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.
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
Study/Reference
|
Patient Cohort Description
|
Sample Type(s)
|
Methodologies
|
Results Summary
|
Billecke et al. 2013 [20]
|
36 MM patients, 17 with EMD at diagnosis or relapse; 11 bone-related and 6 extraosseous
|
BM
|
FISH
|
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
|
BM
|
FISH
|
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
|
FISH
|
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
|
BM
|
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
|
FISH
|
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
|
|
This entry is adapted from the peer-reviewed paper 10.3390/ijms241411259