Targeting GRP78 in drug resistant myeloma

Purpose: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma (MM) and both, its surface expression as well as its biological significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface (s) GRP78 and leads to disease stabilization when used as single-agent in a clinical trial. In this paper, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens. Experimental Design: GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of MM. Activity of PAT-SM6 was evaluated in combination with anti-MM agents lenalidomide, bortezomib and dexamethasone in vitro. Finally, we report on a MM patient with relapsed and refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide. Results: Although sGRP78 expression was present at all stages, it increased with disease progression and was even stronger elevated in patients with drug-resistant and extramedullary disease. Pre-treatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti-MM effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant MM treated with PAT-SM6, bortezomib and lenalidomide experienced partial remission of both intra- and extramedullary lesions. Conclusions: PAT-SM6 therapy in combination regimens showed efficacy in relapsed refractory MM.

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