Multiple Myeloma Patients Have a Specific Serum Metabolomic Profile That Changes after Achieving Complete Remission

Abstract

Purpose: Multiple myeloma remains an incurable disease. New approaches to develop better tools for improving patient prognostication and monitoring treatment efficacy are very much needed. In this study, we aimed to evaluate the potential of metabolomics by 1 H-NMR to provide information on metabolic profiles that could be useful in the management of multiple myeloma. Experimental Design: Serum samples were collected from multiple myeloma patients at the time of diagnosis and after achieving complete remission. A matched control set of samples was also included in the study. The 1 H-NMR measurements used to obtain the metabolic profile for each patient were followed by the application of univariate and multivariate statistical analyses to determine significant differences.Results: Metabolic profiles of multiple myeloma patients at diagnosis exhibited higher levels of isoleucine, arginine, acetate, phenylalanine, and tyrosine, and decreased levels of 3-hydroxybutyrate, lysine, glutamine, and some lipids compared with the control set. A similar analysis conducted in multiple myeloma patients after achieving complete remission indicated that some of the metabolic changes (i.e., glutamine, cholesterol, lysine) observed at diagnosis displayed a variation in the opposite direction upon responding to treatment, thus contributing to multiple myeloma patients having a closer metabolic profile to those of healthy individuals after the disappearance of major disease manifestations.Conclusions: The results highlight the potential of metabolic profiles obtained by 1 H-NMR in identifying multiple myeloma biomarkers that may be useful to objectively discriminate individuals with and without multiple myeloma, and monitor response to treatment.

Glutamine-derived 2-hydroxyglutarate is associated with disease progression in plasma cell malignancies

“…However, an assessment by Puchades-Carrasco of MM patients at diagnosis exhibited decreased levels of glutamine in the peripheral blood compared with healthy controls (29). Furthermore, after achieving complete remission, the glutamine levels in these MM patients normalized to levels similar to healthy individuals (29). This supports our findings in that glutamine metabolism is important in MM and peripheral blood levels of glutamine are likely lower in active disease, as it is being utilized by clonal PCs to support glutamine anaplerosis.…”

“…Though these studies were different from this study, as they utilized an untargeted metabolite profiling methodology via NMR spectroscopy, they were able to identify metabolite profiles that correlated with the presence of either active disease, remission, or precursor states such as MGUS. However, an assessment by Puchades-Carrasco of MM patients at diagnosis exhibited decreased levels of glutamine in the peripheral blood compared with healthy controls (29). Furthermore, after achieving complete remission, the glutamine levels in these MM patients normalized to levels similar to healthy individuals (29).…”

“…Almost all HMCLs have primary MYC translocations involving an immunoglobulin gene locus, making their levels of c-MYC expression high (22). Other metabolomic-based approaches have been undertaken in the past using archived biofluids such as peripheral blood and urine samples from patients with MM (27)(28)(29). Though these studies were different from this study, as they utilized an untargeted metabolite profiling methodology via NMR spectroscopy, they were able to identify metabolite profiles that correlated with the presence of either active disease, remission, or precursor states such as MGUS.…”

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

“…[6][7][8][9][10][11][12] Recently, multivariate analysis based on 1 H-NMR spectroscopy analysis of serum samples has shown that a specific metabolic profile characterized MM patients vs healthy controls, including Gln levels significantly lower in the MM group. 13 Overall, these data suggest that Gln is highly metabolized in MM cells. To satisfy metabolic requirements of Gln, mammalian cells rely on glutamine synthetase (GS), the enzyme that obtains Gln from glutamate (Glu) and NH 4 1 .…”

Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis

“…Several hematological malignancies, including multiple myeloma, are also expected to be responsive to GLS inhibition due to the prevalent role of MYC in their pathogenesis (7,57,58). In fact, myeloma may depend on GLS, since low circulating glutamine levels measured before therapy return to normal after standard treatment (59). With the emergence of new chemical GLS inhibitors heading for clinical use, our foundational study paves the way for exploring whether inhibition of GLS alone or in combination with other therapies will prove to be useful clinically.…”