Immunoglobulin Expression Is a Major Determinant Of Patient Sensitivity To Proteasome Inhibitors

Several therapies for multiple myeloma are now approved and many more are in development, promising improved outcomes for patients with this incurable cancer. With expanding treatment options, however, comes a pressing need to pair each patient with the most efficacious and safe treatment. Proteasome inhibitors, such as carfilzomib and bortezomib, have become a standard therapy across all lines of multiple 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 uniquely 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 proteasome inhibitor sensitivity. This simple model is supported by published studies of murine and human myeloma cell lines (e.g., Meister et al. & Bianchi et al.). As part of company-sponsored Phase II & III clinical trials of proteasome inhibitors, CD138+ tumor cells collected during patient screening were banked for comprehensive genomic analyses. Patient samples banked on bortezomib trials were utilized in now-published microarray-based RNA studies, while samples from carfilzomib trials are currently being used for NGS-based DNA and RNA studies. Here, examining our early carfilzomib data along with publically-available bortezomib data, we find a strong association between higher immunoglobulin expression and sensitivity to each compound (Wilcoxon P-value = 3x10^-3 and P-value = 2x10^-4, respectively). In fact, using IGH expression alone, we are able to classify response with 55% sensitivity and 91% specificity in our carfilzomib training data. As expected for a bona fide predictive biomarker of proteasome inhibition, an association between IG expression and response was not found in patients treated with single agent dexamethasone (Wilcoxon P-value = 0.82). Median time to progression for IGH-high carfilzomib patients was 6-fold longer than for IGH-low carfilzomib patients (7.6 months vs. 1.4 months; log-rank P-value = 0.003). This is the first report that high levels of IG expression correlate with response to proteasome inhibitors and therefore IG expression represents, to our knowledge, the first validated biomarker for this important class of anti-tumor agents.