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Haematological Malignancies, Multiple Myeloma
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Multiple Myeloma: A New Paradigm in Cancer Therapy

Published Online: June 3rd 2011
Authors: Paul Richardson, Noopur Raje, Kenneth C Anderson
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Overview

Multiple myeloma (MM) is an incurable heematologic cancer responsible for 2% of cancerrelated deaths. Preclinical studies have underlined the significance of the bone marrow milieu in promoting tumour cell growth, survival, progression and the development of drug resistance. MM has emerged as a novel paradigm for cancer therapy since targeting both the MM cell and its microenvironment has resulted in improvements in patient outcome. This article will focus on the treatment of MM, with an emphasis on novel biologically based therapies.

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Introduction
MM is a haematologic cancer arising from a common progenitor of the B-cell lineage. It is characterised by a clonal expansion of plasma cells in the bone marrow (BM) and is nearly always accompanied by the presence of a monoclonal immunoglobulin (Ig) or Ig fragment in the serum and/or urine of patients.1,2 It is the second most common haematologic malignancy, and is responsible for at least 2% of cancer-related deaths. In 2006, an estimated 16,570 new cases of MM will be diagnosed in the US, and 11,310 deaths will be attributed to this disease.3 The last several years have seen the introduction of a number of novel agents in the treatment of this otherwise incurable cancer. Important advances, including drugs such as thalidomide (Thal), lenalidomide, and bortezomib, have provided effective therapeutic options for patients with MM.4 These and other novel agents hold promise to translate MM into a chronic disease.

Identification and Validation of Novel MM Therapies
In order to overcome resistance to conventional therapies and improve patient outcome, novel treatment approaches that target mechanisms whereby MM cells grow and survive in both the BM and extramedullary microenvironment are needed.

Our in vitro and animal model studies have demonstrated the importance of the BM microenvironment in promoting MM cell growth, survival, drug resistance and migration. These model systems have allowed for the development of several promising biologically based therapies that can target the MM cell in its BM microenvironment and thereby overcome classic drug resistance in vitro, including Thal and its more potent immunomodulatory analog, lenalidomide, as well as the proteasome inhibitor bortezomib.4 Once in vitro promise of these novel agents was demonstrated, efficacy was tested in murine models. Importantly, these laboratory studies have been translated to phase I, II, and III trials to evaluate their clinical efficacy and toxicity. In this context, bortezomib was FDAapproved for the treatment of relapsed and/or refractory MM;5 and both Thal and lenalidomide are currently being considered for approval by the agency. Several other classes of novel biologics, including histone deacetylase inhibitors, heat shock protein inhibitors, mTOR inhibitors, cyclin d inhibitors, pAKT inhibitors and oral proteasome inhibitors, among others are undergoing preclinical and clinical evaluation.These preclinical studies have informed the use of rational combination treatments in ongoing clinical trials.

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