Multiple myeloma is a type of B-cell neoplasm characterized by the slow proliferation of well-differentiated plasma cells in the bone marrow. Although mature plasma cells are the predominant type of cell found in multiple myeloma, pre-B, myeloid, and T-cells are coexpressed with the mature plasma cell. The population of malignant cells is collectively refrerred to as myeloma cells.
Multiple myeloma tumor progression is a multistep process that can be described to occur in 3 distinct phases (Pratt, 2002):
2. Unchecked Cell Proliferation
3. Dissemination of the Malignant Plasma Cells
The disease may first present as a monoclonal gammopathy of undetermined significance (MGUS), a clinical term used to describe a single plasma cell that has formed a limited number of clones (Dalton et al., 2001). The precise cellular origin is not well understood, but is believed to be an immature B-cell that has been repeatedly exposed to antigen in the germinal centers of the lymphoid tissue. The disease advances when the transformed cells clonally expand and grow in the bone marrow (intramedulllary myeloma). During this time, the disease is usually chemosensitive and may enter a dormant phase (Pratt, 2002). The myeloma cells receive growth and anti-apoptotic signals that facilitate their survival through interactions with the bone marrow microenvironment (Dalton, 2003). For example, expression of the adhesion receptors, very late antigen-4 (VLA-4) and very late antigen-5 (VLA-5) permits myeloma cells to bind fibronectin, whereas the expression of the beta2 integrin lymphocyte function associated antigen-1 allows for cell-cell aggregation. Such interactions stimulate the secretion of various cytokines from myeloma and stromal cells in the bone marrow microenvironment (Klein et al., 2003). IL-6, the main plasma cell activating factor, stimulates cell proliferation via the Ras/Mitogen-activated kinase (Ras/MAPK) signaling cascade. IL-6 also induces myeloma cell migration and angiogenesis via vasuclar epithelial growth factor (VEGF) induction. Advanced disease is distinguished by independence from growth factors in the bone marrow microenvironment and proliferation to extramedullary sites (Pratt, 2002). Throughout this time, advanced myeloma is characterized by resistance to apopotosis and chemotoxic agents.
Understanding the bone marrow microenviornment in multiple myeloma disease pathogenesis has had a role in the development of new cytotoxic agents. For example, bortezomib was the first proteasome inhibitor to be evaluated in clinical trials for the treatment of hematological malginancies. Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome. The 26S proteasome is a large protein complex that degrades proteins that have been post-translationally modified with ubiquitin (Ub). Thus, the ubiquitin-proteasome pathway has an important role in regulating the intracellular concentration of ubiquitinated proteins.
Bortezomib, is now available under the brand name Velcade and is distributed by Millenium Pharmaceuticals. Velcade is FDA approved for the treatment of people with multiple myeloma and is also indicated for the treatment of people diagnosed with mantle cell lymphoma who have received at least 1 prior therapy. There are at least 2 well documented clinical studies of bortezomib for the treatment of people with multiple myeloma. One study was a randomized, open-label trial consisting of 682 patients with previously untreated multiple myeloma that obtained bortezomib in combination with melphalan and prednisone and were compared to melphalan and prednisone in patients also with previously untreated multiple myeloma. Details results of the trial can be reviewed by clicking here. Briefly, the combination of bortezomib, melphalan, and prednisone treatment resulted in statistically significant results for time to progression, progression free survival, overall survival, and response rate. The second trial involved 669 patients enrolled in a randomized prospective phase 3 study comparing bortezomib to high-dose dexamethasone therapy following 1-3 therapies. In summary, the study suggests that bortezomib resulted in statistically significant improvement in time to progression relative to the dexamethasone arm.
Additional clinical and pre-clinical studies are underway to determine additional drug combinations and drug sequencing can further improve clinical outcomes of patients undergoing multiple myeloma therapy.
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