Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 173, Issue 6, Pages 884-895Publisher
WILEY
DOI: 10.1111/bjh.14014
Keywords
molecular analysis; multiple myeloma; myeloma therapy; pharmacology; trials
Categories
Funding
- Onyx Pharmaceuticals, Inc. (South San Francisco, CA), an Amgen
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While proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme-linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15-56mg/m(2)), dose-dependent inhibition of c20S and i20S chymotrypsin-like active sites was observed [whole blood: 67%; peripheral blood mononuclear cells (PBMCs): 75%]. A similar inhibition profile was observed in bone marrow-derived CD138(+) tumour cells. Carfilzomib-induced proteasome inhibition was durable, with minimal recovery in PBMCs after 24h but near-complete recovery between cycles. Importantly, the ProCISE assay can be used to quantify occupancy of individual c20S and i20S subunits. We observed a relationship between MM patient response (n=29), carfilzomib dose and occupancy of multiple i20S subunits, where greater occupancy was associated with an increased likelihood of achieving a clinical response at higher doses. ProCISE represents a new tool for measuring proteasome inhibitor activity in clinical trials and relating drug action to patient outcomes.
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