Gene expression profiles of tumor biology provide a novel approach to prognosis and may guide the selection of therapeutic targets in multiple myeloma

Abstract

Purpose: Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) comprise heterogeneous disorders with incompletely understood molecular defects and variable clinical features. We performed gene expression profiling (GEP) with microarray data to better dissect the molecular phenotypes, sensitivity to particular chemotherapeutic agents, and prognoses of these diseases.

Methods: Using gene expression and clinical data from 877 patients ranging from normal plasma cells (NPC) to relapsed MM (RMM), we applied gene expression signatures reflecting deregulation of oncogenic pathways and tumor microenvironment to highlight molecular changes that occur as NPCs transition to MM, create a high-risk MGUS gene signature, and subgroup International Staging System (ISS) stages into more prognostically accurate clusters of patients. Lastly, we used gene signatures to predict sensitivity to conventional cytotoxic chemotherapies among identified clusters of patients.

Results: Myc upregulation and increasing chromosomal instability (CIN) characterized the evolution from NPC to RMM (P < .0001 for both). Studies of MGUS revealed that some samples shared biologic features with RMM, which comprised the basis for a high-risk MGUS signature. Regarding MM, we subclassified ISS stages into clusters based on shared features of tumor biology. These clusters differentiated themselves based on predictions for prognosis and chemotherapy sensitivity (eg, in ISS stage I, one cluster was characterized by increased CIN, cyclophosphamide resistance, and a poor prognosis).

Conclusion: GEP provides insight into the molecular defects underlying plasma cell dyscrasias that may explain their clinical heterogeneity. GEP also may also refine current prognostic and therapeutic models for MGUS and MM.

Fig 1.

Genomic expression signatures of tumor biology characterize phenotypes of plasma cell dyscrasias. (A) Mean predicted probabilities of oncogenic pathway deregulation in normal plasma cells (NPCs; n = 37) and certain plasma cell dyscrasias: monoclonal gammopathy of undetermined significance (MGUS; n = 66), smoldering multiple myeloma (SMM; n = 36), multiple myeloma (MM; n = 74), and relapsed multiple myeloma (RMM; n = 27). (B) Application of signatures of an altered tumor microenvironment to the same samples as in A. B-CAT, beta-catenin; HYP, hypoxia; CIN, chromosomal instability; TNF, tumor necrosis factor; WH, wound healing.

Fig 2.

Dissection of International Staging System (ISS) stage I (low risk) into subphenotypes based on tumor biology. Subgroups based on molecular differences within ISS stage I carry prognostic implications. CIN, chromosomal instability; WH, wound healing; TNF, tumor necrosis factor; HYP, hypoxia; B-CAT, beta-catenin.

Fig 3.

Dissection of International Staging System (ISS) stage II (intermediate risk) into subphenotypes based on tumor biology. Subgroups based on molecular differences within ISS stage II carry prognostic implications. CIN, chromosomal instability; WH, wound healing; TNF, tumor necrosis factor; HYP, hypoxia, B-CAT, beta-catenin.

Fig 4.

Dissection of International Staging System (ISS) stage III (high risk) into subphenotypes based on tumor biology. Subgroups based on molecular differences, within ISS stage III carry prognostic implications. CIN, chromosomal instability; WH, wound healing; TNF, tumor necrosis factor, HYP, hypoxia; B-CAT, beta-catenin.

Fig A1.

Development of relapsed multiple myeloma (RMM) –like high-risk monoclonal gammopathy of undetermined significance (MGUS) signature. (A) A heatmap representing the probability of oncogenic pathway deregulation and altered tumor microenvironment in the MGUS cohort (red = high probability, blue = low probability). (B) Unsupervised hierarchical clustering analysis. Gene expression profiling clearly differentiates normal plasma cells (NPCs) from RMM, and MGUS samples intersperse themselves among both (top panel). This enabled the development of a RMM-like MGUS gene signature (bottom panel). stage III.

Fig A3.

Example of prospective trial design in multiple myeloma. A newly diagnosed multiple myeloma patient, who is not a transplantation candidate, may be stratified to either a control (standard of care) arm or a genomics-guided arm. ISS, International Staging System.

Fig A4.

Differences in tumor biology between distinct phenotypes. Normal plasma cells (NPCs) and the plasma cell dyscrasias (monoclonal gammopathy of undetermined significance [MGUS], multiple myeloma [MM], and relapsed multiple myeloma [RMM]) were characterized by distinct patterns of biologic derangement. SMM, smoldering multiple myeloma.