Proteomic profiling of naïve multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib‐based treatment regimens

Abstract

SummaryToward our goal of personalized medicine, we comprehensively profiled pre-treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib-based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially-regulated proteins indicative of at least a very good partial response (VGPR) or complete response/near complete response (CR/nCR) to two treatment regimens containing either bortezomib, liposomal doxorubicin and dexamethasone (VDD), or lenalidomide, bortezomib and dexamethasone (RVD). Our results suggest enrichment of 'universal response' pathways that are common to both treatment regimens and are probable predictors of favourable response to bortezomib, including a subset of endoplasmic reticulum stress pathways. The data also implicate pathways unique to each regimen that may predict sensitivity to DNA-damaging agents, such as mitochondrial dysfunction, and immunomodulatory drugs, which was associated with acute phase response signalling. Overall, we identified patterns of tumour characteristics that may predict response to bortezomib-based regimens and their components. These results provide a rationale for further evaluation of the protein profiles identified herein for targeted selection of anti-myeloma therapy to increase the likelihood of improved treatment outcome of patients with newly-diagnosed myeloma.

Comparative proteomic profiling of sera from patients with refractory multiple myeloma reveals potential biomarkers predicting response to bortezomib-based therapy

“…24 Notably, thioredoxin was found in our previous studies 8,16 to have a potential role in resistance to bortezomib-based chemotherapy. The extracellular location of QSOX1 suggests that it may be involved in remodeling of the extracellular matrix, particularly because QSOX1 can catalyze the formation of disulfide bridges, which are needed for the appropriate folding and stability of various matrix proteins.…”

“…We have recently shown the usefulness of the proteomic approach using bone marrow plasma cells. 8,16 However, due to the cost and inconvenience for patients, bone marrow is not an ideal source of biomarkers in daily practice. To our knowledge, our study is the first analysis of pretreatment sera by modern proteomics in order to establish biomarkers that predict optimal…”

“…These pathways were found in our previous studies performed on pretreatment plasma cells. 8,16 One of the most interesting proteins involved in this pathway is QSOX1, which was found to be upregulated in the PD/SD group. There was a linear trend in the abundance of QSOX1 in all analyzed groups (FIGURE 3).…”

Proteomic analysis of serum for identification of potential biomarkers predicting response of patients with refractory multiple myeloma to bortezomib‑based therapy

“…[6][7][8] Bone marrow plasma cells are obtained by an invasive method of bone marrow biopsy, which is not useful in routine clinical practice. Therefore, Łuczak et al 4 have used proteomic analysis of se rum to overcome this obstacle.…”

Proteomic Characterization of Plasma Cells from Patients with Multiple Myeloma

“…The clinical applicability of the few published reports on cellular profiling of MM cells are hampered at least in part by the following: 1) the different techniques and statistical platforms used by different investigators, hence not allowing cross-validation; 2) the lack of standard procedures for sample collection, storage, and processing, hence causing background noises and lowered sensitivity of the test; and 3) limited sample numbers, hence lacking statistical power for clinical correlation analysis. In addition, to date proteomic profiling in MM has mostly been based on cell lines in culture [14,15], which may not be representative of primary samples. Primary MM cells are not sustainable in culture due to their crucial reliance on bone marrow niche.…”