Expression of BCMA, a cell surface receptor in the TNF superfamily, is restricted to B cells at later stages of differentiation and is requisite for the survival of long lived plasma cells. BCMA is expressed on MM cells at variable levels.

GSK2857916 is a humanized IgG1 anti-BCMA antibody conjugated to the microtubule disrupting agent monomethyl auristatin-F via a stable, protease-resistant maleimidocaproyl linker. Upon binding to BCMA, GSK2857916 is rapidly internalized and active drug is released within the cell. GSK2857916 also exhibits enhanced antibody-dependent cell-mediated cytotoxicity resulting from afucosylation of the FC domain which increases affinity to FCγRIIIa expressed on immune effector cells. The rationale for investigating GSK2857916 in MM is supported by the restricted pattern of BCMA expression and by evidence from preclinical studies.


BMA117159 (NCT02064387) is a Phase I open-label study investigating safety, pharmacokinetics (PK), pharmacodynamics (PD), antidrug antibodies (ADA) and clinical activity of GSK2857916 in relapsed/refractory MM and other hematologic malignancies expressing BCMA. Dose escalation (Part 1) is conducted exclusively in MM patients; primary objective is safety, determination of maximum tolerated dose (MTD) and recommended phase 2 dose. GSK2857916 is administered every 3 weeks as a1 hr intravenous infusion with no mandatory prophylaxis for infusion related reactions (IRR). Bayesian Logistic Regression Model is applied for dose recommendations. Eligible MM patients must have prior treatments with alkylators, proteasome inhibitors, immunomodulators and stem cell transplantation, if transplant eligible, and have documented disease progression on or within 60 days of last therapy. Additional key inclusion criteria include: ANC >1x109/L; hemoglobin >8 g/dL; PLT >50x109/L; INR <1.5; PTT <1.5xULN; total bilirubin ≤1.25xULN; AST and ALT <1.5xULN; serum creatinine <1.2xULN or calculated creatinine clearance >60 mL/min; albuminuria <500mg/24hr; LVEF >50% and troponin <1xULN. Patients remain on treatment until progression, unacceptable toxicity, consent withdrawal or completing 16 treatment cycles. Blood is collected for PK and ADA analyses; blood and bone marrow aspirates are collected for PD analyses.


To date 24 MM patients have enrolled and completed the 21 day DLT observation period. Patients were enrolled at the following 8 dose levels: 0.03 (n=1); 0.06 (n=1); 0.12 (n=4); 0.24 (n=4); 0.48 (n=4); 0.96 (n=3); 1.92 (n=4), and 3.4 mg/kg (n=3). The median age is 60 years (range 39-71); 50% are male. Eighty-three percent received ≥4 prior lines. Sixty-three percent had IgG and 29% had IgA types. Seven patients (29%) had adverse cytogenetics defined as del17p13, or t(4;14) . Overall, 23 patients (96%) experienced adverse events (AE); the most frequent (≥20%) regardless of cause were nausea (42%), fatigue (38%), anemia (29%), chills (29%), pyrexia (29%), thrombocytopenia (29%), dry eye (21%), and hypercalcemia (21%). Grade 3/4 AEs reported in ≥10% of patients were thrombocytopenia, anemia, and neutropenia. Eight serious AEs were reported in 6 patients with 1 event of limbal stem cell dysfunction considered drug related; this event has not resolved. There were no AEs leading to treatment discontinuation. Four patients required dose reduction due to AEs: ocular toxicity (n=1), corneal disorder/ocular toxicity (n=1), dry eyes (n=1), and keratitis (n=1). IRRs (all Grade 1 or 2) were reported in 7 patients (29%) across dose levels and occurred with the first dose administration. The most frequent symptoms were chills. No DLTs were reported. Sixteen patients discontinued treatment due to disease progression (n=14), patient decision (n=1), completing 16 cycles of scheduled treatment (n=1); 8 patients are ongoing. There was1 MR at 0.24 mg/kg, and 1 VGPR, 3 PR, and1 MR at doses ≥0.96 mg/kg; resulting in a clinical benefit rate of 25% (unconfirmed responses).


GSK2857916 was well tolerated with no DLTs up to 3.4mg/kg q3w; MTD was not reached. AEs were manageable with ocular toxicity emerging as the most frequent reason for dose modifications. Clinical activity has been seen at higher doses. Complete safety, ADA, PD, and clinical activity data from all dose levels evaluated in Part 1 for q3w schedule will be presented.

Study is funded by GlaxoSmithKline; drug linker technology is licensed from Seattle Genetics


Cohen:Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy, Research Funding. Trudel:Glaxo Smith Kline: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Equity Ownership, Honoraria; Oncoethix: Research Funding; BMS: Honoraria; Amgen: Honoraria. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees. Anderson:Takeda: Speakers Bureau; AMGEN/Onyx: Speakers Bureau; Celegene: Speakers Bureau. DeWall:GlaxoSmithKline: Employment, Equity Ownership. Ellis:GlaxoSmithKline: Employment, Equity Ownership. He:GlaxoSmithKline: Employment, Equity Ownership. Mazumdar:GlaxoSmithKline: Employment, Equity Ownership. Wang:GlaxoSmithKline: Employment, Equity Ownership. Opalinska:GlaxoSmithKline: Employment, Equity Ownership. Voorhees:GlaxoSmithKline: Research Funding; Celgene, BMS: Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy.

Author notes


Asterisk with author names denotes non-ASH members.

Sign in via your Institution