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Monoclonal gammopathies of undetermined significance and smoldering myeloma

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a clonal plasma cell disorder implicated as a precursor of multiple myeloma (MM), while smoldering multiple myeloma (SMM) is a malignant plasma cell disorder without evidence of a myeloma-defining event(s) (MDE). This is a review article of both disorders outlining their current definition and management according to the current standard of care. We focus on the pathogenesis of MM and the role of MGUS and SMM in the development of active MM. MGUS is a benign disorder and, subsequently, is followed by observation. In contrast, for SMM, although the current standard of care is “watch and wait”, this paper will explore the circumstances in which treatment should be considered to prevent MDE.


Introduction
Monoclonal gammopathies are a group of disorders with altered immunological homeostasis and the presence of abnormal monoclonal protein in the blood and/or urine. These proteins may have no immediate or long-term clinical significance or can be associated with clinical relevance such as monoclonal gammopathy of renal significance (MGRS), paraneoplastic syndromes (e.g., neuropathy) or evolution into malignant clonal diseases (MM, AL amyloidosis, Waldenström's macroglobulinemia, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma). The condition of benign monoclonal gammopathy was first described in 1978 by Dr Kyle in 241 asymptomatic patients with evidence of monoclonal protein in the serum, yet no evidence of MM, AL amyloidosis, or Waldenström's macroglobulinemia at the time of diagnosis [1,2]. Ultimately, the term was changed to monoclonal gammopathy of undetermined significance (MGUS) [3]. Smoldering multiple myeloma (SMM), a disorder first coined in 1980, described six patients with 10% or more plasma in the bone marrow (BM) and no evidence of endorgan dysfunction at diagnosis; however, with a potential of malignant transformation to MM, it was defined as asymptomatic multiple myeloma (AMM) [4]. SMM includes a broad spectrum of patients from low to a high risk of development of end-organ damage defining MM [5].
The definitions of multiple myeloma (MM), SMM, and MGUS, with detailed diagnostic criteria are presented in table I [6].

Multiple myeloma
MM is usually a progressive plasma cells (PCs) malignancy leading to end-stage organ disease with significant morbidity and subsequent mortality. It is diagnosed based on the International Myeloma Working Group (IMWG) criteria updated in 2014 [7], including the presence of clonal BM PCs ≥10% confirmed via trephine biopsy or biopsyproven solitary bony or extramedullary plasmacytoma and at least one myeloma-defining event(s) (MDE). Prior to 2014, the end-organ destruction was classified under the acronym CRAB. However, in the newest criteria it has evolved into MDEs, updated to SLiM CRAB acronym, which identifies the following MM symptoms: C (calcium) -hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL); The diagnostic criteria were updated to identify the group of patients who would have been previously diagnosed with SMM, but who have biomarkers that almost always predetermined the development of CRAB features. This would prolong the inevitable diagnosis of MM and significantly delay the implementation of treatment.
MM is the second most common blood malignancy following lymphoma with an estimated 32,110 new diagnoses and 12,960 deaths in 2019 in the United States, which was roughly 1.8% of all new cancer cases in the United States [8]. Most commonly, the median age of MM at diagnoses is 69-70 years; only 2% of patients are <40 years and 38% >70 years [9,10].
The prognosis has vitally improved in recent years; the overall survival (OS) was only 1 year prior to the introduction of alkylating agents in the 1950s to a median of 5.5 years in the 2000s [11]. This improvement in survival is due to the introduction of target therapy (proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies) and the incorporation of high-dose chemotherapy with autologous stem cell transplants [12,13].
Despite the growing improvements in treatment and survival, MM remains an incurable disease; therefore, increasing survival, improving quality of life, and researching its evolution are the relevant goals of ongoing research [14].

Pathogenesis and role of premalignant conditions in the development of MM
MM is a disease characterized by uncontrolled growth and proliferation of malignant PCs. The pathogenesis remains poorly understood. Numerous risk factors have been implicated; however, a specific cause/effect has yet to be elucidated. An epidemiologic study carried out by Alexander et al. [15] confirmed that incidence rates increase with age, particularly after age 50, and are higher in men, particularly African American men. Although relatively low, there is an increased propensity for the development of MM and other B-cell malignancies in families. Although a variety of autoimmune diseases have been implicated as increasing the risk of development of MM, only pernicious anemia and ankylosing spondylitis have been associated with an increased risk [16]. Many environmental factors, such as ionizing radiation, exposure to benzenes, and petroleum as well as smoke and other industrial and agricultural toxins, were hypothesized to contribute to the pathogenesis [16,17]. The US government recognizes three potential risk groups: troops exposed to Agent Orange during the Vietnam War period, extensively exposed workers after 9/11, and troops who served at Camp Lejeune, North Carolina. As mentioned, MGUS is a precursor of MM. In a study conducted by Landgren et al. [17], they found that almost all MM cases studied had a preceding incidence of MGUS [17,18,19].

Similar findings have been described in studies carried out by the
Mayo Clinic in the group of United States veterans, thus highlighting the pivotal role of MGUS in the pathogenesis of MM [18,19]. There is increasing data to support the concept of intraclonal heterogeneity and the existence of simultaneous multiple clones of tumor cells at the time of diagnosis [20][21][22][23][24][25]. This was demonstrated for MM by Morgan et al. [24] and Keats et al. [26], describing clonal evolution from MGUS to MM and plasma cell leukemia (PCL). As this theory is likely to be a part of the natural progression of MM, it also serves to emphasize a potential target for treatment or the need to initiate treatment in the early stages of this heterogeneity, for instance, MGUS [13,22,24,[25][26][27][28].
Although MM is thought to evolve in this sequence, its propagation is

Monoclonal gammopathy of undetermined significance
MGUS is a premalignant PC disorder. The more prevalent type, non-IgM MGUS, generally originates from mature PCs that have had switch recombination and may lead to MM [31,39]. The specific diagnostic criteria for MGUS defined by the IMWG are presented in table I [40].  [41][42][43][44][45]. The prevalence of MM is twofold higher in the African American populations, which is due to a higher incidence of MGUS, thought to be due to the initial pathogenesis beginning at an earlier age [44].

Progression of MGUS to MM
The risk of progression to MM has been demonstrated by Kyle et al. to increase cumulatively by 1.5% per year [40,41,46]. The risk of progression can be estimated based on defined risk factors; the most definitive of these are the concentration of M protein > 1.5 g/dl, immunoglobulin isotype (non-IgG), and abnormal serum-free light chain (sFLC) ratio [40,47]. Focusing on non-IgM MGUS patients, the projected risk at 20 years is 30% if they possess two risk factors, 20% for those with only one risk factor, and 7% for those who possess no risk factors (Tab. II) [39].
The immunoglobulin isotype is also a key indicator of risk. Patients with IgM or IgA monoclonal proteins are at higher risk of progression in contrast to those with IgG monoclonal protein. By analyzing the M spike concentration and serum FLC for each patient sample, they found that they were both increased and correlated with a higher risk of MM. The high-risk score was evident in the serum for up to 5 years before the diagnosis of the MM, thus highlighting the biomarkers that can predict MGUS progression and the potential for the treatment of high-risk MGUS before disease in and, further, the importance of constant follow-up in MGUS patients [52,53].

Management of MGUS
Traditionally, the management of MGUS has been a "watch and wait" strategy. MGUS patients are monitored, as recommended above, for progression to MM; the frequency of the recommended serial evaluations is described below.

MGUS with low risk of progression
If the serum monoclonal protein is <15 g/L, IgG type, and the FLC ratio is normal, the risk of eventual progression to myeloma or related malignancy is low. In these patients, complete blood count, creatinine, and calcium values are usually indicative of MGUS and should be evaluated regularly. A BM examination or radiography is not routine; however, if a patient presents with renal insufficiency, hypercalcemia, bone lesions, or unexplained anemia, a BM aspiration would be required. These patients should have their serum protein electrophoresis in 6 months, and if this is not indicative, they can be followed up every 2-3 years [40,41,54].

MGUS with intermediate and high risk of progression
If an MGUS patient has a serum monoclonal protein >15 g/L, IgA or IgM protein type, or an abnormal FLC ratio, a BM aspirate and biopsy should be done to rule out an MM or another PC malignancy.
BM needs to be evaluated by both conventional cytogenetics and fluorescence in situ hybridization (FISH) [40,41,54].

Implications of MGUS and roles for potential treatments
Whereas the standard of care for MGUS is observation, recent clinical trials support the concept that early treatment initiation may improve survival and decrease the risk of an MDE [55].
Melton et al. [56] described the prevalence of osteoporosis and fractures among MGUS patients. They were greater than in the High-risk (all three factors abnormal) 53 20.8 58 27 Adapted from Monoclonal gammopathy of undetermined significance and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspective risk factors for progression and guidelines for monitoring and management [40] general population of age-matched controls. Further research demonstrated the increased incidence of fractures, in particular of the hip and vertebral column, in addition to greater osteoporosis and hypercalcemia [57,58]. This highlights a potential proactive role of bisphosphonates or rank-ligand inhibitors as well as calcium/ vitamin D supplementation in MGUS patients, as has been routinely incorporated into the management of osteoporosis [59].
Although there is no specific treatment for MGUS, it has been shown to reduce life expectancy even when a malignant transformation is not Patients with impaired immune system are two to three times more likely to develop bacterial and viral infections [58]. In several studies on survival in MGUS, infections have shown to have a standard mortality ratio (SMR) of between 1.5 and 2, and with pneumonia, sepsis, pyelonephritis, and tuberculosis as the most common causes of death [62,63]. This is likely to be due to impairment of both innate and adaptive immunity and, in particular, a reduction in the number of NK cells, CD 19 + cells, as well as the blood immunoglobulin level [64]. Therapy should be modeled after the treatment paradigms for MM targeting the clonal PCs producing the immunoglobulins with the goal of improving/maintaining renal function [60].

Recommendations
Currently, a population study is being carried out in Iceland called

iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma).
This study aims to assess the blood of 140,000 adults aged > 40 in Iceland to assess the first signs of MM. Simultaneously, the study is looking into particular areas in Iceland where MM cases are known to be higher, to try to identify risks associated with the development of the disease. The results of this study will no doubt implicate precursors of myeloma such as MGUS and potentially identify a greater rationale for treatment [66]. In light of the issues mentioned above and the risk

Progression and risk factors
The risk of progression to symptomatic disease or MM differs from that of MGUS; Kyle et al. projected the risk of 10% per year for the first 5 years following diagnosis, decreasing to 3% for the next 5 years and finally 1% in the years following to the 10th year [67,68].
Given these figures the probability of advancement to symptomatic disease was 51% at 5 years, 66% at 10 years, and 73% at 15 years [40,71]. The prognostic factors associated with the greatest risk of evolution of SMM to MM are dependent on BM plasmacytosis and the serum monoclonal protein level at diagnosis [71].
In 2014, the IMWG redefined the criteria for MM diagnosis. They included patients with high-risk SMM into the treated group, since earlier these patients were followed only by observation [7,72].

How to identify high-risk SMM in the remaining patients
There are several models on how to predict the risk of progression in SMM; the most widely accepted models from the Mayo Clinic and PETHEMA are presented in table III [73].

Genetic models
Neben et al. [77] analyzed chromosomal alterations by FISH. This group found that previously proven high-risk aberrations for MM had implications in SMM, del(17p13), and t(4;14) and +1q21 leads to poor prognosis, time to progression (TTP), and requirement of treatment in SMM. The highest risk was associated with del(17p13) [77,78]. Another study using human genome analysis in multiple arrays using the GEP-70 score (a genomic assay for prediction of event-free and OS in asymptomatic, newly diagnosed, and relapsed MM) in addition to the proliferation index may accurately reflect the malignant potential of the tumor cells. These findings, which correlate high-risk MM with high risk of progression in progenitor diseases, highlight how understanding the biology of high-risk MM may be the key to disease prevention [79,80].

Radiographic models
Newer imaging techniques such as MRI and PET/CT can detect the myeloma-defining phenomenon significantly earlier than plain radiographs. While CT and plain radiographs can detect lytic bone lesions in the bone, MRI can assess the BM, therefore demonstrating certain growth patterns and may identify disease in its early stage [31]. In a large study using MRI for diagnosis of MM, focal lesions were noted in 74% of patients using MRI versus 56% of patients with skeletal surveys [33,73]. Furthermore, Hillengass et al. [81] reported in a study of 544 SMM patients that MRI found that at least 30% of patients had BM manifestations of myeloma similar to that seen in MM. In SMM patients, the presence of bone lesions on MRI has shown to significantly increase their TTP [82]. A study by Wang et al. [82] found that TTP could be as little 1.5 years in patients with abnormal MRI in comparison to 5 years when the MRI was normal.
Hillengass et al. [83] also identified that 28% of SMM patients had focal lesions not detected with routine radiographs; even a single lesion was predictive for disease progression.

Like MRI, FDG-PET/CT is important, as FDG-PET uptake can show
focal FDG avid disease while CT demonstrates bone damage.
This imaging may play a potential role in evaluating the treatment response in patients [84,85]. Although PET/CT has low sensitivity lenalidomide and observation groups [86]. The primary endpoint was progression-free survival (PFS). They reported that at 35 months there was a 72% reduction in the risk of progression to symptomatic disease in the lenalidomide group. When comparing the two groups, they found that PFS at 1, 2, and 3 years in the treatment arm was 98%, 93%, and 91% in the lenalidomide arm, in comparison to 89%, 75%, and 66% in the observation arm. They concluded that patients with high-risk SMM using the 20 February 20 model were candidates for early treatment with lenalidomide [87]. Despite this, there were several faults noted with this study. Biran et al. [88] noted that only 56 of the patients were high-risk defined by the Mayo 2018 criteria and, subsequently, out of these 56 high-risk patients, 31 were randomized to the observation arm. Furthermore, these patients an accurate marker in a disease with no current cure available. Therefore, it would be more factual to state that time-to-myeloma is delayed rather than prolonged survival. Finally, the question of why would one treat a myeloma patient with single-agent lenalidomide, when essentially all studies show that triplets, or even quadruplets, are superior to doublets in frontline myeloma therapy [88]. As noted previously, and by the authors of this article, clonal evolution is a pivotal process in the development of MM, thus a single-agent treatment is unlikely to target clonal heterogeneity.

Management
All patients suspected of SMM should have the following diagnostic and baseline screening tests: • Complete blood count; • Chemistry profile with measurement of calcium, creatinine, albumin, beta-2 microglobulin, and LDH; • Quantitative immunoglobulins, serum protein electrophoresis, serum immunofixation electrophoresis, and sFLC assay; • 24-h urine collection for total urine protein, urine protein electrophoresis, and urine immunofixation electrophoresis; • A baseline BM biopsy for cytogenetics, FISH can be done, however, it is not routinely preformed in SMM; • A skeletal survey, including low-dose whole-body CT, PET-CT, or MRI of the whole-body or spine [7].
The IMWG recommends all the tests mentioned above, initially and at follow-up 2-3 months after the diagnosis. While an MRI is not mandatory, a BM biopsy and skeletal survey are recommended.
Paraprotein parameters should be repeated every 4-6 months for at least 1 year and, if they remain stable, intervals can be increased to every 6-12 months [40,72]. Depending on the results and risk stratification using the recommended models, the follow-up plan can be estimated in a way similar to that presented in table IV [40,71]. Regular monitoring is mandatory as recent studies have shown how serum immune markers for precursors of MM can change over time [29,52].

Treatment
Historically, similar to MGUS, the treatment for SMM was observation.
Older studies on SMM treatments have failed to show an OS or quality-of-life benefit. This was mainly due to ineffective available therapies and toxicities of these therapies (mainly alkylating agents).
More modern therapies are targeted with a number of potential combinations which are substantially better tolerated.

Early trials
Three small studies compared early therapy with melphalan plus prednisone versus observation or melphalan plus prednisone treatment at the time of progression. These studies failed to show any increase in OS [89,90].
Similarly, other trials with thalidomide and bisphosphonates failed to show improvement in OS and had numerous adverse events associated in particular with neuropathy [91], while thalidomide alone in SMM also proved disappointing [92].
Witzig et al. [93] presented a Phase III study of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with SMM.
They demonstrated that the risk of progression to active MM could be decreased using this combination of drugs; however, the study limitations were small sample size and high toxicity of the study drugs.

Modern approaches in SMM
The Spanish (PETHEMA) myeloma group tested lenalidomide plus dexamethasone for high-risk SMM (see definitions above). A total of 119 patients were randomized to the treatment or observation. In the treatment group the TTP was not met, while the median TTP in the observation arm was 21 months. Similarly, the 3-year OS in the treatment arm was higher, at 94% versus 80%. In all, 79% of treated patients in the induction phase and 90% in the maintenance phase achieved a partial response. Therefore, this treatment in early high-risk SMM decreased TTP and improved OS in this study [94].
Although this study demonstrated increased PFS and OS, the study had limitations as it is difficult to assess the efficacy of a combination treatment and the lack of accurate imaging in this study makes it difficult to confirm whether these patients had no myeloma-defining criteria. Furthermore, the median follow-up was 6 years, which was not a significant time to assess PFS [87].  As a result, we must consider whether such an intense regimen is necessary [97].
The treatment of this disease in the absence of symptoms is a difficult decision. The main role of therapy in SMM is to improve OS and not impact the quality of life; therefore, the future of the therapeutic intervention in SMM may be the use of novel therapies that work directly on the immune system regulation and surveillance and maintain control of the malignant cells or treatments, which ultimately cure this disease at its earliest stage [72,98]. The diagnostic and therapeutic management of MGUS, SMM, and MM is summarized in table V.

Future approaches to MGUS and SMM
In the future, better-defined biomarkers will be evaluated in clinical trials to select those patients who are at the highest risk for developing

Authors' contributions
All authors contributed to the writing of the paper based on the current literature review.

Conflict of interests
None.

Financial support
The manuscript was prepared without any financial support.

Ethics
The work described in this article has been carried out in accordance