Expression of Myeloma Cell and Soluble B-Cell Maturation Antigen (BCMA) in Relapsed and Refractory Multiple Myeloma Patients Treated with GSK2857916 in BMA117159
Authors: Dettman E.J. , Rigat Fabio , Albert Josh , Barnard Ruth , Birchler Mary , Deghenhardt Yan , DeWall Stephen , Gaye Boyenoh , He Zangdong , Liu Veronica , Opalinska Joanna 
Published: October 2019

Introduction:

B-cell maturation antigen (BCMA) is a cell surface receptor that is widely expressed on multiple myeloma (MM) cells. GSK2857916 is a humanized Fc enhanced IgG1 anti-BCMA antibody conjugated to the microtubule inhibitor monomethyl auristatin-F (MMAF). Safety and clinical efficacy of a Q3W GSK2857916 dosing schedule were assessed in relapsed/refractory MM subjects in the first time in human trial BMA117159. In the dose escalation phase, 38 subjects were treated with doses from 0.03 mg/kg up to 4.60 mg/kg, followed by an expansion cohort of 35 subjects at a dose of 3.40 mg/kg where an overall response rate (ORR) of 60% (21/35; 95% CI 42.1-76.1) by IMWG criteria was demonstrated (Trudel, et al. Blood 2017). Several novel biomarkers were followed during the BMA117159 study, including: the level of BCMA expression on MM cells and circulating soluble BCMA (sBCMA).

Methods:

The expression of BCMA on MM cells was measured in subjects enrolled in BMA117159 at baseline in formalin-fixed paraffin-embedded bone marrow aspirate samples using a BCMA Immunohistochemistry (IHC) assay and a dual color IHC assay with BCMA and CD138 (plasma cell marker). The antibody to detect BCMA (J6M0) uses the same CDR regions as GSK2857916. BCMA staining was quantified as a percentage positive of all cells, percentage of plasma cells as determined by morphology, or in CD138+ cells (for the dual color IHC assay). Soluble BCMA was measured in serum samples collected at pre- and post-infusion at cycle 1 using immunoassays to determine the levels of free and GSK2857916-bound sBCMA. All measurements were performed at central laboratories.

Results:

Among the subjects enrolled in BMA117159, the baseline BCMA expression was found specifically in plasma cells using BCMA IHC, with a median of 100% plasma cells expressing BCMA across all subjects, compared to a median of 5% of all bone marrow cells expressing BCMA. In the dose expansion cohort, no differences by response group were noted in BCMA staining with both responders (PR or better) and non-responders having 100% BCMA positivity in plasma cells. Comparable results were observed using a dual staining IHC assay for BCMA and CD138, where 95% of CD138+ cells expressed BCMA in non-responders compared with 88% in responders.

Examination of circulating sBCMA in BMA117159 subjects revealed high sBCMA levels, with a baseline median concentration of free sBCMA of 58 ng/mL across all doses (n = 68; range 4 ng/mL to >1000 ng/mL). Among patients enrolled in the expansion phase, the median baseline sBCMA concentrations were higher in non-responders compared to responders (81 ng/mL, n = 12; compared to 43 ng/mL, n = 19). However, high baseline sBCMA levels were also found in responders with levels up to 262 ng/mL. To examine whether sBCMA may act as a surrogate for BCMA expression in tumor cells, the relationship between these measures was examined; however, no strong associations were observed between baseline sBCMA and BCMA IHC staining (Spearman rho = 0.27).

The binding of GSK2857916 to sBCMA can be measured by comparing the post-infusion levels of free sBCMA measured 60 minutes after the start of infusion to those found at pre-infusion. It was found that the reduction in free sBCMA appeared to be related to the dose level administered, and doses above 1.92 mg/kg consistently achieved a greater than 90% reduction of free sBMCA.

Conclusions:

These preliminary data indicate that tumor cells from MM patients participating in BMA117159 consistently expressed the BCMA receptor at baseline, and the levels of expression did not appear to be associated with response to treatment. At higher dose levels, it was found that GSK2857916 bound a large fraction of sBCMA, and responses to GSK2857916 were observed in 60% of dose expansion subjects with either low or high baseline sBCMA. However, at present, the sample sizes are limited, and further investigations in future studies are necessary to understand the value of these biomarkers for treatment decisions.

Study is funded by GlaxoSmithKline (NCT02064387); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT® Technology licensed from BioWa.

Disclosures

Dettman: GlaxoSmithKline: Employment, Equity Ownership. Rigat:GlaxoSmithKline: Employment, Equity Ownership. Albert:GlaxoSmithKline: Employment, Equity Ownership. Barnard:GlaxoSmithKline: Employment, Equity Ownership. Birchler:GlaxoSmithKline: Employment, Equity Ownership. Deghenhardt:GlaxoSmithKline: Employment, Equity Ownership. DeWall:GlaxoSmithKline: Employment, Equity Ownership. Gaye:GlaxoSmithKline: Employment, Equity Ownership. He:GlaxoSmithKline: Employment, Equity Ownership. Liu:GlaxoSmithKline: Employment, Equity Ownership. Opalinska:GlaxoSmithKline: Employment, Equity Ownership.