Extramedullary Multiple Myeloma
Extramedullary Multiple Myeloma
Introduction: Multiple myeloma (MM) is the second most common blood cancer worldwide and is characterised by clonal proliferation of malignant plasma cells within the bone marrow. These MM plasma cells secrete a monoclonal antibody, often known as M-protein. This can lead to bone destruction, anaemia, myelosuppression and have implications on renal function and other systems.1 Although survival rates are constantly improving with the introduction of new therapies, MM is still incurable as patients will eventually relapse or stop responding to available therapies. Since MM cells usually reside in the bone marrow, most therapies work to target cell types within this microenvironment. However, in rare cases MM can present in a particularly aggressive form whereby the cancer cells have become independent of the bone marrow and may infiltrate other organ systems (Figure 1). This is known as extramedullary MM (EMM) and occurs in only around 7% of patients at diagnosis (primary EMM), and up to 20% of patients at relapsed stage (secondary EMM).2 Even in the era of novel therapies, the incidence of EMM is increasing. Many hypothesise that EMM can arise from particularly aggressive MM clones originating in the bone marrow. Since most current therapies have been designed to target the bone marrow and its niche, it is possible that these therapies are driving malignant plasma cells to evolve and escape the bone marrow and present as EMM. With a particularly poor prognosis, it is important that we are aware of EMM, and improve our understanding of its presentation and pathogenesis. Here I give an overview of the disease, our current understanding of pathogenesis, and treatment approaches.
Definition
The definition of EMM can vary widely between groups but generally, it can be classified into two broad groups; bone-related/ osseous EMM and extraosseous EMM. Bone-related EMM are soft tissue masses arising from bone and growing contiguously, whereas soft tissue masses tend to be in isolated extraosseous locations as a result of haematogenous spread.2, 3 Some groups restrict the definition to exclude bone-related EMM. EMM may occur at any anatomic site, but involvement of lymph nodes, skin, central nervous system (CNS) and effusions are more common. It is important to distinguish between osseous and extraosseous EMM as patients with extraosseous have a worse prognosis. Solitary plasmacytomas are explicitly excluded from EMM definition as these can occur in the absence of MM diagnosis.2 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%. However, it is also usually excluded from the definition of EMM since it is characterised as a unique entity with a defined clinco-pathological state.2
Detection and Incidence
In patients with a confirmed MM diagnosis, EMM is usually detected by identification of pathologic soft tissue masses using imaging techniques (computed tomography (CT)-scan, PET/ CT, magnetic resonance imaging (MRI), or ultrasound), biopsy or physical examination. Patients who present with EMM during disease progression tend to have lower levels of serum M-protein, lower haemoglobin, and higher lactate dehydrogenase (LDH) than those with EMM at diagnosis.2
It is believed that the incidence of EMM is largely underestimated given the wide range of definitions used and methods used for detection. Moreover, many studies predate the use of routine sensitive imaging meaning EMM may have gone undetected. Reported incidence therefore varies across studies but overall, the incidence of EMM at relapse is much greater than at diagnosis, which is in concordance with its consideration to be a high-risk feature. Additionally, bone-related EMM is more common than extraosseous EMM. At diagnosis, extraosseous EMM is present in less than 5% of patients whilst bone-related EMM is reported in between 7 and 23% of patients.3 Alternatively at relapse, the incidence of extraosseous EMM ranges from 3 to 10%, and bone-related from 6 to 23%.3
Pathogenesis and Genetic Hallmarks
There are very limited studies published addressing the underlying pathogenesis of EMM. We do know however that in MM, the bone marrow microenvironment has an extremely important role to play. Briefly, the bone marrow niche can activate signalling cascades that promote adhesion of MM cells to the bone marrow, as well as tumorigenesis and even drug resistance. These signalling pathways are controlled by many factors including gene transcription and expression. A commonly employed pathway in MM is known as the RAS signalling pathway, and gene mutations in RAS pathway members are associated with EMM. Moreover, changes in the Wnt pathway signalling and interleukin-6 (IL-6) signalling have been shown in EMM, and are associated with migration and invasion of tumour cells.3, 4
For years now, cytogenetic abnormalities in MM are routinely tested for both at diagnosis and relapse. These are commonly translocations involving the IGH gene (chromosome 14) but also deletions such as del(17p) and chromosome amplifications such as gain(1q)/amp(1q), and these are usually detected using fluorescence in situ hybridisation (FISH). Several studies have investigated the incidence of these common markers in patients with EMM and generally, the markers associated with inferior prognosis are more frequent.5 This includes t(4;14), gain(1q), del(1p) and del13). On the other hand, a t(11;14) translocation is associated with standard-risk MM and is less likely to occur in patients with EMM. Most of these studies so far have only genomically characterised the bone marrow of EMM patients, but increasingly studies are using the tissue from extramedullary sites as well. This is crucial for the understanding of EMM disease biology, as clonal evolution plays a huge role and as such, spatial heterogeneity can occur i.e. patients present with differential cytogenetics/mutations/gene expression between anatomical sites. Many hypothesise that aggressive clones are selected for in the bone marrow, which are more likely to escape the bone marrow and infiltrate elsewhere.
Recent studies have also used gene expression based methods to understand EMM. Gene expression profiling (GEP) has become an alternative method to FISH for risk classification of MM. Although studies are limited, patients classified as high-risk by GEP are more likely to experience EMM.5 Additionally, more in-depth transcriptomic sequencing of EMM has revealed differentially expressed gene pathways that may contribute to pathogenesis. Single-cell sequencing approaches have also identified different cell subpopulations in extramedullary sites vs bone marrow, many of which are immune cell types.4
As mentioned previously, RAS pathway mutations are associated with EMM. DNA-based sequencing methods have also identified mutations in DNA repair pathways such as ATM and ATR, and important tumour suppressors such as TP53.5 I hope that further genomic studies will uncover mechanisms behind EMM progression, and possible new biomarkers to predict its occurrence.
Prognosis
EMM is described as a very aggressive subentity of MM as it is associated with high tumour burden. As a result, patients tend to have very exacerbated MM manifestations such as severe anaemia, thrombocytopenia, hypercalcaemia and high rates of renal impairment. Moreover, patients also present with high serum lactate dehydrogenase and serum β2 microglobulin level ≥ 5.5 g/dL.2 Generally, prognosis for EMM is very poor with a median overall survival of less than 1 year in patients who are refractory to standard treatments. If eligible, an autologous stem cell transplant (ASCT) is the most effective MM treatment, but even so, EMM prognosis is still only 3 years. Many other factors can also influence EMM prognosis, such as subtype and anatomical site. For example, in patients receiving an ASCT, progression free survival was longer in those with bone-related EMM compared to extraosseous (51.7 months vs 38.9 months).2 Additionally, patients presenting with secondary EMM have a worse prognosis than those with primary EMM. Moreover, EMM at certain sites such as blood, CNS, liver, lung and muscles has been associated with earlier mortality than in cases where these sites were not involved. More recently, studies have also shown that certain genetic abnormalities in EMM may influence patient outcome. For example, EMM patients with amp(1q) had inferior survival compared to those without amp(1q) and furthermore, the number of additional copies was also proportionately detrimental to outcome.6
Current and Future Treatment Strategies
Given the lack of consensus on EMM definition and its low incidence, most studies evaluating treatments for EMM have been of a retrospective nature. Additionally, most clinical trials tend to exclude patients with EMM making it even more difficult to assess novel agents in this setting. In general, all MM patients are widely grouped as either transplant-eligible or transplant-ineligible at diagnosis based on factors such as age and co-morbidities.1 Standard of care induction therapy consists of a proteasome inhibitor (PI) such as bortezomib and an immunomodulatory agent (IMiD) such as lenalidomide. This is followed by stem cell harvest and an ASCT for transplant-eligible patients, whilst ineligible patients will receive longer induction therapy followed by maintenance therapy, commonly lenalidomide. Treatment approaches for MM patients with EMM remains the same as patients without EMM, and thus results remain unsatisfactory.2, 7 ASCT has indeed shown survival benefit for patients with both extraosseous and bone-related EMM. However, it still cannot fully overcome the poor prognosis of EMM. Likewise, regimens including bortezomib and/or IMiDs have improved survival of EMM overall, but when compared to those with only classic MM, prognosis is still inferior. The first generation IMiD thalidomide is associated with poor efficacy in EMM compared to second generation IMiDs lenalidomide and pomalidomide.7 Monoclonal antibodies have more recently been incorporated into MM regimens. One such example is CD38-targeting daratumumab, used mainly in the relapsed setting in combination with lenalidomide and dexamethasone (Dara-RD). This is described as one of the most beneficial regimens for relapsed MM. However, limited efficacy is observed in EMM, perhaps due to loss of CD38 expression.7 Other therapies currently approved for MM include elotuzumab (SLAMF7 monoclonal antibody), selinexor (nuclear export inhibitor) and venetoclax (BCL-2 inhibitor). Unfortunately, reports of these in EMM patients are currently lacking. Similarly, data is not yet available for the use of chimeric antigen receptor (CAR) T cell therapy or bispecific T-cell engagers (BiTEs) in EMM. Future trials should aim to incorporate EMM patients, and perhaps in the future regimens specific to EMM may become standard of care. MM with CNS (MM-CNS) involvement is extremely rare (<1%) and particularly difficult to treat due to novel agents’ lack of ability to cross the blood-brain barrier. However, several case reports show that the novel PI marizomib is much more effective at CNS penetration than previous PIs and as thus is beneficial for MM-CNS.7 Data is not yet available for this in EMM. With this in mind however, in the future we may move towards specific targeted therapies for different anatomical sites where EMM may present.
Conclusion
EMM is an extremely high-risk feature in MM patients, which is associated with inferior response and survival. Due to its low prevalence and lack of documentation, our understanding of EMM is only beginning. It is clear that novel therapies have undoubtedly improved the prognosis for MM as a whole. However, for patients with EMM these improvements are not as pronounced and response remains unsatisfactory. EMM patients represent a particularly poor group to treat, and no specific regimen is currently available. We hope that as more clinical trials include patients with EMM, the most beneficial regimens will be uncovered, and perhaps down the line more targeted therapies for specific EMM subtypes. Additionally, more genomic studies are being performed on EMM and will contribute to our understanding of disease biology and molecular hallmarks/biomarkers. Perhaps, genomic characterisation in combination with clinical trials will answer questions regarding the role of clonal evolution in disease progression. Ultimately, risk-adapted therapy is the way forward for EMM.
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