Cytogenetic Abnormalities of Extramedullary Multiple Myeloma: History
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Extramedullary multiple myeloma (or extramedullary disease, EMD) is an aggressive form of multiple myeloma (MM) that occurs when malignant plasma cells become independent of the bone marrow microenvironment. This may occur alongside MM diagnosis or in later stages of relapse and confers an extremely poor prognosis. In the era of novel agents and anti-myeloma therapies, the incidence of EMD is increasing, making this a more prevalent and challenging cohort of patients. Therefore, understanding the underlying mechanisms of bone marrow escape and EMD driver events is increasingly urgent. 

  • genomics
  • high-risk
  • multiple myeloma
  • cytogenetic
  • extramedullary multiple myeloma

1. Introduction

Multiple myeloma (MM) is the second most common blood cancer worldwide and is characterized by the clonal proliferation of malignant plasma cells in the bone marrow (BM) [1][2]. These plasma cells secrete a monoclonal immunoglobulin (Ig), often known as M-protein, which can lead to organ dysfunction, anaemia, renal impairment, and bone lesions. Unfortunately, MM is incurable as eventually all patients relapse, with a median overall survival of 6 years [1][3]. MM is an extremely heterogeneous disease resulting from the accumulation of genetic aberrations that give rise to oncogenic transformation. MM is preceded by well-characterised pre-malignant-stage monoclonal gammopathy of undetermined significance (MGUS) and smouldering MM (SMM), and each have their own genetic background [4]. Progression to symptomatic MM is a result of clonal evolution, and this can further drive patients to become refractory/relapse. In rare cases, patients present with extramedullary disease (EMD), an aggressive form of MM that has become independent of the bone marrow microenvironment and may infiltrate other organ systems. EMD may occur alongside MM at diagnosis in around 7% of patients or manifest at later stages of relapse in 6–20% [5]. EMD is considered to be a high-risk factor, with reports of extremely poor prognosis of no more than 3 years in patients after autologous stem cell transplant (ASCT) and less than 1 year in refractory patients [6][7].
When discussing EMD, it is important to acknowledge that there is controversy over its precise definition. Some groups define it as only extraosseous soft tissue masses that result from haematogenous spread (known as ‘extraosseous’ EMD) [7][8]. Alternatively, a broader definition often used also includes bone-related (or paraskeletal) plasmacytomas, also known as ‘osseous’ or ‘bone-related’ EMD [7][8]. Many studies have included both but typically classify them as two different subtypes for comparisons as, generally, extraosseous EMD is associated with inferior prognosis [6][9]. Solitary plasmacytomas are explicitly excluded from EMD definition as these can occur in the absence of MM diagnosis [8]. Additionally, plasma cell leukaemia (PCL) is an aggressive form of MM that appears when the presence of clonal plasma cells in peripheral blood is greater than 20% [1]. However, it is also excluded from the definition of EMD since it is characterized as a unique entity with a defined clinco-pathological state and established treatment options [8]. EMD is most often diagnosed using sensitive imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography/computerised tomography (PET/CT) [8].

2. Cytogenetic Abnormalities

Cytogenetic abnormalities are a hallmark of MM, with 90% of patients presenting with such aberrations at diagnosis [10]. These occur due to chromosomal instability and can both initiate disease and establish clonal evolution seeding with respect to bone marrow and, eventually, EMD sites [11]. The initiation of cytogenetic abnormalities is most commonly attributed to trisomies of odd-numbered chromosomes (hyperdiploidy) and translocations involving the IGH gene locus on chromosome 14q32. Secondary cytogenetic events are more prevalent in later disease stages, and common examples include del(13), del(17p13), gain(1q), and del(1p). These abnormalities can be detected using fluorescence in situ hybridization (FISH) and may be used to guide patient prognosis. For example, the Revised-International Staging System (R-ISS) incorporates the presence of high-risk abnormalities, such as t(4;14), t(14;16), or del(17p), to stratify patients into three prognostic groups [12]. The 5-year survival rates for R-ISS stages I, II, and III are 82%, 62%, and 42%, respectively, highlighting the differential disease severity and prognoses for each patient [12]. Additionally, the Mayo Stratification for Myeloma and Risk-adapted Therapy (mSMART) guidelines use several more genetic factors to guide genetic risk [13]. The overall survival for high-risk MM patients is generally less than 3 years, whilst standard-risk patients exhibit survival rates of 7–10 years [1]. Given the importance of cytogenetic events in MM pathogenesis, most studies on EMD have aimed to establish their incidence in this setting. A summary of these findings are shown in Table 1. 
Table 1. Summary of main cytogenetic studies performed on EMD


Patient Cohort Description

Sample Type(s)


Results Summary

Billecke et al. 2013 [20]

36 MM patients, 17 with EMD at diagnosis or relapse; 11 bone-related and 6 extraosseous



High incidence of del(17p) in both EMD groups compared to non-EMD


Qu et al. 2015 [16]

Retrospective study of 300 patients, 41 of which had EMD at diagnosis or progression



Del(17p13) and amp(1q21) associated with EMD


Besse et al. 2016 [14]

31 EMD patients either at MM diagnosis or relapse, 15 bone-related, 16 extraosseous


Paired BM & EMD



In unrelated samples, higher incidence of t(4;14) in EMD compared to BM. In paired samples, gain(1q) frequent in BM & EMD.


Smetana et al. 2018[27]

1 MM patient with EMD at relapse

BM (diagnostic)

Array-CGH, Targeted NGS

Patient presented with huge chromothripsis of chromosome 18 and mutations in NRAS, RAF1, TP53, CUX1 and POU4F1 before progression to EMD.



Liu et al. 2020 [23]

10 patients with EMD, 4 at diagnosis and 6 at relapse

BM & EMD, paired where possible

FISH, Targeted NGS, SNP microarray

Gain(1q21) and del(1p32) common in BM and EMD lesions. High prevalence of RAS mutations


Kriegova et al. 2021 [19]

11 newly diagnosed MM patients, 4 with bone-related EMD



Whole-genome optical mapping


Large intrachromosomal rearrangements within chromosome 1 detected in all EMD patients


Xia et al. 2022 [15]

30 patients with EMD; 19 bone-related & 11 extraosseous

Paired BM & EMD


Higher frequency of genomic aberrations in EMD tissue vs BM. Higher prevalence of gain(1q) and P53 deletion in EMD, and higher in bon-related EMD compared to extraosseous


Generally, most studies have shown increasing cytogenetic complexity at EMD sites compared to BM, demonstrating that EMD is an aggressive form of MM with defined clonal evolutionary properties [14][15]. Specifically, many of these additional abnormalities are high-risk, such as t(4;14), del(17p13), del(13) and chromosome 1 aberrations, in keeping with the concept that high-risk cytogenetic features drive relapse not only in the bone marrow but also at selective EMD sites. Besse at al. [14] used FISH to detect abnormalities in paired samples from BM plasma cells and EMD sites for 12 patients. In these cases, del(13q14) and 14q32 disruptions were more prevalent in BM sites compared to EMD, but the frequency of genomic events was increased in patients at the time of EMD diagnosis compared to samples collected previously. Moreover, in paired samples, gain(1q) occurred in both BM and EMD plasma cells in 66.7% of all cases. However, when comparing unrelated BM samples to the overall EMD samples, an increased frequency of t(4;14) was observed in EMD [14]. Alternatively, a retrospective study showed no difference in the prevalence of del(13q14) and t(4;14) in diagnostic BM aspirates collected from patients with or without EMD; however, plasma cells from EMD sites were not assessed [16]. In this study, there was a higher frequency of del(17p13) and amp(1q21) in EMD vs. non-EMD (31% vs. 13% and 55% vs. 31%, respectively). The authors also reported cytogenetics for patients who present with EMD at diagnosis (21 patients) vs. at relapse (8 patients), and there were no significant differences between the two [16]. Another retrospective study described that the presence of any IGH translocation, del(13/13q), and del(17) in BM at diagnosis did not predict progression to EMD (neither osseous nor extraosseous) in a cohort of 117 patients treated with bortezomib with or without lenalidomide [17]. However, the authors did note that no patients with t(11;14) developed extraosseous EMD, and this was also reported in an earlier study [18]. This corroborates the consensus that t(11;14) is generally associated with standard-risk disease. Overall, studies such as these demonstrate no unitive underlying genomic process accounting for the diverse and unpredictable nature of EMD, likely indicating that deeper and broader genomic studies are required to truly profile this form of MM.
Kriegova et al. [19] performed whole-genome optical mapping on BM plasma cells in a small cohort of 11 newly diagnosed MM patients, 4 of which presented with bone-related EMD. This method enabled the detection of large chromosomal rearrangements as well as small structural variants and copy number variations. Strikingly, chromosome 1 abnormalities were present in all EMD patients and consisted of various intrachromosomal rearrangements that resulted in copy number changes of genes, including recurrent regions encompassed by del(1p32) and gain(1q21). Additionally, del(17p13) was detected in two of the EMD patients but not in any patients presenting without EMD, which is indicative of a trend similar to that of other studies linking del(17p13) to EMD [19][20]. Promisingly, where optical mapping revealed changes in common MM-associated regions, the FISH results were able to confirm these findings in the majority of cases. Most of the studies discussed did not explore del(1p32) despite it largely being considered a high-risk MM abnormality [21][22]. Nevertheless, another study using a small cohort of EMD patients revealed that del(1p32) and gain(1q21) were common occurrences both in BM plasma cells and at EMD lesion sites, suggesting that chromosome 1 abnormalities may indeed be an important factor [23]. Moreover, gain(1q) was associated with poor survival in EMD patients, with the number of extra copies being proportional to worsened survival rates [15][19]. Together these findings suggest chromosome 1 abnormalities may play a role in the initiation and progression of high-risk EMD.
Chromothripsis is a catastrophic event involving a maximum of two chromosomes whereby chromosomes are shattered and rejoined at random, resulting in tens to hundreds of chromosomal rearrangements [24]. A recent WGS study revealed that 20–30% of newly diagnosed MM patients have chromothripsis (higher than previously thought), and this is an adverse prognostic marker [25][26]. Chromothripsis has also been proposed as a prognostic marker in EMD; however, currently, it has only been described in one patient [27]. This patient presented with chromothripsis of chromosome 18 in BM plasma cells at diagnosis. This consisted of six breakpoints including several deletions and amplifications, with five to six copies of 18q21 detected [27]. 18q21 harbours many important genes associated with haematological malignancies, including anti-apoptotic protein BCL-2. As more in-depth genomic analyses are performed for EMD, more complex chromosomal structural variations may be identified.

This entry is adapted from the peer-reviewed paper 10.3390/ijms241411259


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