Can we change the disease biology of multiple myeloma?

Abstract

Despite improvements in disease management, multiple myeloma (MM) remains incurable. Conventional treatment methods are unsatisfactory, leading to a pattern of regression and remission, and ultimately failure. This pattern suggests that one of the possible strategies for improving outcomes is continuous therapy to maintain suppression of the surviving tumor cells. Optimal management of MM requires potent agents and modalities with direct tumoricidal activity, which can also provide continuous suppression of the residual tumor to prevent disease relapse. Immunomodulatory agents exert immunomodulatory and tumoricidal effects, and cause disruption of stromal cell support from the bone marrow microenvironment. Therefore continuous therapy with immumomodulatory agents may be able to provide both tumor reduction and tumor suppression, enabling physicians to consider the possibility of incorporating continuous therapy into the treatment paradigm of patients with MM.

Introduction

Multiple myeloma (MM) is characterized by the accumulation of clonal plasma cells in the bone marrow, the presence of monoclonal immunoglobulin (Ig) in the serum or urine, osteolytic bone lesions, renal disease, and immunodeficiency. It is principally a disease of older patients, with a median age at diagnosis of 65–70 years. The first stage in the development of MM is the emergence of asymptomatic monoclonal gammopathy of undetermined significance (MGUS). In some of these patients, this progresses to smoldering MM and ultimately to symptomatic MM, with an annual risk of around 1% for patients with MGUS [1]. The reasons why MGUS progresses to MM in only a small proportion of patients are unclear, and both genetic and environmental factors have been implicated [2]. Progression to MM is associated with a series of complex genetic events in MM cells, as well as changes in the bone marrow microenvironment, including increased angiogenesis, suppression of the immune response, increased bone resorption, and the establishment of aberrant signalingloops involving cytokines and growth factors associated with the clinical features of MM and its resistance to treatment [3].

Despite the improvements in overall survival associated with the use of conventional high-dose chemotherapy and autologous stem-cell transplantation (HDT-ASCT), median overall survival remained at around 33 months until the introduction of the novel anti-myeloma agents, thalidomide, lenalidomide, and bortezomib [4]. For patients diagnosed since 2000, the use of the novel agents has improved survival times significantly, particularly for younger patients 5, 6. The median survival time for patients under 65 years of age treated with novel agents is 56 months [6]. The course of MM treated with conventional chemotherapy, such as single-agent alkylating drugs, corticosteroids or combination chemotherapy involving novel anti-myeloma agents is characterized by a pattern of remission and relapse, with a decreasing duration of response and increasing number of salvage regimens (Fig. 1). This reflects the development of drug resistance, which eventually results in refractory disease (Fig. 1) [7]. This pattern suggests the presence of residual disease after treatment, even following an apparently complete response. Therefore, the incurable nature of MM necessitates treatment with agents and modalities that not only provide direct tumoricidal effects to reduce tumor burden, but also suppress residual disease with continuous use.

The development of novel anti-MM agents relies on an understanding of the biology of MM and the multiple factors involved in its pathogenesis and response to treatment. As well as genetic aberrations in essential growth- and tumor-suppressor genes, there is increasing evidence that interactions between tumor cells and their bone marrow microenvironment play a pivotal role in the development, maintenance, and progression of MM, and thus, in the development of drug resistance. This knowledge has improved treatment options leading to the approval of drugs such as thalidomide, bortezomib, and lenalidomide, which not only target malignant cells directly, but also their supporting bone marrow microenvironment. In addition to their tumoricidal effects, immunomodulatory agents also act on the immune system, potentially helping to overcome MM-associated immunodeficiency and enhancing anti-MM immune activity.

This article aims to give an overview of the biology of MM, focusing on the pivotal role of the bone marrow microenvironment and its relevance to tumor survival and proliferation. It will also discuss how new agents have the potential to modify MM biology, offering the prospect of a shift in treatment paradigm to a focus on sustaining disease control with long-term treatment, which may transform myeloma into a chronic disease.