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Introduction


Multiple myeloma: an introduction


Multiple myeloma is a clonal plasma cell malignancy that accounts for approximately 10% of all haematologic cancers and a review of the disease is presented here


Marie Larcher Haematology Unit Jill Corre PharmD PhD Myeloma Genomic Unit Murielle Roussel MD Haematology Unit, IUCT Oncopole, CHU Purpan, Toulouse, France


Multiple myeloma (MM) or Kahler’s disease, is a heterogeneous clonal plasma cell disorder that occurs mainly in elderly population (median age at diagnosis ~ 66 years) and that accounts for approximately 10% of haematologic cancers and 1% of all cancers.1


MM is


slightly more common in men than in women, and is twice as common in African–Caribbean ethnic groups than in Caucasians. Because of major improvements in the general care of patients over the past 30 years, leading to a marked increase in longevity, the incidence of MM is increasing worldwide. In 2012, over 38,900 new cases were diagnosed in the EU.2


Pathophysiology 2


The first well-documented case was reported in 1844 by a British surgeon, Samuel Solly. Solly thought that the disease was an inflammatory process that began with a ‘morbid action’ of the blood vessels in which the ‘earthy matter of the bone was absorbed and thrown out by the kidneys in the urine’. The most commonly recognised case is that of Thomas Alexander McBean in 1850. McBean excreted a large amount of protein that was subsequently described by Henry Bence Jones. One of the best-known cases of MM was that of Dr Loos, reported by


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Otto Kahler. The recognition of plasma cells and subsequently their product, a monoclonal protein, has been described in detail.3


MM is a clonal malignancy that results from an aberrant genomic event occurring during the maturation of a B-cell to an antibody-producing plasma cell. The initiation of the disease is mediated by the interaction of environmental factors and inherited genetic events. The oncogenic transformation in MM is thought to occur within the secondary lymphoid organs at the time of the somatic hypermutation (SHM) process and the class switch recombination (CSR). Multiple lines of evidence have broadly supported this theory. First, malignant plasma cells present a high rate of somatic mutations, with no heterogeneity, suggesting that the oncogenetic event occurred after the end of the SHM process, which physiologically takes place in the germinal centres. The second piece of evidence is the nature of the monoclonal immunoglobulin (Ig), essentially IgG and IgA, rarely IgD or IgM. Here again, the CSR process is supposed to occur in the germinal centres. Finally, the molecular analyses of some of the oncogenic events, and especially of recurrent chromosomal translocations involving the IGH gene showed that the t(4;14) largely involves the switch regions, suggesting errors during the CSR process,4,5


whereas the


t(11;14) may result from errors during the SHM process.5


Until recently, traditional tumour modelling (including in myeloma) had proposed that, following this initiating event, other genomic aberrations linearly accumulate over time, eventually leading


to the clinical manifestations of the disease. This model of tumour evolution implied that all clones within a tumour are linearly related to each other and homogeneous in their mutational landscape. However, genome deep- sequencing studies are now contradicting this model and revealing a more complex clonal architecture of Darwinian-like somatic evolution, where tumour progression proceeds in a branching rather than linear manner, with substantial clonal diversity and coexistence of wide genetic heterogeneity.6,7


MM is composed of several


genomically distinct subclones coexisting in varying proportions and dynamically competing for the bone marrow stromal niches.8


These findings have profound therapeutic implications and should reshape our thinking with regards to the treatment paradigms or regimen combinations required to eradicate disease and ultimately achieve cure.


Pre-malignant stage


It is currently accepted that all MM cases are preceded by an asymptomatic pre-malignant stage, termed monoclonal gammopathy of undetermined significance (MGUS).9


In some patients,


an intermediate asymptomatic, but more advanced, pre-malignant stage referred to as smouldering multiple myeloma (SMM) is observed. MGUS or SMM will evolve to symptomatic MM in a fraction of these individuals, but most of the MGUS cases will remain totally asymptomatic. Symptomatic MM is defined by clinical symptoms, evidence of organ damage and susceptibility to bacterial infections, mainly pneumococcus pneumonia. MGUS is present in more than 3% of the population above the age of 50 years


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