Background: BION-1301 (BION) is first in class humanized monoclonal antibody directed against a proliferation-inducing ligand (APRIL) for treatment of relapsed/refractory (R/R) multiple myeloma (MM). APRIL secreted by cells in the bone marrow (BM) niche binds to BCMA (B-Cell maturation antigen) and TACI (transmembrane activator and CAML interactor) expressed on human MM cells to drive their proliferation and survival. In patients (pts) with MM, serum APRIL levels are elevated and are correlated with promotion of malignancy, chemo- and immune-resistance. This study evaluated tolerability and clinical activity of BION monotherapy in R/R MM pts. Methods: Adults with MM, progression after ≥3 systemic therapies, and ECOG 0-1 were enrolled in this phase 1/2, open-label study. The phase 1 study is evaluating 6 cohorts with increasing BION doses of 50, 150, 450, 1350, and 2700 mg administered Q2W intravenously (cohort 6 - 1350 mg dose given QW and Q2W). Response was assessed by investigators Q4W. Serum was analyzed for BION, anti-drug antibodies (ADA), and soluble unbound “free APRIL” (fAPRIL) and evaluated by PK-PD modeling. Results: As of 7Dec2018, 15 pts were enrolled in 4 cohorts at doses between 50-1350 mg given Q2W. 5/15 (33%) had ECOG 0 and pts received median of 6 prior systemic therapies (range: 4-17). Related treatment emergent adverse events (TEAE) were reported in 8/15 (36%); most common related TEAE included anemia (n=3), arthralgia (n=2), and dysgeusia (n=2). 1 subject receiving 4^th dose of BION experienced grade 3 wheezing considered infusion-related and serious. No dose-limiting toxicities were observed. Of 14/15 evaluable for response, no objective response was observed and 5/14 (36%) had stable disease. Median time on treatment was 2 months (range: 0.9-4.9+) and median of 3 doses of BION (range: 2-11) were administered. BION exposure increased dose proportionally from 50-1350 mg, and half-life (T_1/2) and clearance (CL) did not differ significantly (median T_1/2 = 9.0 days [range: 3.9-20], median CL = 0.52 L/day [range: 0.32-0.72]). Levels of fAPRIL in serum and BM decreased with increasing BION doses. By 450 mg, 95% target engagement (TG) was achieved around peak exposure levels. Non-neutralizing ADA was detected in 1/15 pts. Conclusions: BION, at doses 50-1350 mg given Q2W, was well-tolerated and dose-dependently reduces serum levels of fAPRIL. To date, objective responses have not been observed. The study is ongoing with pts exposed to higher and/or more frequent doses with the objective of achieving accelerated and sustained APRIL TG. Clinical trial information: NCT03340883