Harrison, Simon J

Abstract The B-cell maturation antigen (BCMA)–targeting bispecific T-cell engager pavurutamab (AMG 701) directs the cytotoxic T-cell response toward multiple myeloma (MM) cells. This phase 1/1b, open-label, dose-exploration and dose-expansion study evaluated the safety, tolerability, and efficacy of pavurutamab monotherapy in patients with triple-class relapsed/refractory MM (RRMM). Pavurutamab (5-18 000 μg) was administered IV weekly with step-up dosing in week 1. Overall, 172 patients received at least 1 dose of pavurutamab; 73 received the recommended phase 2 dose (RP2D; 18 000 μg), with 2 different step-up dosing regimens in phase 1b. Twelve patients had dose-limiting toxicities, which included cytokine release syndrome (CRS) and increased transaminases; none of which occurred at the RP2D. The most frequently reported treatment-emergent adverse events included CRS (74.4%), anemia (61.0%), neutropenia (47.1%), and hypophosphatemia (45.3%). Grade ≥3 infections were noted in 60 patients (34.9%). The overall response rate (ORR) was 46.5% among all patients and 65.8% (very good partial response [VGPR] or better, 60.3%) among 73 patients treated at the RP2D. At median follow-up of 17.2 months, median duration of response (DOR) was 36.6 months (95% confidence interval [CI], 22.3 to not estimable). Median progression-free survival (PFS) for all patients was 5.5 months (95% CI, 2.8-10.1) and 16.8 months (95% CI, 5.0 to not estimable) with the RP2D. Pavurutamab exposure generally increased in a dose-proportional manner, with high soluble BCMA levels correlating with lower exposure level. The acceptable safety profile, pharmacokinetics, and preliminary efficacy of pavurutamab supports anti-BCMA T-cell engager therapy in heavily pretreated patients with RRMM. This trial was registered at www.clinicaltrials.gov as NCT03287908.

Abstract Introduction: Cilta-cel is approved in the US and the EU for the treatment of patients (pts) with lenalidomide-refractory multiple myeloma (MM) after ≥1 prior line of therapy (pLOT), including a proteasome inhibitor and an immunomodulatory agent based on the CARTITUDE-1 (CART-1, NCT03548207) and CARTITUDE-4 (CART-4, NCT04181827) studies. Cilta-cel led to deep and durable responses and significant survival benefit in pts with relapsed/refractory MM (RRMM) after ≥3 pLOT in CART-1. In CART-4, cilta-cel led to a significant overall survival benefit with a higher proportion of pts achieving deep, sustained minimal residual disease negativity vs standard of care in pts with lenalidomide-refractory MM after 1–3 pLOT. We investigated the mechanism of action of cilta-cel by correlating biomarkers from peripheral blood and the bone marrow TME with progression-free survival (PFS) and number of pLOT in pts with RRMM from CART-1 and CART-4. Methods: Biomarker analyses were performed using peripheral blood and bone marrow aspirates (BMAs) collected in both CART-1 and CART-4 studies. Immunophenotyping by flow cytometry was performed using peripheral blood at baseline/time of apheresis in samples from both studies. Immune fitness at baseline was assessed in pts by pLOT and in association with PFS. Gene set enrichment scores were derived from RNA sequencing data of the TME using BMAs. Mixed-effects models were used to identify signatures/pathways modulated over time (day [D] 28 and at 6 months [mo] post infusion vs screening) and in association with PFS and pLOT. Results: In total, 176 CART-4 and 97 CART-1 pts received cilta-cel as study treatment. Immunophenotyping data were available from 248 peripheral blood samples (1 pLOT, n=56; 2 pLOT, n=61; ≥3 pLOT, n=131). At apheresis, CD4+ naïve T cells (%) were higher in pts with 1 or 2 pLOT, compared with those with ≥3 pLOT, while no difference was found in pts with ≥3 pLOT with further breakdown (i.e., 3–4 vs 5–6 vs ≥7 pLOT). Further, higher baseline levels of CD4+ naïve T cells were associated with longer PFS. These data suggest that the negative impact on peripheral immune fitness with the addition of LOT may plateau when pts have received ≥3 pLOT. TME gene expression data were available from 148 BMA samples (screening, n=50; D28, n=50; 6 mo, n=48) from CART-4. Analyses of gene expression signatures suggest depletion of B cells and antibodies at D28 post cilta-cel infusion, with partial recovery at 6 mo. This was corroborated in parallel by flow cytometry and immunoglobulin quantification. Further, elevated expression of genes associated with myeloid cells, including tumor-associated macrophages (TAM, likely M1), and of genes associated with cytotoxic T cells were also observed at D28. Elevated expression of genes associated with B-cell receptors, T-cell differentiation and activation, and cytokine signaling pathways were found at both D28 and 6 mo. Pts with longer PFS (>18 mo) had higher levels of M1 TAM at D28, while those with shorter PFS had higher levels of regulatory T cells and more suppressed interferon pathway genes at 6 mo, suggesting that relapse may be associated with a more suppressive immune response. In pts with fewer pLOT, more profound B-cell depletion on D28, better recovery at 6 mo, and elevated B-cell receptor signaling were inferred from gene expression data. Pts with 1 pLOT also demonstrated higher elevation of M1 TAM expression on D28 from screening as compared with pts with 3 pLOT, similar to what was observed in pts with longer PFS. Conclusions: Correlative biomarker data suggest that longer PFS is associated with better immune fitness at baseline and stronger immune responses post cilta-cel infusion, as observed in peripheral blood and within the TME of pts with RRMM in CART-1 and CART-4. The peripheral immune fitness was more pronounced in pts with 1 and 2 pLOT vs 3 pLOT and beyond, where deterioration plateaued. This suggests the impact of T-cell immune fitness on PFS may be limited beyond the third LOT. Importantly, other covariates, including factors within the immune TME and tumor burden, may play a significant role in balancing this compromised intrinsic T-cell immune fitness at apheresis, thereby contributing to PFS durability after 3 pLOT. Overall, these results support increased benefits in treating pts with MM with cilta-cel in earlier LOTs.

Background Emerging evidence has demonstrated rare subacute to late neurological toxicities (NTs) after BCMA CAR T-cell therapy (CAR-T) in multiple myeloma (MM). These adverse events can be categorized as: 1) Parkinsonism (PD), 2) cranial nerve (CN) palsies, and 3) peripheral neuropathies/Guillan Barré syndrome (GBS). These toxicities can cause significant morbidity, but given their relative rarity in clinical trials, there is limited data regarding evaluation and treatment. To our knowledge, this is the largest and only global registry of delayed NTs after BCMA CAR-T. Methods We retrospectively established a registry of NTs via the Immune Therapy Working Committee of the International Myeloma Working Group (IMWG). We gathered data pertaining to demographics, MM characteristics, MM response, NT signs/symptoms, diagnostic workup, and treatment. Result A total of 52 patients with delayed neurotoxicity were included from 14 institutions and 6 countries; 92% received ciltacel, 4% idecel, and 4% investigational CAR-T. Median age at CAR-T infusion was 65 years; 69% were male and 88% were Caucasian. Median bone marrow plasma cell (PC) burden was 15% prior to CAR-T (range 0-95%). Patients received a median of 4 prior lines of therapy (LOT), with 67% progressing on last LOT. Seventeen percent had pre-existing neurological diagnoses (including stroke, epilepsy, migraines). We identified sixteen cases of PD (94% with movement disorder, 69% with cognitive impairment, 75% with personality changes), occurring at a median of 26 days (range: 15-87) after CAR-T. Ninety four percent had CRS (grade (G)1 50%, G2 38%, G3 6%, G4 0%), while 19% had ICANS (G1 13%, G2 6%, G3-G4 0%). Median peak absolute lymphocyte count (ALC) was 9.5 x 109/L, peak C-reactive protein (CRP) 60.9 mg/L, and peak ferritin 1893.5 ug/L within the first 30 days. Concurrently, 3 upper respiratory infections (URIs) and 2 low-level HHV7 in the cerebrospinal fluid (CSF) were detected. A median of 73% of T-cells in the CSF were CAR-T, based on a flow cytometry assay. Ten patients received steroids (median 19 days after symptoms, 70% partial response, 20% no response, 10% unknown), 2 received intrathecal (IT) methotrexate-based therapy (median 32 days after symptoms, 1 with no response, 1 unknown), 5 received intravenous (IV) cyclophosphamide (median 31 days after symptoms, 40% full response, 20% partial response, 40% no response), 4 received high-dose IVIG ≥1g/kg for one or more dose (50% partial response, 50% no response), and 6 received dopamine agonists. There were 37 CN palsies (76% CN7, 15% CN6, 7% CN5, 2% CN3), occurring at a median of 37.5 days (range: 7-482) after CAR-T. Eighty one percent had CRS (G1 68%, G2 14%, G3-G4 0%); 11% had G1 ICANS (G2-G4 0%). Median peak ALC was 4.1 x 109/L, CRP 25.4 mg/L, and ferritin 543 ug/L within the first 30 days. We identified 2 concurrent URIs, 4 CMV viremia (50% with viral load >1500 IU/mL), 1 HHV6 viremia, and 1 HSV in the CSF. Thirty-two (86%) received steroids for a median duration of 12 days, 50% with full response, 3% with no response, and 47% with partial response (of which 43% had later full recovery without further intervention). One received IT methotrexate and another received IV cyclophosphamide without response. Thirteen (41%) received IVIG, of which 38% was high-dose IVIG. Four patients with CN palsies developed peripheral neuropathy/GBS. Eight patients (15%) in this cohort were not heavily pre-treated (≤1 prior LOT); 7 developed CN palsies (6 after ciltacel, 1 after investigational CAR-T) and 1 PD (after idecel). These patients had median <5% PC; none had extramedullary disease. Median ALC was 4.14 x 109/L, CRP 33 mg/L, and ferritin 448.5 ug/L within the first 30 days. Conclusions Delayed NT requires prompt recognition, evaluation for alternative causes, and treatment. In our cohort, the majority of patients were male and Caucasian, suggesting that sex and race may impact the likelihood of developing NT. Individuals with PDs had greater inflammatory response (CRS, ALC, CRP, ferritin) compared to those with CN palsies. CN palsies responded to steroids and/or IVIG, whereas PD had at best partial response to steroids, prompting additional therapy. These toxicities notably did occur in less heavily pre-treated patients, perhaps driven by immune fitness and greater circulating T-cells rather than MM burden. At the time of the annual meeting, data will be updated with additional NTs from less heavily pre-treated patients.

Abstract Background: Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage, and at a higher level on myeloma cells than on normal B cells. Cevostamab is a FcRH5xCD3 bispecific antibody (BsAb) that facilitates T cell-directed killing of myeloma cells. Initial data from the dose-escalation phase of the ongoing Phase I study (NCT03275103) of cevostamab monotherapy in patients (pts) with heavily pre-treated RRMM demonstrated promising activity and manageable safety, along with near ubiquitous FcRH5 expression on myeloma cells (Cohen et al. ASH 2020; Sumiyoshi et al. EHA 2021). We present updated safety and efficacy data from a larger cohort of pts, including results comparing Cycle (C) 1 single step-up (SS) and double step-up (DS) dosing for the mitigation of cytokine release syndrome (CRS). Methods: Participants have RRMM for which no established therapy is available or appropriate. Cevostamab (intravenous infusion) is administered in 21-day cycles. In the SS cohorts, the step dose (0.05-3.6mg) is given on C1 Day (D) 1 and the target dose (0.15-198mg) on C1D8. In the DS cohorts, the step doses are given on C1D1 (0.3-1.2mg) and C1D8 (3.6mg), and the target dose (60-160mg) on C1D15. In both regimens, the target dose is given on D1 of subsequent cycles. Cevostamab is continued for a total of 17 cycles, unless progressive disease or unacceptable toxicity occurs. CRS is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: At data cut-off (18 May 2021), 160 pts had been enrolled (median age: 64 years, range: 33-82 years; male: 58.1%); 21.3% of pts had extramedullary disease. Median number of prior lines of therapy was 6 (range: 2-18). Most pts (85.0%) were triple-class refractory (PI, IMiD, anti-CD38 antibody). 28 pts (17.5%) had received ≥1 prior CAR-T, 13 pts (8.1%) ≥1 prior BsAb, 27 pts (16.9%) ≥1 prior antibody-drug conjugate (ADC), and 54 pts (33.8%) ≥1 prior anti-BCMA targeting agent. Median follow-up in exposed pts was 6.1 months. Almost all had ≥1 adverse event (Table). The most common was CRS (128/160 pts [80.0%]; Grade [Gr] 1: 42.5%; Gr 2: 36.3%; Gr 3: 1.3%). Immune effector cell-associated neurotoxicity syndrome (ICANS) associated with CRS was observed in 21 pts (13.1%) and in 34/211 (16.1%) CRS events (Gr 1: 8.5%; Gr 2: 6.2%; Gr 3: 1.4%). Most CRS events occurred in C1 (87.2%), arose within 24 hours of cevostamab administration (70.5%), and resolved within 48 hours of onset (83.4%). In the pts with CRS, tocilizumab was used for CRS management in 43.8% and steroids in 25.8% (both agents: 18.0%). In SS dose-escalation (68 pts), 3.6mg was chosen as the most effective C1D1 SS dose for limiting CRS in C1, with no target dose-dependent increase in the rate or severity of CRS observed after the C1D8 administration. Likewise, in DS dose-escalation (30 pts), 0.3/3.6mg was identified as the preferred C1D1/C1D8 DS dose for limiting CRS in C1. Notably, the overall rate of CRS was lower in the pts who received the 0.3/3.6mg/target DS regimen than in those who received the 3.6mg/target SS regimen (77.3% [34/44] vs 88.2% [75/85], respectively). The rate of ICANS associated with CRS was also lower in the 0.3/3.6mg/target DS cohort than in the 3.6mg/target SS cohort (4.5% [2/44] vs 21.2% [18/85], respectively). At data cut-off, 158/160 pts were efficacy evaluable. In dose-escalation, responses were observed at the 20-198mg target dose levels, and data suggested a target dose-dependent increase in clinical efficacy. Median time to response was 29 days (range: 20-179 days). Two dose-expansion cohorts were opened: ORR was higher at the 160mg dose level (54.5%, 24/44 pts) than at the 90mg dose level (36.7%, 22/60). At target dose levels >90mg, ORRs in pts with prior exposure to CAR-Ts, BsAbs, ADCs, and anti-BCMA targeting agents were 44.4% (4/9 pts), 33.3% (3/9), 50.0% (7/14), and 36.4% (8/22) respectively. Median follow-up among all responders (n=61) was 8.1 months; estimated median duration of response was 15.6 months (95% CI: 6.4, 21.6). Conclusions: Cevostamab monotherapy continues to show clinically meaningful activity in a large cohort of pts with heavily pre-treated RRMM, with a target dose-dependent increase in ORR, but no increase in CRS rate. Responses appear durable, and are observed in pts with prior exposure to CAR-Ts, BsAbs, and ADCs. Compared with SS dosing, DS dosing at the 0.3/3.6mg level appears to be associated with a trend for an improved C1 safety profile. Figure 1 Figure 1. Disclosures Trudel: Amgen: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy; Genentech: Research Funding; Pfizer: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sanofi: Honoraria. Cohen: BMS/Celgene: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Oncopeptides: Consultancy; Novartis: Research Funding; Genentech/Roche: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Takeda: Consultancy. 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. Fonseca: Kite: Consultancy; Juno: Consultancy; Merck: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aduro: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; AbbVie: Consultancy; GSK: Consultancy; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Amgen: Consultancy; Mayo Clinic in Arizona: Current Employment; Celgene: Consultancy; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Spencer: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berdeja: Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; Abbvie, Acetylon, Amgen: Research Funding; EMD Sorono, Genentech: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding. Lesokhin: Serametrix, Inc: Patents & Royalties; Behringer Ingelheim: Honoraria; Genetech: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding; pfizer: Consultancy, Research Funding; bristol myers squibb: Research Funding; Trillium Therapeutics: Consultancy. Forsberg: University of Colorado: Current Employment; Karyopharm, Sanofi, Genentech: Research Funding. Costa: Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, 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. Kaedbey: Takeda, Sanofi: Honoraria; Celgene/BMS, Janssen: Honoraria; Royal Victoria Hospital Lakeshore Hospital: Ended employment in the past 24 months; Jewish General Hospital - McGill University: Current Employment. Richter: Janssen, Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive biotechnologies: Speakers Bureau; BMS, Karyopharm, Antengene: Membership on an entity's Board of Directors or advisory committees; Tisch Cancer Institute: Icahn School of Medicine at Mount Sinai: Current Employment. Mateos: Takeda: 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; Regeneron: 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; Pfizer: 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; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: 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: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bluebird bio: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria. Thomas: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Acerta Pharma: Research Funding; X4 Pharma: Research Funding; Ascentage Pharma: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Wong: Genentech: Current Employment; CTMX, UBX, BMRN: Current equity holder in publicly-traded company. Li: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Choeurng: Genentech: Current Employment, Current equity holder in publicly-traded company. Vaze: Roche/Genentech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Samineni: Genentech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Sumiyoshi: Genentech: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cooper: Genentech: Current Employment; Roche: Current holder of individual stocks in a privately-held company. Harrison: Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: 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, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; Terumo BCT: Consultancy, Honoraria. OffLabel Disclosure: Cevostamab is a FcRH5xCD3 bispecific antibody that facilitates T cell-directed killing of myeloma cells. Cevostamab is an investigational agent.

Abstract Background: Multiple myeloma (MM) is a heterogenous cancer of terminally differentiated plasma cells that typically express elevated levels of antiapoptotic proteins, such as BCL-2. Venetoclax (Ven), a highly selective, potent, oral BCL-2 inhibitor, induces apoptosis in MM cells, and when combined with bortezomib and dexamethasone showed promising efficacy in patients (pts) with relapsed/refractory MM (RRMM; Moreau et al. Blood. 2017;130:2392-2400). The Phase 3 BELLINI study primary analysis showed significantly improved response rates and progression-free survival (PFS) in pts with RRMM treated with Ven added to bortezomib and dexamethasone versus placebo (Pbo); however, increased mortality was observed in the Ven group (Kumar et al. Lancet Oncol. 2020;21:1630-1642). At the initial data cutoff (November 26, 2018), the PFS hazard ratio (HR) was 0.63 (95% CI, 0.44-0.90) and overall survival (OS) HR was 2.03 (95% CI, 1.04-3.95). Pts with t(11;14) translocation or high BCL2 expression showed improved responses and PFS without increased mortality. Here, we present updated safety and efficacy data from the prespecified final OS analysis. Methods: BELLINI (NCT02755597) is a Phase 3, randomized, double-blind, multicenter study of Ven or Pbo combined with bortezomib and dexamethasone in pts with RRMM who had received 1-3 prior lines of therapy and were either sensitive or naïve to proteasome inhibitors. Pts were randomized 2:1 to receive Ven 800 mg/day or Pbo plus bortezomib and dexamethasone. Cycles 1-8 were 21-day cycles with bortezomib 1.3 mg/m 2 on Days 1, 4, 8, and 11 and dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12. Cycles 9 and beyond were 35-day cycles with bortezomib 1.3 mg/m 2 on Days 1, 8, 15, and 22 and dexamethasone 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23. The primary endpoint was PFS assessed by independent review committee. Key secondary endpoints included overall response rate and OS. BCL2 expression was measured by quantitative polymerase chain reaction with the cutoff for high BCL2 determined using bootstrapping and aggregating thresholds from trees. Results: Of 291 randomized pts (194 to Ven and 97 to Pbo), 33 pts were receiving ongoing treatment (28 with Ven and 5 with Pbo) as of the final OS analysis data cutoff (March 15, 2021). At a median follow-up of 45.6 months, there were 78 (40%) deaths in the Ven arm versus 36 (37%) in the Pbo arm. Updated PFS and OS among all pts and those with t(11;14) or high BCL2 expression are shown in the Table. Among all pts, the median PFS per investigator was 23.4 months in the Ven arm versus 11.4 months in the Pbo arm (HR, 0.58 [95% CI, 0.43-0.78]). In pts with t(11;14), the median PFS was 36.8 months in the Ven arm versus 9.3 months in the Pbo arm (HR, 0.12 [95% CI, 0.03-0.44]). In pts with high BCL2, the median PFS was 30.1 months in the Ven arm versus 9.9 months in the Pbo arm (HR, 0.37 [95% CI, 0.21-0.64]). Median OS was not reached in the Ven or Pbo arm among all pts (HR, 1.19 [95% CI, 0.80-1.77]), pts with t(11;14) (HR, 0.61 [95% CI, 0.16-2.32]), pts with high BCL2 (HR, 0.70 [95% CI, 0.32-1.51]), and pts with t(11;14) or high BCL2 (HR, 0.82 [95% CI, 0.40-1.70]). The most common treatment-emergent adverse events (AEs) with Ven (versus Pbo) were diarrhea (60% versus 50%), nausea (38% versus 23%), and constipation (35% versus 31%). The most common Grade 3/4 AEs (Ven versus Pbo) were thrombocytopenia (16% versus 30%), neutropenia (23% versus 8%), pneumonia (19% versus 13%), anemia (16% versus 15%), and diarrhea (15% versus 11%). Serious AEs occurred in 57% of Ven- and 55% of Pbo-treated pts, with serious infections and infestations occurring in 35% and 29% of pts, respectively. Overall, 26% of pts in the Ven arm and 11% of pts in the Pbo arm experienced an AE leading to Ven or Pbo discontinuation. AEs led to 12 deaths in the Ven arm, with 9 of these deaths due to serious infection; an AE led to 1 death in the Pbo arm. A total of 16 (6%) treatment-emergent deaths occurred (14 [7%] with Ven and 2 [2%] with Pbo), with 3 of these deaths due to disease progression (2 [1%] with Ven and 1 [1%] with Pbo). Conclusion: In the final OS analysis, the addition of Ven to bortezomib and dexamethasone showed significantly improved PFS but resulted in increased mortality versus Pbo in the total population. Consistent with results from previous analyses, Ven added to bortezomib and dexamethasone showed the greatest PFS improvement in pts with t(11;14) or high BCL2, with a favorable benefit-risk profile. Figure 1 Figure 1. Disclosures Kumar: Beigene: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Antengene: Consultancy, Honoraria; Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Harrison: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavo: Novartis: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: 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, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Rubia: Ablynx/Sanofi: Consultancy; Amgen, Bristol Myers Squibb,: Honoraria, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene, Takeda, Janssen, Sanofi: Honoraria; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations; GSK: Consultancy; Takeda: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees. Popat: Abbvie, Takeda, Janssen, and Celgene: Consultancy; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Janssen and BMS: Other: travel expenses. Gasparetto: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Oncopeptite: Consultancy, Honoraria, Speakers Bureau; Janssen: 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; BMS: Consultancy; Connect Registry: 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, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau. Hungria: Sanofi: Honoraria, Other: Support for attending meetings/travel ; Takeda: Honoraria; Abbvie: Honoraria; Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel . Salwender: Oncopeptides: Honoraria; GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Chugai: Honoraria; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Suzuki: Japanese Red Cross Medical Center: Current Employment; Janssen: Honoraria; AbbVie: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; ONO: Honoraria; Novartis: Honoraria. Kim: Seoul National University Hospital: Current Employment. Onishi: Roche: Current Employment, Current equity holder in publicly-traded company; Genentech: Current Employment. Ku: Roche: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Genentech: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Pothacamury: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Sehgal: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Masud: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Dobkowska: AbbVie: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pharmacyclics: Current Employment. Moreau: Celgene BMS: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria.

Background: Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by a complex genomic landscape with molecular and clinical heterogeneity. Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor currently under investigation as a potential targeted therapy for the treatment of relapsed/refractory (RR) MM. Using a next-generation sequencing (NGS)-based approach, the mutational landscape and gene expression profile (GEP) of patients (pts) with RRMM in BELLINI was evaluated for potential impact on observed clinical outcomes in key biomarker subgroups. Methods: BELLINI (NCT02755597) is a randomized, double-blind, multicenter Phase 3 study of bortezomib + dexamethasone (Bd) + either Ven or placebo (Pbo) in pts with RRMM who received 1-3 prior therapies and were sensitive or naïve to proteasome inhibitors. Pts were randomized 2:1 to receive Ven 800 mg/d or Pbo + Bd. The following biomarker analyses were performed by central laboratory assessments of CD138-enriched bone marrow mononuclear cells collected at baseline: BCL2 gene expression by quantitative PCR (qPCR), cytogenetic abnormalities by interphase fluorescence in situ hybridization (FISH), identification of somatic mutations by whole-exome sequencing (WES), and transcriptomic analysis by RNA sequencing (RNAseq). Correlation between mutational status, BCL2high status (Harrison et al. Blood. 2019:134 suppl:142), cytogenetics, GEP, and survival outcomes were examined by pairwise t-test and by hazard ratio (HR) from Cox proportional hazard model. Results: As of the data cutoff (13 Sep 2019), 291 pts were randomized (194 to Ven and 97 to Pbo); 262 pts (90.0%) were evaluable by FISH, 257 pts (88.3%) by qPCR, 197 pts (67.7%) by WES, and 184 pts (63.2%) by RNAseq. The mutational landscape of evaluable pts was highly heterogeneous (Figure 1A). MAPK pathway mutations were the most prevalent (62/197 pts; 31.5%); however, recurrent mutations in the NF-kB pathway (TRAF3 or CYLD) were also observed (12/197 pts; 6.1%). Within the MAPK pathway, the most frequently mutated genes were KRAS (39/197 pts; 19.8%), NRAS (8/197 pts; 4.1%), BRAF (8/197 pts; 4.1%), and NF1 (12/197 pts; 6.1%). Although a higher rate of pts with a MAPK mutation was observed in the t(11;14) and BCL2high subgroup compared to pts without these biomarkers (39/101 pts [38.6%] vs 23/95 pts [24.2%]; P=.04), improvement in progression-free survival (PFS) with Ven+Bd was observed in pts with (HR=0.08; 95% CI, 0.02-0.31; P<.001) or without (HR, 0.31 [95% CI, 0.16-0.63]; P=.001) a MAPK pathway mutation. High somatic mutation loads are associated with increased genomic instability, resistance to therapy, and decreased overall survival (OS) in MM. High tumor mutation burden (TMB), defined as ≥20 mutations/megabase of sequenced DNA, was observed in 12/197 pts (6.1%). Although there were a limited number of high TMB pts, reduced PFS (HR, 4.55 [95% CI, 2.33-8.88]; P<.001) and OS (HR, 3.89 [95% CI, 1.76-8.56]; P<.001) compared to low TMB pts was observed regardless of treatment arm. WES detected a recurrent BCL2 mutation (Ala43Thr) in 15/197 pts (7.6%). This BCL2 mutation has not previously been identified in MM and did not appear to affect survival outcomes among pts in either arm. Supervised clustering of RNAseq data grouped pts into respective MM GEP (Zhan et al. Blood. 2006;108:2020) at the following frequencies: CD-1 (2.7%), CD-2 (8.2%), HY (40.2%), MF (1.6%), MS (10.9%), LB (5.4%), and PR (31.0%). As shown in Figure 1B, 16/20 pts (80%) allocated to the CD-1/CD-2 cluster had a t(11;14) mutation, but 17/20 pts (85%) and 2/3 pts (67%) in MS and MF GEP groups had t(4;14) or t(14;16) mutations, respectively. The HY GEP group was primarily (56/74 pts; 76%) hyperdiploid by FISH. Though a higher rate of pts with a HY GEP (50/98 pts [51.0%] vs 24/86 pts [27.9%]; P<.001) and a lower rate of PR GEP (11/98 pts [11.2%] vs 46/86 pts [53.5%]; P<.001) were observed in the t(11;14) and BCL2high subgroups compared with non-t(11;14) and BCL2low subgroups, respectively, improvement in PFS with Ven+Bd was independent of GEP classification. Conclusion: Using an integrative approach of genomic and transcriptomic profiling, response to Ven+Bd in key biomarker subgroups was shown to be independent of concurrent mutations in key oncogenic signaling pathways and GEPs known to be prognostic in MM; however, high mutation load appears to be a clinically relevant risk factor that negatively affects survival in MM. Disclosures O'Dwyer: Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Research Funding; Carrick Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy; ONK Therapeutics: Consultancy, Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Spencer:Roche: Honoraria; Sanofi: Consultancy, Honoraria; Pharmamar: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; HaemaLogiX: Consultancy, Honoraria, Research Funding. Kumar:Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genecentrix: Consultancy; Cellectar: Other; MedImmune: Research Funding; Karyopharm: Consultancy; Sanofi: Research Funding; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Carsgen: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding. Popat:AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol Myers Squibb: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria. Moreau:Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Novartis: Honoraria. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Jalaluddin:AbbVie: Current Employment, Other: may hold stock or stock options. Yang:Abbvie: Current Employment, Current equity holder in publicly-traded company. Lu:AbbVie: Current Employment, Current equity holder in publicly-traded company. Zha:Abbvie: Current Employment, Current equity holder in publicly-traded company. Dunbar:Abbvie: Current Employment, Current equity holder in publicly-traded company. Vishwamitra:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Mantis:Abbvie: Current Employment, Current equity holder in publicly-traded company. Melhem-Bertrandt:AbbVie: Current Employment; Astellas: Ended employment in the past 24 months. Ross:AbbVie: Current Employment, Current equity holder in publicly-traded company. Harrison:F. Hoffmann-La Roche: Consultancy, Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; GSK: 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Janssen: Honoraria; Haemalogix: Consultancy; BMS: Consultancy, Honoraria.

Introduction: New targets and treatment modalities are needed for multiple myeloma (MM). Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed on B cells and plasma cells, and is found on myeloma cells with near 100% prevalence. BFCR4350A, a humanized immunoglobulin G-based T-cell-engaging bispecific antibody (bsAb), targets the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 on T cells. Dual binding facilitates efficient immunological synapse formation, resulting in T-cell activation and potent killing of myeloma cells (Li et al. Cancer Cell 2017). GO39775 (NCT03275103) is an ongoing, multicenter Phase I trial evaluating the safety, activity, pharmacodynamics, and pharmacokinetics of BFCR4350A monotherapy in pts with relapsed/refractory (R/R) MM. We present dose-escalation data from the single step-up dosing cohort (Arm A). Methods: All pts have R/R MM for which no established therapy is available, appropriate, or tolerated. Prior exposure to CAR-T cells, T-cell engaging bsAbs, and antibody-drug conjugates (ADCs), including those targeting BCMA, is allowed. In dose-escalation, pts receive BFCR4350A by IV infusion in 21-day cycles (Q3W). In Arm A, a single step-up dose is used in Cycle (C) 1 to mitigate the risk for cytokine release syndrome (CRS), with the step dose (0.05-3.6mg) given on C1 Day (D) 1 and the target dose (0.15-132mg) given on C1D8, and on D1 of each subsequent cycle. Results: At cut-off (April 13, 2020), 51 pts (median age: 62.0 years [range: 33-80]; high-risk [HR] cytogenetics [1q21, t(4;14), t(14;16), or del(17p)]: 28 pts) had been enrolled into Arm A. Median number of prior lines of therapy was 6 (range: 2-15). Prior treatments included: proteasome inhibitors (PIs), 100% (94.1% refractory); immunomodulatory drugs (IMiDs), 100% (98.0% refractory); anti-CD38 mAbs, 78.4% (92.5% refractory); autologous stem cell transplant, 86.3%. Overall, 66.7% of pts were triple-class refractory (≥1 PI, ≥1 IMiD, and ≥1 anti-CD38 mAb), and 94.1% of pts were refractory to their last therapy. At cut-off, 46/51 pts were evaluable for efficacy. Responses were observed at the 3.6/20mg dose level and above, in 15/29 pts (51.7%) (Table). Responses included 3 stringent CRs, 3 CRs, 4 VGPRs, and 5 PRs (Table). At the 3.6/20mg dose level and above, responses were observed in pts with HR cytogenetics (9/17), triple-class refractory disease (10/20), and prior exposure to anti-CD38 mAbs (11/22), CAR-Ts (2/3), or ADCs (2/2). Duration of response data are evolving, with 6/15 pts in response for >6 months at cut-off. Median follow-up for safety was 6.2 months (range: 0.2-26.3 months). Almost all pts (49/51) had ≥1 treatment-related AE. The most common treatment-related AE was CRS (Lee et al. 2014 criteria; 38/51 pts, 74.5%). CRS was Grade (Gr) 1 in 20 pts (39.2%), Gr 2 in 17 pts (33.3%), and Gr 3 in 1 pt (2%) (due to Gr 4 transaminase elevation). CRS was most common in C1 (38 pts) and was uncommon or absent in subsequent cycles (4 pts). Most CRS events (49/58, 84.5%) resolved within 2 days. 18/38 (47.3%) pts with CRS received tocilizumab and/or steroids. Other treatment-related AEs in ≥5 pts were neutropenia and lymphocyte count decreased (6 pts each, 11.8%), aspartate aminotransferase increased and platelet count decreased (5 pts each, 9.8%). Treatment-related Gr 3-4 AEs (20 pts, 39.2%) in ≥3 pts were lymphocyte count decreased (6 pts, 11.8%), neutropenia (5 pts, 9.8%), anemia and platelet count decreased (3 pts each, 5.9%). No treatment-related Gr 5 (fatal) AEs were observed. Treatment-related AEs leading to withdrawal of treatment were uncommon (1 pt, 2.0%). One DLT (Gr 3 pneumonia) was observed in the 3.6/90mg cohort, but the MTD was not reached. BFCR4350A PK was linear across the active dose levels tested and the estimated half-life was supportive of the Q3W dosing regimen. Conclusions: BFCR4350A monotherapy demonstrates promising activity in heavily pre-treated R/R MM, with deep and durable responses observed in pts with HR cytogenetics, triple-class refractory disease, and/or prior exposure to anti-CD38 mAbs, CAR-Ts, or ADCs. Toxicity was manageable, with C1 single step-up dosing effectively mitigating the risk for severe CRS and allowing escalation to clinically active doses. Updated data will be presented. Disclosures Cohen: Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: 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; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Harrison:Takeda: 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, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Haemalogix: Consultancy; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Krishnan: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; Takeda: Speakers Bureau; Amgen: Speakers Bureau; BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau; Sanofi: Consultancy. Fonseca:Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Forsberg:Celgene: Speakers Bureau; Genentech, Inc., Sanofi, Karyopharm, Abbvie: Research Funding. Spencer:AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; Celgene, Janssen and Takeda: Speakers Bureau. Berdeja:BMS: Consultancy, Research Funding; Glenmark: Research Funding; Genentech, Inc.: Research Funding; Bioclinica: Consultancy; Teva: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Cellularity: Research Funding; Acetylon: Research Funding; CURIS: Research Funding; Legend: Consultancy; Lilly: Research Funding; Constellation: Research Funding; EMD Sorono: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy; Poseida: Research Funding; Amgen: Consultancy, Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Bluebird: Research Funding; Karyopharm: Consultancy; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Kesios: Research Funding. Li:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment. Choeurng:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Vaze:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Samineni:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Sumiyoshi:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cooper:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Fine:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Trudel:Janssen: Honoraria, Research Funding; Sanofi: Honoraria; GSK: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Karyopharm: Honoraria; AstraZeneca: Honoraria; BMS: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Honoraria. OffLabel Disclosure: BFCR4350A is a humanized IgG-based T-cell-engaging bispecific antibody that targets the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 on T cells. Dual binding facilitates efficient immunological synapse formation, resulting in T-cell activation and killing of myeloma cells. BFCR4350A is an investigational agent.