Multiple myeloma (MM) is a B-cell malignancy that is currently felt to be incurable. Despite recently approved novel targeted treatments such as lenalidomide and bortezomib, most MM patients' relapse is emphasizing the need for effective and well-tolerated therapies for this deadly disease. The use of oncolytic viruses has garnered significant interest as cancer therapeutics in recent years, and are currently under intense clinical investigation. Both naturally occurring and engineered DNA and RNA viruses have been investigated preclinically as treatment modalities for several solid and hematological malignancies. Presently, only a genetically modified measles virus is in human clinical trials for MM. The information obtained from this and other future clinical trials will guide clinical application of oncolytic viruses as anticancer agents for MM. This paper provides a timely overview of the history of oncolytic viruses for the treatment of MM and future strategies for the optimization of viral therapy for this disease. 1. Introduction Multiple myeloma (MM) is a clonal neoplasm of plasma cells derived from the B-lymphocyte lineage that is part of a spectrum of diseases ranging from monoclonal gammopathy of undetermined significance (MGUS) to plasma cell leukemia. It is the most common primary bone cancer and involves malignant plasma cells progressively infiltrating the bone marrow and producing a monoclonal immunoglobulin (Ig) (M-protein) [1]. Overt myeloma (advanced disease) is manifested by pathophysiological consequences such as osteolytic bone lesions, hypercalcemia, recurrent bacterial infections, anemia, and renal failure [2]. Over 70,000 people in North America are currently affected by MM with an annual incidence of greater than 15,000. Presently, MM accounts for 10% of hematological malignancies and represent 1-2% of all cancer-related deaths [3]. The disease remains incurable with current treatments with a median survival of 3–5 years [4, 5]. MM follows a relapsing course in the majority of patients, regardless of treatment regimen or initial response to treatment. Accordingly, it has become imperative to find novel, more effective treatment options for MM. 1.1. Currently Available Therapies for Multiple Myeloma Disease management of MM has improved with the introduction of several new agents such as bortezomib (Velcade, a proteasome inhibitor), thalidomide, and the thalidomide analogue lenalidomide (Revlimid, immune modulator), and thus these drugs have now become current mainstays in MM treatment. These agents as monotherapies (bortezomib)
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