Levels of Individual Mid and Long Chain Polyunsaturated Triacylglycerols (TAGs) Are Different between the Bone Marrow Microenvironment of Patients with Multiple Myeloma (MM) and Monoclonal Gammopathy of Unknown Significance (MGUS)

Background: It has been recently demonstrated that altered lipid metabolism involving increased free fatty acids (FFAs) uptake supports the growth and proliferation of MM cells (Panaroni et al. Blood 2022; Farell et al. Elife 2023). Whether the availability of FFAs in the bone marrow (BM) microenvironment is associated with the pathogenesis of MM from MGUS has not been previously evaluated. Thus, we evaluated if individual species of FAs or FA-containing lipids such as triacylglycerols (TAGs), diacylglycerols (DAGs), and monoacylglycerols (MAGs) are differentially present between the BM microenvironment of MGUS and MM patients.

Methods: Lipid profiles of BM plasma samples (reflective of the BM microenvironment) from patients with a spectrum of plasma cell disorders (22 MGUS and 24 MM (15 newly diagnosed and 9 relapsed/refractory)) were acquired by liquid chromatography (LC)/tandem mass spectrometry (MS), and individual lipid species were quantified based on single-point quantification using 55 isotopically labeled internal standards. Concentration-based lipid species data was analyzed by the web-based tool MetaboAnalyst 5.0. Data was normalized by quantile normalization, log transformed and scaled by Pareto scaling. p values <0.05 were considered significant.

Results: A total of 993 distinct lipid species were quantified by the MS-based targeted lipidomics assessment. Of these lipid species, the levels of individual mid-chain (≤50 carbon chain length) and long-chain (≥52 carbon chain length) polyunsaturated TAGs were the most differentially present in the BM plasma of MM compared to MGUS patients (Figure 1A). Even though a principal component analysis (PCA) involving all lipid species showed moderate separation of MM from MGUS patients, five MGUS patients (categorized as MGUS-other (MGO)) who clustered more towards MM patients compared to the remaining MGUS patients had a distinct pattern of individual mid and long-chain polyunsaturated TAG levels that were comparable to MM patients (Figure 1B). Furthermore, the proliferation rate of clonal plasma cells in the BM of these MM and MGUS as measured by the S-phase% was found to be directly correlated with the level of long-chain polyunsaturated TAGs.

Conclusions: Mid and long-chain polyunsaturated TAGs are present in lower and higher levels, respectively, in the BM microenvironment of MM compared to MGUS patients. These findings continue to support the importance of FA-containing TAGs and other lipids in the pathogenesis of MM. Future confirmatory studies evaluating the biological significance of these differences are required to determine if they can be exploited for diagnostic and therapeutic purposes.