New approaches to stratify multiple myeloma patients based on prognosis and therapeutic decision-making, or prediction, are needed since patients are currently managed in a similar manner regardless of individual risk factors or disease characteristics. However, despite new and improved biomarkers for determining the prognosis of patients, there is currently insufficient information to utilise biomarkers to intensify, reduce or altogether change treatment, nor to target patient-specific biology in a so-called predictive manner. The ever-increasing number and complexity of drug classes to treat multiple myeloma have improved response rates and so clinically useful biomarkers will need to be relevant in the era of such novel therapies. Therefore, the field of multiple myeloma biomarker development is rapidly progressing, spurred on by new technologies and therapeutic approaches, and underpinned by a deeper understanding of tumour biology with individualised patient management the goal. In this review, we describe the main biomarker categories in multiple myeloma and relate these to diagnostic, prognostic and predictive applications.

The aim of this study is to determine whether manipulation of the drug transporter Pglycoprotein improves the efficacy of proteasome inhibitors in multiple myeloma cells. Pglycoprotein is a well-known drug transporter that is associated with chemotherapy resistance in a number of cancers but its role in modulating the efficacy of proteasome inhibitors in multiple myeloma is not well understood. Research has shown that the second generation proteasome inhibitor carfilzomib is a substrate of P-glycoprotein and as such its efficacy may correlate with P-glycoprotein activity. In contrast to carfilzomib, research concerning the first-in-class proteasome inhibitor bortezomib is inconsistent with some reports suggesting that inhibition of P-glycoprotein increases bortezomib cytotoxicity in multiple myeloma cells whereas others have shown no effect. Through the mining of publicly available gene expression microarrays of patient bone marrow, we show that P-glycoprotein gene expression increases with the disease stages leading to multiple myeloma. However, RNA-seq on LP-1 cells treated with bortezomib or carfilzomib demonstrated minimal basal P-glycoprotein expression which did not increase with treatment. Moreover, only one (KMS-18) of nine multiple myeloma cell lines expressed P-glycoprotein, including RPMI-8226 cells that are resistant to bortezomib or carfilzomib. We hypothesised that by inhibiting P-glycoprotein, multiple myeloma cell sensitivity to proteasome inhibitors would increase, thus providing a potential approach to improving responses and reversing resistance to these agents. However, the sensitivity of multiple myeloma cells lines to proteasome inhibition was not enhanced by inhibition of P-glycoprotein with the specific inhibitor tariquidar. In addition, targeting glucosylceramide synthase with eliglustat did not inhibit P-glycoprotein activity and also did not improve proteasome inhibitor efficacy except at a high concentration. We conclude that P-glycoprotein is poorly expressed in multiple myeloma cells, its inhibition does not enhance .

Multiple myeloma remains an incurable malignancy of plasma cells. Novel therapies, notably proteasome inhibitors and immunomodulatory drugs, have improved the survival of multiple myeloma patients; however, patients either present with, or develop resistance to, these therapies. Resistance to traditional chemotherapeutic agents can be caused by cellular drug efflux via adenosine triphosphate (ATP)-binding cassette (ABC) transporters, but it is still not clear whether these transporters mediate resistance to proteasome inhibitors and immunomodulatory drugs in multiple myeloma. Solute carrier (SLC) transporters also play a role in cancer drug resistance due to changes in cell homeostasis caused by their abnormal expression and changes in the solutes they transport. In this review, we evaluate resistance to novel therapies used to treat multiple myeloma, as mediated by drug and solute transporters.

Haematological malignancies are heterogeneous groups of cancers of the bone marrow, blood or lymph nodes, and while therapeutic advances have greatly improved the lifespan and quality of life of those afflicted, many of these cancers remain incurable. The iron-dependent, lipid oxidation-mediated form of cell death, ferroptosis, has emerged as a promising pathway to induce cancer cell death, particularly in those malignancies that are resistant to traditional apoptosis-inducing therapies. Although promising findings have been published in several solid and haematological malignancies, the major drawbacks of ferroptosis-inducing therapies are efficient drug delivery and toxicities to healthy tissue. The development of tumour-targeting and precision medicines, particularly when combined with nanotechnologies, holds potential as a way in which to overcome these obstacles and progress ferroptosis-inducing therapies into the clinic. Here, we review the current state-of-play of ferroptosis in haematological malignancies as well as encouraging discoveries in the field of ferroptosis nanotechnologies. While the research into ferroptosis nanotechnologies in haematological malignancies is limited, its pre-clinical success in solid tumours suggests this is a very feasible therapeutic approach to treat blood cancers such as multiple myeloma, lymphoma and leukaemia.

The aim of this study is to determine whether manipulation of the drug transporter P-glycoprotein improves the efficacy of proteasome inhibitors in multiple myeloma. P-glycoprotein is a well-known drug transporter that is associated with chemotherapy resistance in a number of cancers but its role in modulating the efficacy of proteasome inhibitors in multiple myeloma is not well understood. Research has shown that the second generation proteasome inhibitor carfilzomib is a substrate of P-glycoprotein and as such its efficacy may correlate with P-glycoprotein function. In contrast to carfilzomib, research concerning the first-in-class proteasome inhibitor bortezomib is inconsistent. Some researchers have demonstrated that inhibition of P-glycoprotein increases bortezomib cytotoxicity in multiple myeloma cells whereas others have shown no effect. Through the mining of publicly available gene expression microarrays of patient bone marrow, we show that P-glycoprotein gene expression increases with the disease stages leading to multiple myeloma. However, RNA-seq on LP-1 cells treated with bortezomib or carfilzomib demonstrated minimal basal P-glycoprotein expression which did not increase with treatment. Moreover, only one (KMS-18) of nine multiple myeloma cell lines expressed P-glycoprotein, including RPMI-8226 cells that are resistant to bortezomib or carfilzomib. We hypothesised that by inhibiting P-glycoprotein, multiple myeloma cell sensitivity to proteasome inhibitors would increase, thus providing a potential approach to improving responses and reversing resistance to these agents. However, the sensitivity of multiple myeloma cells lines to proteasome inhibition was not enhanced by inhibition of P-glycoprotein with the specific inhibitor tariquidar. In addition, targeting glucosylceramide synthase with eliglustat did not inhibit P-glycoprotein function and also did not improve proteasome inhibitor efficacy except at a high concentration. We conclude that P-glycoprotein is poorly expressed in multiple myeloma cells, its inhibition does not enhance the efficacy of proteasome inhibitors, and it is unlikely to be a useful avenue for further translational research.