Multiple myeloma (MM) is the second most common hematological malignancy, arising from terminally differentiated B cells, namely plasma cells. miRNAs are small non-coding RNAs that participate in the post-transcriptional regulation of gene expression. In this study, we investigated the role of nine miRNAs in MM. CD138+ plasma cells were selected from bone marrow aspirates from MM and smoldering MM (sMM) patients. Total RNA was extracted and in vitro polyadenylated. Next, first-strand cDNA synthesis was performed using an oligo-dT–adapter primer. For the relative quantification of the investigated miRNAs, an in-house real-time quantitative PCR (qPCR) assay was developed. A functional in silico analysis of the miRNAs was also performed. miR-16-5p and miR-155-5p expression was significantly lower in the CD138+ plasma cells of MM patients than in those of sMM patients. Furthermore, lower levels of miR-15a-5p, miR-16-5p, and miR-222-3p were observed in the CD138+ plasma cells of MM patients with osteolytic bone lesions, compared to those without. miR-125b-5p was also overexpressed in the CD138+ plasma cells of MM patients with bone disease that presented with skeletal-related events (SREs). Furthermore, lower levels of miR-223-3p were associated with significantly worse overall survival in MM patients. In conclusion, we propose a miRNA signature with putative clinical utility in MM.

Multiple myeloma (MM) is a common hematological malignancy arising from terminally differentiated plasma cells. In the majority of cases, symptomatic disease is characterized by the presence of bone disease. Multiple myeloma bone disease (MMBD) is a result of an imbalance in the bone-remodeling process that leads to increased osteoclast activity and decreased osteoblast activity. The molecular background of MMBD appears intriguingly complex, as several signaling pathways and cell-to-cell interactions are implicated in the pathophysiology of MMBD. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of their target mRNAs. Numerous miRNAs have been witnessed to be involved in cancer and hematological malignancies and their role has been characterized either as oncogenic or oncosuppressive. Recently, scientific research turned towards miRNAs as regulators of MMBD. Scientific data support that miRNAs finely regulate the majority of the signaling pathways implicated in MMBD. In this review, we provide concise information regarding the molecular pathways with a significant role in MMBD and the miRNAs implicated in their regulation. Moreover, we discuss their utility as molecular biomarkers and highlight the putative usage of miRNAs as novel molecular targets for targeted therapy in MMBD.

High-dose chemotherapy with autologous stem cell support (ASCT) is the standard of care for eligible newly diagnosed Multiple Myeloma (MM) patients. Stem cell graft contamination by aberrant plasma cells (APCs) has been considered a possible predictive marker of subsequent clinical outcome, but the limited reports to date present unclear conclusions. We prospectively estimated the frequency of graft contamination using highly sensitive next-generation flow cytometry and evaluated its clinical impact in 199 myeloma patients who underwent an ASCT. Contamination (con+) was detected in 79/199 patients at a median level 2 × 10⁻⁵. Its presence and levels were correlated with response to induction treatment, with 94%, 71% and 43% achieving CR, VGPR and PR, respectively. Importantly, con+ grafts conferred 2-fold and 2.8-fold higher patient-risk of not achieving or delaying reaching CR (4 vs. 11 months) and MRD negativity (5 vs. 18 months) post ASCT, respectively. Our data also provide evidence of a potentially skewed bone marrow (BM) reconstitution due to unpurged grafts, since con+ derived BM had significantly higher prevalence of memory B cells. These data, together with the absence of significant associations with baseline clinical features, highlight graft contamination as a potential biomarker with independent prognostic value for deeper responses, including MRD negativity. Longer follow-up will reveal if this corresponds to PFS or OS advantage.

Waldenstrom’s macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma with indolent course and prolonged disease course. The first-in-class Bruton’s tyrosine kinase inhibitor, ibrutinib, has shown significant activity and a distinct adverse event profile among both newly diagnosed and relapsed/refractory WM patients. Interestingly, clinical responses to ibrutinib have been shown to be dependent on patients’ MYD88 and CXCR4 mutational status. The recent outcomes of the Phase III iNNOVATE trial showed that the combination of ibrutinib with rituximab resulted in a significantly prolonged progression-free survival compared with rituximab monotherapy, which provides a novel therapeutic option in the clinical practice especially for the rituximab-refractory WM patients. However, the need for continuous drug administration along with the unique toxicity manifestations may render the patient management challenging. Furthermore, our understanding of the underlying resistant mechanisms to ibrutinib is currently being evolved.

Background: Multiple myeloma bone disease (MMBD) constitutes a common and severe complication of multiple myeloma (MM), impacting the quality of life and survival. We evaluated the clinical value of a panel of 19 miRNAs associated with osteoporosis in MMBD. Methods: miRNAs were isolated from the plasma of 62 newly diagnosed MM patients with or without MMBD. First-strand cDNA was synthesized, and relative quantification was performed using qPCR. Lastly, we carried out extensive biostatistical analysis. Results: Circulating levels of let-7b-5p, miR-143-3p, miR-17-5p, miR-214-3p, and miR-335-5p were significantly higher in the blood plasma of MM patients with MMBD compared to those without. Receiver operating characteristic curve and logistic regression analyses showed that these miRNAs could accurately predict MMBD. Furthermore, a standalone multi-miRNA–based logistic regression model exhibited the best predictive potential regarding MMBD. Two of those miRNAs also have a prognostic role in MM since survival analysis indicated that lower circulating levels of both let-7b-5p and miR-335-5p were associated with significantly worse progression-free survival, independently of the established prognostic factors. Conclusions: Our study proposes a miRNA signature to facilitate MMBD diagnosis, especially in ambiguous cases. Moreover, we provide evidence of the prognostic role of let-7b-5p and miR-335-5p as non-invasive prognostic biomarkers in MM.