Overcoming multiple myeloma drug resistance in the era of cancer ‘omics’

Abstract

Multiple myeloma (MM) is among the most compelling examples of cancer in which research has markedly improved the length and quality of lives of those afflicted. Research efforts have led to 18 newly approved treatments over the last 12 years, including seven in 2015. However, despite significant improvement in overall survival, MM remains incurable as most patients inevitably, yet unpredictably, develop refractory disease. Recent advances in high-throughput 'omics' techniques afford us an unprecedented opportunity to (1) understand drug resistance at the genomic, transcriptomic, and proteomic level; (2) discover novel diagnostic, prognostic, and therapeutic biomarkers; (3) develop novel therapeutic targets and rational drug combinations; and (4) optimize risk-adapted strategies to circumvent drug resistance, thus bringing us closer to a cure for MM. In this review, we provide an overview of 'omics' technologies in MM biomarker and drug discovery, highlighting recent insights into MM drug resistance gleaned from the use of 'omics' techniques. Moving from the bench to bedside, we also highlight future trends in MM, with a focus on the potential use of 'omics' technologies as diagnostic, prognostic, or response/relapse monitoring tools to guide therapeutic decisions anchored upon highly individualized, targeted, durable, and rationally informed combination therapies with curative potential.

Concurrent lipidomics and proteomics on malignant plasma cells from multiple myeloma patients: Probing the lipid metabolome

“…In MM, initial lipidomic studies comparing malignant plasma cells to healthy plasma cells have reported decreased levels of phosphatidylcholines [8], and differing fatty acid composition of cellular membranes [8,9]. There are limited studies on the metabolic changes that occur during MM relapse, with most studies focusing at the genomic level [10]. Using Raman spectroscopy to compare between drug resistant and sensitive MM cell lines, Franco et al suggested differences in nuclear structure, as reflected by altered DNA:RNA ratio as well as cholesterol and phosphatidylethanolamine content [11].…”

Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma

“…Advanced mature B cell malignancies, including MM, represent a wide range of frequent cancers and are still considered incurable for many patients. Despite significant progress in understanding the pathogenesis of these malignancies, novel targeted therapies have been successful for only some subentities and specific scenarios (28). To develop alternative preclinical models, we here generated a mouse model on a C57BL/6 background where conditional L-gp130 activation was directed to the hematopoietic system at different developmental stages.…”

Concurrent lipidomics and proteomics on malignant plasma cells from multiple myeloma patients: Probing the lipid metabolome

“…In MM, initial lipidomic studies comparing malignant plasma cells to healthy plasma cells have reported decreased levels of phosphatidylcholines [8], and differing fatty acid composition of cellular membranes [8, 9]. There are limited studies on the metabolic changes that occur during MM relapse, with most studies focusing at the genomic level [10]. Using Raman spectroscopy to compare between drug resistant and sensitive MM cell lines, Franco et al .…”