Molecular mechanisms of novel therapeutic approaches for multiple myeloma

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Multiple myeloma (MM) is a B-cell malignancy that is characterized by an excess of monotypic plasma cells in the bone marrow (BM) that is in association with monoclonal protein in serum and/or urine, decreased normal immunoglobulin levels and lytic bone disease. Although conventional therapies can extend patient survival to an average of 3–4 years and high-dose therapy that is followed by autologous stem-cell transplantation can modestly prolong the survival to 4–5 years, MM remains largely incurable. MM cells home to the host bone marrow by binding to adhesion molecules on extracellular matrix proteins and bone-marrow stromal cells. This localizes tumour cells in the BM microenvironment and confers cell-adhesion-mediated drug resistance. Cytokines (such as interleukin-6 (IL-6), insulin-like growth factor 1 (IGF1), tumour necrosis factor-α (TNF-α) and stromal-cell-derived factor-1α (SDF-1α)) mediate MM cell growth, survival and migration and, following treatment, the development of drug resistance in the bone-marrow microenvironment. MM cell proliferation, survival and, following treatment, drug resistance by anti-apoptotic mechanisms are mediated through the RAF/mitogen-activated protein kinase (MAPK) kinase (MEK)/p42/p44 MAPK, Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and phosphatidylinositol (PI3K)/AKT signalling cascades, respectively. Novel biologically based treatments (such as thalidomide/immunomodulatory derivatives (IMiDs) and PS-341) target not only the MM cell, but also the interaction between MM cells and the host or the BM microenvironment, and can overcome conventional drug resistance in vitro and in vivo in preclinical models. Thalidomide/IMiDs and PS-341 have already shown remarkable activity against MM in Phase I/II clinical trials of patients with relapsed and refractory disease, with manageable toxicity profiles. These drugs, when used with conventional and/or other novel therapies, represent a new treatment model to improve patient outcome in MM. Ongoing gene microarray and proteomic studies of these new agents are identifying molecular targets that confer drug sensitivity versus resistance, to derive more selective targeted therapies for validation in animal models and the translation to the clinic in clinical trials.