Multiple myeloma: the bone marrow microenvironment and its relation to treatment

Abstract

Multiple myeloma is the most common haematological malignancy yet currently it remains incurable. For decades the mainstay in therapy has been non-targeted approaches including genotoxic agents and immunosuppressants. With myeloma predominantly affecting an elderly population, who are vulnerable to aggressive therapy, these non-specific approaches have resulted in poor survival. However, in recent years an explosion of collaborative research into myeloma has identified molecular interactions between myeloma cells and the bone marrow microenvironment as promoting myeloma development and associated complications such as bone lesions due to osteolysis. At the same time, a better understanding of the adhesion molecules, cytokines and signalling pathways involved in myeloma has led to the development of new targeted therapies, which are improving the quality of life for patients and significantly extending median patient survival. This review explores the current understanding of molecular pathways that promote myeloma progression and lead to bone destruction, with particular reference to the influence of interactions with the bone marrow microenvironment. It describes molecular targets for therapy with reference to the new therapeutics and their improved efficacy. While the outlook for myeloma patients has improved in recent years as a result of these new approaches, drug resistance remains a problem and future therapies will also need to address the molecular mechanisms of resistance in order to improve further the outcome for patients with this disease.

Bone Disease in Multiple Myeloma: Pathophysiology and Management

“…The cellular part consists of clonal plasma cells (MCs), immune cells (T-lymphocytes) and BMSCs, whereas proteins in extracellular matrix, cytokines, and growth factors in extracellular fluid make up the noncellular compartment 26. MCs are noticed to be present in large amounts near the site of active bone resorption, and their interactions with BM-mic play an important role in the development and spread of disease 27,28. MCs produce decoy receptor 3 (DcR3), which is responsible for OCs differentiation and activation 26.…”

Gene expression profiling for targeted cancer treatment

“…Besides identifying transcription factors as top-ranking HYPs in cancer samples [65,66], running SNEA on Pathway Studio database often identifies hormones and their receptors as top-ranking HYPs in cancer. Hormone levels in cancer can be changed either through autocrine stimulation [67][68][69][70][71] or supplied by tumor symbiotic microenvironment [72][73][74][75]. Extracellular matrix proteins and their receptors are another major class of HYPs generated from expression profiles of patients with advanced cancer.…”

Myeloid-derived suppressor cells: The green light for myeloma immune escape

“…Transformation of MGUS to MM seems to be caused by a developing permissive myeloma microenvironment which leads to “immune escape” and advancement toward full-blown myeloma 12,17 . Also, the myeloma microenvironment has a substantial role in chemotherapy resistance and thereby the persistence of residual disease, which is the source of frequent relapses leading to poor clinical outcomes 18–21 .…”

“…The MM microenvironment includes osteoclast, osteoblasts, endothelial and immune cells with the structural support of an extracellular matrix, adhesion molecules and cytokines 21 . Increased immune suppressor cells have been reported in the bone marrow of myeloma patients, which correlates with clinical outcomes, emphasizing the important role of these cells in providing the “immune escape” that favors myeloma progression.…”