Understanding the Molecular Biology of Myeloma and Its Therapeutic Implications

Kevin D Boyd; Charlotte Pawlyn; Gareth J Morgan; Faith E Davies

Disclosures

Expert Rev Hematol. 2012;5(6):603-617. 

In This Article

Abstract and Introduction

Abstract

Myeloma develops due to the accumulation of multiple pathological genetic events, many of which have been defined. Hyperdiploidy and reciprocal translocations centered on the immunoglobulin heavy chain variable region constitute primary genetic lesions. These primary lesions co-operate with secondary genetic events including chromosomal deletions and gains, gene mutations and epigenetic modifiers such as DNA methylation to produce the malignant phenotype of myeloma. Some of these events have been linked with distinct clinical outcome and can be used to define patient groups. This review explores the molecular biology of myeloma and identifies how genetic lesions can be used to define high- and low-risk patient groups, and also defines potential targets for therapy. The authors also explore how this information can be used to guide therapeutic decision-making and the design and interpretation of clinical trials, both now and in the future.

Introduction

Recent advances in molecular biology have given insights into the molecular basis of myeloma, and it is now understood that myeloma is not a single disease, but is rather a number of related diseases, each of which has a distinct molecular pathogenesis. We perceive the future of cancer treatment as being in the development of personalized medicine strategies, and myeloma is an excellent example of a cancer where this approach can be tested. Myeloma therapy is currently determined by age and performance status rather than tumor biology. A biologically heterogeneous disease is, therefore, treated as a single entity with the result that individual therapeutic success is varied. As the antimyeloma therapeutic armamentarium increases, it is becoming increasingly important to identify patients who will derive the most benefit from individual treatments. Thus, if we are to improve the outcome of myeloma overall, we have to embrace the concept of myeloma heterogeneity and design specific trials and treatments based on the pathogenic mechanism of the subgroup being targeted. Achieving this aim will require the development of tests able to identify subgroups of patients for trial entry strategies. This approach will require a full understanding of the genetics of myeloma and the integration of this data with standard clinical prognostic information.

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