Genetic changes in the development of multiple myeloma

Abstract

Multiple myeloma (MM) is a malignancy of clonal plasma cells (PC) which develops as a consequence of a multistep process of transformation from a normal PC to an asymptomatic stage known as monoclonal gammopathy of undetermined significance (MGUS) to MM to the more aggressive plasma cell leukaemia (PCL). MGUS is the most common PC disorder and the majority of cases never progress to MM requiring treatment, as progression only occurs in ~1% of patients per year. From a genetic point of view, specific abnormalities represent initiating events (i.e. IgH translocations or hyperdiploidy) of this multistep process while others occur at later stages. In this study, interphase-FISH showed that initiating events are present in MGUS (n=187) and asymptomatic MM (SMM, n=128) at similar frequencies as found in MM (n=400) (the only exception was t(4;14)) and showed that these abnormalities alone, regardless of their biological impact in MM, cannot drive progression to overt disease. The time of occurrence of deletion/monosomy of chromosome 13 (13) was found to depend on the presence of specific concurrent abnormalities. 13 was extremely rare in MGUS and SMM with translocations directly involving CCND1 and CCND3 suggesting a possible role of 13 in the progression of disease specifically in these genetic sub-groups. However, it was clear that, excluding 13 in these sub-groups, standard interphase-FISH abnormalities are insufficient to predict progression of MGUS and SMM. High resolution array CGH showed an increasing level of genomic complexity from MGUS (n=25) to SMM (n=15) to MM (n=47) to PCL (n=11). In MGUS, the number of copy number changes per case was highly associated with progression (P=0.003). The simplest profiles belonged to MGUS cases with t(11;14) and t(14;20); surprisingly, none of these patients had progressed to MM by the end of this study (median follow-up=72 months). The integration of results from interphase-FISH, array CGH and metaphase analysis suggested that there were various abnormalities (corresponding to distinct molecular pathways) responsible for disease progression. A number of chromosomal changes were found to be strongly associated with progression (del(1)(p22.3-p23); del(6)(q25), MYC changes, del(12)(p13), 13 in t(11;14), abnormalities involving members of the NF-B pathway, del(17)(p13)). Such associations were not only suggested by the fact that these abnormalities were rare in MGUS/SMM compared to MM, but also by the observation that all pre-malignant patients positive for these changes progressed to overt disease. However, among patients who did progress and carried the same abnormalities, time to progression was found to be highly variable from case to case. This suggested that other factors (genetic or otherwise) must be interacting with chromosomal abnormalities in order to lead to progression. Other changes, e.g. 1q21 gain, despite being rare in pre-malignant cases compared to MM and despite some being associated with a dismal prognosis in MM, did not appear to be linked to rapid progression. This study has made significant progress towards understanding the progression from pre-malignant disease to MM, which will provide information towards potential novel targets for therapy to prevent progression or prolong the pre-malignant phase of a highly aggressive disease

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Identifiers

ORCID for Nicholas C.P. Cross: orcid.org/0000-0001-5481-2555

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