Feb-2021. Pts had a median (range) age of 64 (32-86) years, and 26% were Black/African American or Asian. Pts had a median of 6 prior regimens, 98% had triple-class relapsed/refractory disease, 45% had prior high-dose chemotherapy with stem cell transplantation, and 22% had prior BCMA-targeted therapy. The most common all causality TEAEs included CRS (n=48, 83%; none higher than G2), lymphopenia (n=37, 64%; 12% G3, 52% G4), neutropenia (n=37, 64%; 31% G3, 29% G4), anemia (n=32, 55%; 38% G3, 0% G4), injection site reaction (n=31, 53%; none higher than G2), and thrombocytopenia (n=30, 52%; 14% G3, 17% G4). At the RP2D of 1000μg/kg, median duration of CRS decreased by 50% from 4 days to 2 days with priming. Two of 58 pts had DLT including G4 thrombocytopenia (Part 1.1) and G4 neutropenia (POM). Exposure increased with dose, cytokine increases occurred with the first dose, and increased T-cell proliferation was observed in peripheral blood. Median duration of follow-up was 7.5, 2.3, and 1.9 months for the dose escalation, priming, and LEN/POM combination cohorts, respectively. For pts treated across the efficacious dose range (215-1000μg/kg) in Part 1, confirmed overall response rate (ORR) was 70% (14/20) with complete response (CR)/stringent CR (sCR) rate of 30% (6/20). For the 14 pts with confirmed responses, median duration of response had not yet been reached; the probability (95% CI) of responders being event free at 6 months was 92.3% (56.7-98.9). Confirmed ORR at the RP2D was 83% (5/6). Responses in this RRMM population included sCR (n=5), CR (n=1), very good partial response (VGPR; n=7), and partial response (n=1). Median time to response was 22 days. Importantly, 100% (4/4) of evaluable pts with baseline dominant sequence and on-treatment sample at CR/sCR achieved MRD negativity at 1×10 -5 by IMWG criteria, and 75% (3/4) of pts with prior BCMA-targeted therapy achieved response (1 sCR, 2 VGPR). Updated efficacy, safety, and MRD results will be presented for SC parts of the study. Conclusions: Elranatamab as a single agent, administered either Q1W or Q2W, had a manageable safety profile for pts with RRMM. Across the efficacious dose range, elranatamab achieved confirmed ORR of 70% and CR/sCR rate of 30%, with confirmed ORR of 83% at the RP2D. Importantly, elranatamab induces deep and durable clinical responses in RRMM pts with and without prior BCMA-targeted therapy and 100% MRD negativity in MRD evaluable pts. These results, along with emerging combination data, support continued development of elranatamab as a single agent and in combination with standard therapies for MM. Disclosures Sebag: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Research Funding; Bristol Myers-Squibb: Consultancy, Honoraria. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Bahlis: GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genentech: Consultancy; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Dholaria: Pfizer: Research Funding; Poseida: Research Funding; Angiocrine: Research Funding; MEI: Research Funding; Jazz: Speakers Bureau; Takeda: Research Funding; Janssen: Research Funding; Celgene: Speakers Bureau. Solh: Partner Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; ADCT Therapeutics: Consultancy, Research Funding. Levy: Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; GSK: Consultancy, Other: Promotional speaker. Tomasson: Pfizer, Inc.: Research Funding; Rafael Pharmaceuticals: Research Funding; syros Pharmaceuticals: Research Funding; Janssen R & D: Research Funding; Seagen, Inc.: Research Funding. Dube: Pfizer: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Damore: Pfizer: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Lon: Pfizer: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Basu: Pfizer: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Skoura: Pfizer: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Chan: Pfizer: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Trudel: Amgen: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy; Janssen: Honoraria, Research Funding; Sanofi: Honoraria; Pfizer: Honoraria, Research Funding; Genentech: Research Funding. Jakubowiak: Gracell: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Chu: Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Teva: Consultancy, Honoraria. Gasparetto: Janssen: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; Oncopeptide: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Gsk: Consultancy, Honoraria, Speakers Bureau. Lesokhin: pfizer: Consultancy, Research Funding; Behringer Ingelheim: Honoraria; Trillium Therapeutics: Consultancy; bristol myers squibb: Research Funding; Genetech: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding; Serametrix, Inc: Patents & Royalties.