Multiple Myeloma and Bone Marrow Microenvironment

Dear Colleagues,

Multiple myeloma (MM) comprises a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. It accounts for approximately 1.8% of all hematologic and solid cancers and > 15% of hematologic malignancies in the United States. MM is typically sensitive to different classes of cytotoxic drugs, both as frontline treatment and as treatment for relapsed disease. Unfortunately, even if responses are typically durable, nowadays, MM is not considered curable with the current approaches.

However, MM survival rates have significantly improved due to the introduction of novel agents; patients diagnosed after 2010 have reported higher rates of novel therapy use and better survival outcomes compared with those of earlier years. The most relevant therapeutic advances over the past few decades have been the introduction of novel therapies, such as immune-modifying agents (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib), with or without stem cell transplantation.

Moreover, in the last few years, the MM therapeutic “toolbox” has shown further improvement with the approval of new generation IMID (pomalidomide), the monoclonal antibodies daratumumab and elotuzumab, as well as the new-generation proteasome inhibitors carfilzomib and ixazomib.

At the same time, our understanding of MM tumor biology is increasing, creating the rationale for new combinations of drugs and new therapy development. Discovery of the associated cytogenetic abnormalities confirm the hypothesis that MM is a heterogeneous disease, suggesting that risk-adapted therapies and individualized treatment will help to further improve patient management.

However, patients with triple-class refractory MM, whose cells exhibit triple-class resistance to PIs, immunomodulatory drugs (IMiDs), and monoclonal antibodies (MoAb), continue to have an OS of < 6 months, emphasizing the urgency of this unmet medical need.

Drug resistance in MM patients needs to be deeply studied, and it can occur via intrinsic and extrinsic mechanisms, including intraclonal heterogeneity, drug efflux pumps, alterations of drug targets, the inhibition of apoptosis, increased DNA repair and interactions with the bone marrow (BM) microenvironment, cell adhesion, and the release of soluble factors.

MM–BM microenvironment interactions could play an important role, particularly due to the cross-talk between BM stromal cells, adipocytes, osteoclasts, osteoblasts, endothelial cells, and immune cells. Considering these complex mechanisms that drive MM, next-generation treatments that potentially avoid drug resistance must target both the neoplastic clone and its non-malignant environment.

Moreover, it is important to better define the role of cancer stem cells in the development of the disease, patient relapse, and drug resistance to improve disease management, particularly in heavily pretreated patients.

In fact, overcoming inherent and acquired drug resistance of MM cells, especially in the context of the immunosuppressive tumor microenvironment, remains a major challenge in the implementation of effective therapy of high-risk or relapsed/refractory myeloma.

We welcome the submission of original research, review, clinical trial, hypothesis and theory, and opinion articles.

Dr. Claudio Cerchione
Dr. Daniele Derudas
Prof. Dr. Alessandro Isidori
Guest Editors

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• multiple myeloma (MM)
• hematologic malignancies
• cancer stem cells
• relapsed myeloma
• refractory myeloma
• bone marrow (BM) microenvironment