Several therapies are now approved for multiple myeloma treatment, creating a pressing need to predict which drug or combination of drugs will be most effective and safe for each patient. Proteasome inhibitors (PrIs), including carfilzomib and bortezomib, are one such class of drugs that has become a standard therapy across all lines of myeloma treatment. Despite extensive study, the mechanism of selective tumor cell death following proteasome inhibition is poorly understood. However, the uniquely high sensitivity of myeloma cells to proteasome inhibition, the high burden of protein (immunoglobulin) secretion these cells experience, and the key role of the proteasome in maintaining protein homeostasis together point toward a unifying model in which protein load drives tumor sensitivity to PrIs. This simple model is supported by published studies of myeloma cell lines. As part of company-sponsored Phase II & III clinical trials of single-agent PrIs, CD138+ tumor cells collected during patient screening were banked for comprehensive genomic analyses. Here, examining our carfilzomib RNA-Seq data along with publically-available bortezomib microarray-based RNA data, we find a strong association between higher immunoglobulin (Ig) expression and sensitivity to both carfilzomib (N = 60; P = 3x10-3) and bortezomib (N = 167; P = 2x10-4). In fact, using IGH expression alone, we are able to classify carfilzomib response with 56% sensitivity and 91% specificity. Median time to progression for IGH-High carfilzomib patients was 5.4-fold longer than for IGH-Low patients (7.3 vs. 1.3 months; P = 0.005). As expected for a bona fide predictive biomarker of proteasome inhibition, no association was found between IGH expression and response to single-agent, high-dose dexamethasone (P = 0.82). Looking more comprehensively, we identified a large set of associations between gene expression and carfilzomib response (N = 361 at FDR < 15%). The set is strongly enriched for genes encoding structural folds of the Ig superfamily (P < 10-13), implying that high expression of this class of proteins sensitizes cells to PrIs. One such gene is Fc gamma receptor 2B (FCGR2B), which binds Ig and down-modulates its production in B cells. High FCGR2B expression, therefore, may demarcate a tumor that is experiencing particularly high levels of proteotoxic stress from Ig production. Combining FCGR2B and IGH expression, we are able to classify carfilzomib response with 70% sensitivity and 94% specificity. Median time to progression for IGH/FCGR2B+ patients was 7.3-fold longer than for IGH/FCGR2B- patients (8.9 vs. 1.2 months; P = 3x10-5). IGH expression is, to our knowledge, the first retrospectively validated biomarker for this important class of anti-tumor agents and therefore represents a promising basis for the development of a PrI companion diagnostic.
Citation Format: Brian B. Tuch, Andrea Loehr, Jeremiah D. Degenhardt, Kevin A. Kwei, Eric Lowe, Kristi Stephenson, Jonathan J. Keats, Christopher J. Kirk. Expression of immunoglobulin and its receptor are major determinants of multiple myeloma patient sensitivity to proteasome inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 898. doi:10.1158/1538-7445.AM2014-898