1. bookVolume 51 (2020): Issue 4 (December 2020)
Journal Details
License
Format
Journal
First Published
30 Mar 2018
Publication timeframe
4 times per year
Languages
English
access type Open Access

Monoclonal gammopathies of undetermined significance and smoldering myeloma

Published Online: 01 Dec 2020
Page range: 193 - 202
Received: 04 Aug 2020
Accepted: 08 Sep 2020
Journal Details
License
Format
Journal
First Published
30 Mar 2018
Publication timeframe
4 times per year
Languages
English

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.

Keywords

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 end-organ 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].

Criteria for diagnosis of MGUS, smoldering MM, and MM

MGUSSmoldering MMMultiple myeloma
Serum M protein <3g/dL assessed in electrophoresis and immunofixationSerum monoclonal protein (IgG/IgA)≥3g/dL or urinary monoclonal protein ≥500 mg per 24 hM protein present (IIMM, LCMM) or absent (NSMM) – not required for the diagnosis
Clonal bone marrow plasma cells <10% in the trephine biopsyClonal bone marrow plasma cells 10%–60% in the trephine biopsyClonal bone marrow plasma cells ≥10% in the trephine biopsy
Absence of end-organ damage (no CRAB features) and amyloidosisAbsence of myeloma-defining events or amyloidosisMyeloma-defining events
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 biopsy-proven 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);

R (renal insufficiency) – creatinine clearance <40 mL/min or serum creatinine >177 mmol/L (>2 mg/dL);

A (anemia) – hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin value <100 g/L;

B (bone lesions) – at least osteolytic lesions on skeletal radiography, computed tomography (CT), or fusion 18F-fluorodeoxyglucose positron-emission tomography (18F-FDGPET/CT);

as well as the following biomarkers of malignancy:

S (sixty) – clonal BM PC percentage (60%) with clonality established by showing kappa/lambda light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence;

Li (light chains) – involved to uninvolved serum-free light chain ratio > 100 (measured in the serum Freelite assay);

M (magnetic resonance) – more than one focal lesion on magnetic resonance imaging studies, each of them at least 5 mm in size.

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 a result of a multitude of factors: inherited genetic variation, myeloma cell gene mutations, deletions, and amplifications which occur throughout the natural history of the disease [29, 30, 31]. Another crucial factor in the translation of PCs to MM is the impact of the BM microenvironment. This had an implication in the clinical trials focused on altering the microenvironment, with some potential treatment targets revealed [21, 32, 33]. It is now largely acknowledged that the progression of myeloma is as a result of immune dysregulation and loss of immune system surveillance. For instance, the BM microenvironment in MM has been shown to create a protected area for tumor cells through the secretion of growth factors and cytokines and via upregulation of inhibitory receptor/ligand pairs such as programmed death receptor-1/programmed death ligand (PD-1/PDL1). Furthermore, increased numbers of circulating myeloid-derived suppressor cells and the inhibition of effective antigen presentation by dendritic cells, coupled with the loss of regulatory T cells and TH17 cells from the T-cell reserve, are all components believed to contribute to propagation of MM cells, their proliferation, and disease progression [34,35,36,37,38].

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].

Prevalence

Population-based studies have demonstrated that the production of MGUS can begin as young as 30 years of age; however, accurate percentages are not available. MGUS was found in approximately 3% of people aged ≥50 years and roughly 5% of people ≥70 years [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].

Risk stratification for progression of monoclonal gammopathy of undetermined significance to multiple myeloma

Risk groupNo. of patientsRelative riskAbsolute risk of progression at 20 years (%)Absoluter risk of progression at 20 years accounting for death as a competing risk (%)
Low-risk (serum M protein <1.5 g/dL, IgG subtype, normal FLC ratio (0.26–1.65)449152
Low-intermediate-risk (any one factor abnormal)4205.42110
High-intermediate -risk (any two factors abnormal)22610.13718
High-risk (all three factors abnormal)5320.85827

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]

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. The risk of progression among patients with IgM MGUS is nearly 11 times that of a normal, comparable population [48]. Similarly, the percentage of BM PCs is of significance in risk assessment. In a study by Cesana et al. [49], they observed that MGUS patients with greater than 5% BM PCs were at greater risk of malignant transformation. Further studies by this group demonstrated that the evolution of the disease was just 6.8% when the BM PCs were less than 10% while it was significantly greater at 37% in patients with BM PCs at 10%–30% [50]. The IMWG concluded that patients with ≥10% PCs are considered to have SMM or MM [40]. Additionally, serum-free light chain ratios have prognostic value in MGUS. Rajkumar et al. [51] reported that 382/1,148 patients with aberrant FLC ratios at diagnosis demonstrated a higher risk of progression to myeloma compared to those with normal serum-free light chain ratios. Recent studies by Landgren et al. [52] further highlight these prognostic factors in the acceleration of MGUS to MM. They found that changes in the immune marker values varied over time. They studied 685 MGUS patients of which 187 progressed from MGUS to MM and some from light chain MGUS to light chain MM.

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 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 present. MGUS patients have decreased survival from a diagnosis of 8.1 years in comparison to 12.4 years for matched controls [39, 60, 61]. Additionally, MGUS patients have been shown to have numerous complications and associated comorbidities, including MGRS, bone fractures, peripheral neuropathy, cardiovascular diseases, and immunodeficiency [57].

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]. This would seem to highlight the importance of encouraging MGUS patients to have herpes zoster vaccinations following the Centers for Disease Control and Prevention guidelines for routine vaccinations. Similar to MM, which is often associated with renal involvement, MGUS has also been implicated in renal disease. The term MGRS was first coined by the International Kidney and Monoclonal Gammopathy Research Group in 2012. It is a heterogeneous spectrum of renal diseases that culminate as a result of the aggregation of deposited monoclonal immunoglobulin in the kidney [65]. Generally, patients are found to have unidentified deterioration of renal function and proteinuria, which may result in renal failure [60]. These disorders occur as a result of clonal B-cell proliferation with monoclonal antibody production and associated with potential capability of complement deregulation [47, 61]. Treatment is indicated in these disorders to prevent from further deposition of monoclonal immunoglobulins in the tubules and glomeruli, leading to irreversible damage and complications of end-stage renal failure. 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 of malignant transformation associated with high-risk MGUS, clinical trials utilizing anti-myeloma therapeutic approaches are actively enrolling patients to prevent MDE to improve the future quality of life for these patients. One such example is a Phase II clinical trial utilizing the anti-CD38 monoclonal antibody daratumumab in patients with high-risk MGUS and low-risk SMM. Another study is assessing the anti-inflammatory properties of celecoxib in MGUS and SMM patients in preventing the development of MM [2]. A search of the clinicltrials. gov database shows that there are 10 active trials of therapeutic intervention in MGUS with an additional 11 recently completed. The results of these studies, among others, may be pivotal in redefining MGUS and its management in the not so distant future.

Smoldering multiple myeloma
Definition

SMM is synonymous with asymptomatic MM (AMM). It is characterized by at least 10% clonal PCs and/or at least 3 g/dL of monoclonal protein level. These patients are without any evidence of end-organ destruction (no CRAB end-organ damage: hypercalcemia, renal insufficiency, anemia, lytic bone disease). The specific diagnostic criteria for SMM, defined by the IMWG are presented in table I [40].

Prevalence

The median age of incidence is similar to that of MM from 69 to 70 years of age [41, 67, 68]. The incidence of SMM is estimated to be between 10% and 15% of MM patients. Extrapolating from a population study by Ravindran et al., it is believed to have an occurrence rate of 0.9 per 100,000, which corresponds to approximately 4,400 new cases of SMM in the United States in 2019 [8, 69, 70].

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 new laboratory and imaging markers. This allowed for the identification of high-risk SMM patients who were most at risk of progression and, more importantly, in need of treatment to prevent end-organ damage (80% at 2 years likelihood of an MDE). The markers that were included in the new criteria were BM PC infiltration of 60% or greater, an sFLC ratio of ≥100 (or <0.01), or at least one focal lesion on cross-sectional imaging of the whole body by magnetic resonance imaging (MRI) – now termed in acronym SLiM (BM percentage – 60, light chain ratio, MRI) criteria. These criteria highlight biological as well as radiographic findings associated with an increased risk of development of an MDE. The new definition 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].

Smoldering multiple myeloma risk models

ModelMain variantsRisk factors
MayoSerum M protein, BM Plasmacytosis, sFLC ratioM protein level>3 g/dL, plasmacytosis>10%, sFLC ratio < 8
PETHEMAMultiparametric flow cytometry, serum immunoglobulins>95% aberrant plasma cells and immunoparesis
The Mayo Clinic model

This model uses serum M protein, BM plasmacytosis, and the sFLC ratio. Their study, which was carried out on 273 SMM patients, found that an sFLC ratio of >8, a serum M protein level of ≥3 g/dL, or BM PCs of ≥10% lead to a 76% risk of progression in 5 years. Likewise, the progression risk for patients with two risk factors or “intermediate risk” was 51% and 25% if only one risk factor was possessed [74].

The PETHEMA model

This model quantifies aberrant BM PCs by use of flow cytometry. Using flow cytometry, the group was able to distinguish the number of neoplastic cells and normal PCs using surface markers. They found that 95% or greater aberrant BM PCs correlated to a higher risk of progression in SMM patients. In addition, there was immunoparesis, which is defined by a decrease below the lower limit of normal in one or two of non-involved immunoglobulins. This model predicts that patients with both aberrant PCs and immunoparesis have a risk of progression of 72% within 5 years, patients with one risk factor have an intermediate risk of 46% of progression in the same time, and finally, none of these factors would have a 4% chance of progression [75, 76].

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 for early precursors of the disease, a positive result in SMM is an important marker. Conversely, a negative PET/CT in MGUS has a high specificity and, thus, could be used for assessment of the prognostic risk in the future.

20 February 2020 model

In addition to the different models presented above, a new criteria for identification of a high-risk SMM subgroup have been proposed. Lakshman et al. [5] described a higher risk of progression in 400 SMM patients with BM PC%>20%, M-protein>2 g/dL, and FLC ratio > 20 to be predictive for risk of progression: the risk of an MDE was 46% at 2 years. Further supporting this model, a Phase III study was completed by the Eastern Cooperative Oncology Group (ECOG; E306) in 182 SMM patients. Patients were randomized to 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 were only followed for a median of 35 months. Moreover, nearly half of the patients (47.2%) had aberrant findings on MRI when enrolled, which may suggest that these patients had symptomatic MM at the time of randomization. The studies’ primary endpoint of PFS is not 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].

Management of smoldering multiple myeloma [40]

Plasma cell disorderManagement
Low riskAnnual follow-up
Intermediate riskMonitor every 6 months
High riskConsider clinical trial/monitor every 2–3 months
Early myeloma/“Ultra high-risk SMM”Treat as you would treat symptomatic MM
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].

Lonial et al. [86] compared lenalidomide versus observation in 182 patients. In the treatment arm, response to therapy was observed in 50% of patients, in comparison to no response in the observation arm. There was a significant improvement in PFS in the treatment arm in comparison to the observation arm (hazard ratio, 0.28; 95% CI = 0.12–0.62; p = 0.002). Thus, they concluded that lenalidomide treatment delayed progression to an MDE in SMM patients. As discussed previously, there were several drawbacks to this study design.

Korde et al. [94] reported treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) with lenalidomide maintenance in patients with high-risk SMM and newly diagnosed MM. All patients with SMM achieved at least a very good partial response during the study period. Concerning the most common of any-grade adverse events, 12 patients with high-risk SMM lymphopenia (12 [100%]) and gastrointestinal disorders (11 [92%]) were reported. A Phase III study is actively enrolling patients further to test this treatment on SMM patients [95].

In a trial designed to potentially cure early stages of myeloma, GEM-CESAR (NCT02415413) is a Phase II single-arm clinical trial using a KRd backbone for induction followed by high-dose therapy and autologous stem cell transplant and maintenance, essentially treating high-risk SMM as symptomatic myeloma. The primary endpoint of the study was minimal residual disease negativity rate evaluated by next-generation flow post-induction and post-transplant. At a median of 30 months, 93% of the patients are alive and free from progression. Following consolidation, the overall response rate was 100% and the complete response rate was 76%. The minimal residual disease (MRD) negativity rate following consolidation was 63%. Although this is a very intense treatment sequence, with a substantially higher response rate than lenalidomide as a single agent in the ECOG E306 study, the 3-year PFS was similar to that reported in the E306 study. 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.

Diagnostic and therapeutic management in MGUS, SMM, MM

DiseaseMGUSSMMMM
Management

Baseline screening

Follow-up every 2–3 years

Baseline screening

Follow-up initially 2–3 months, then 4–6 months for the first year, if stable every 6–12 months

Baseline screening

Staging as in IMWG recommendations

Treatment

Watch and wait

Watch and Wait

Systemic therapy (chemotherapy) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) in transplant-eligible patients

Preferred multidrug therapy – triplets, including in the frontline the following regimens: bortezomib/lenalidomide/dexamethasone or cortezomib/cyclophosphamide/dexamethasone, although several others are used depending on the patient status

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 MDE. For example, Ghobrial et al. [99] found immune system dysregulation in particular natural killer cells and loss of cytotoxic T cells is a major contributor to the progression of MGUS and SMM. Furthermore, the use of chimeric antigen receptor T cells in MM has been shown to be an interesting target for treatment and several other targets are being tested [100]. At present, all SMM patients must undergo rigorous evaluation at initial workup to exclude subclinical symptomatic disease and provide risk stratification patients with low and intermediate risk. SMM should be closely monitored and potentially included in clinical studies. At present, patients with high-risk SMM should not be treated outside of a clinical trial until we more precisely identify those patients who are most likely to develop MDE.

Diagnostic and therapeutic management in MGUS, SMM, MM

DiseaseMGUSSMMMM
Management

Baseline screening

Follow-up every 2–3 years

Baseline screening

Follow-up initially 2–3 months, then 4–6 months for the first year, if stable every 6–12 months

Baseline screening

Staging as in IMWG recommendations

Treatment

Watch and wait

Watch and Wait

Systemic therapy (chemotherapy) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) in transplant-eligible patients

Preferred multidrug therapy – triplets, including in the frontline the following regimens: bortezomib/lenalidomide/dexamethasone or cortezomib/cyclophosphamide/dexamethasone, although several others are used depending on the patient status

Smoldering multiple myeloma risk models

ModelMain variantsRisk factors
MayoSerum M protein, BM Plasmacytosis, sFLC ratioM protein level>3 g/dL, plasmacytosis>10%, sFLC ratio < 8
PETHEMAMultiparametric flow cytometry, serum immunoglobulins>95% aberrant plasma cells and immunoparesis

Risk stratification for progression of monoclonal gammopathy of undetermined significance to multiple myeloma

Risk groupNo. of patientsRelative riskAbsolute risk of progression at 20 years (%)Absoluter risk of progression at 20 years accounting for death as a competing risk (%)
Low-risk (serum M protein <1.5 g/dL, IgG subtype, normal FLC ratio (0.26–1.65)449152
Low-intermediate-risk (any one factor abnormal)4205.42110
High-intermediate -risk (any two factors abnormal)22610.13718
High-risk (all three factors abnormal)5320.85827

Criteria for diagnosis of MGUS, smoldering MM, and MM

MGUSSmoldering MMMultiple myeloma
Serum M protein <3g/dL assessed in electrophoresis and immunofixationSerum monoclonal protein (IgG/IgA)≥3g/dL or urinary monoclonal protein ≥500 mg per 24 hM protein present (IIMM, LCMM) or absent (NSMM) – not required for the diagnosis
Clonal bone marrow plasma cells <10% in the trephine biopsyClonal bone marrow plasma cells 10%–60% in the trephine biopsyClonal bone marrow plasma cells ≥10% in the trephine biopsy
Absence of end-organ damage (no CRAB features) and amyloidosisAbsence of myeloma-defining events or amyloidosisMyeloma-defining events

Management of smoldering multiple myeloma [40]

Plasma cell disorderManagement
Low riskAnnual follow-up
Intermediate riskMonitor every 6 months
High riskConsider clinical trial/monitor every 2–3 months
Early myeloma/“Ultra high-risk SMM”Treat as you would treat symptomatic MM

Dhodapkar MV. MGUS to myeloma: a mysterious gammopathy of underexplored significance. Blood 2016;128:2599–606.DhodapkarMVMGUS to myeloma: a mysterious gammopathy of underexplored significanceBlood20161282599606Search in Google Scholar

Seth S, Zanwar S, Vu L, Kapoor P. Monoclonal gammopathy of undetermined significance: current concepts and future prospects. Curr Hematol Malig Rep 2020;15:45–55.SethSZanwarSVuLKapoorPMonoclonal gammopathy of undetermined significance: current concepts and future prospectsCurr Hematol Malig Rep2020154555Search in Google Scholar

Kyle RA. Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med 1978;64:814–26.KyleRAMonoclonal gammopathy of undetermined significance. Natural history in 241 casesAm J Med19786481426Search in Google Scholar

Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med 1980;302:1347–9.KyleRAGreippPRSmoldering multiple myelomaN Engl J Med198030213479Search in Google Scholar

Lakshman A, Rajkumar SV, Buadi FK, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J 2018;8:59.LakshmanARajkumarSVBuadiFKRisk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteriaBlood Cancer J2018859Search in Google Scholar

Jurczyszyn A, Suska A. Multiple myeloma. In: Rattan SIS, editor. Encycl Biomed Gerontol Elsevier. vol. 2, Academic Press; 2020, p. 461–78.JurczyszynASuskaAMultiple myelomaIn:RattanSISeditor.Encycl Biomed Gerontol Elsevier2Academic Press202046178Search in Google Scholar

Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538–48.RajkumarSVDimopoulosMAPalumboAInternational Myeloma Working Group updated criteria for the diagnosis of multiple myelomaLancet Oncol201415e53848Search in Google Scholar

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7–34.SiegelRLMillerKDJemalACancer statistics, 2019CA Cancer J Clin201969734Search in Google Scholar

Jurczyszyn A, Suska A. Multiple myeloma. Encycl Biomed Gerontol 2019:461–78.JurczyszynASuskaAMultiple myelomaEncycl Biomed Gerontol201946178Search in Google Scholar

Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78:21–33.KyleRAGertzMAWitzigTEReview of 1027 patients with newly diagnosed multiple myelomaMayo Clin Proc2003782133Search in Google Scholar

Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975–2017, National Cancer Institute, Bethesda, MD.HowladerNNooneAMKrapchoM(eds)SEER Cancer Statistics Review, 1975–2017National Cancer InstituteBethesda, MDSearch in Google Scholar

Kazandjian D. Multiple myeloma epidemiology and survival: a unique malignancy. Semin Oncol 2016;43:676–81.KazandjianDMultiple myeloma epidemiology and survival: a unique malignancySemin Oncol20164367681Search in Google Scholar

Turesson I, Velez R, Kristinsson SY, Landgren O. Patterns of improved survival in patients with multiple myeloma in the twenty-first century: a population-based study. J Clin Oncol 2010;28:830–4.TuressonIVelezRKristinssonSYLandgrenOPatterns of improved survival in patients with multiple myeloma in the twenty-first century: a population-based studyJ Clin Oncol2010288304Search in Google Scholar

Rajkumar SV. Multiple myeloma: 2018 update on diagnosis, risk-stratification, and management. Am J Hematol 2018;93:981–1114.RajkumarSVMultiple myeloma: 2018 update on diagnosis, risk-stratification, and managementAm J Hematol2018939811114Search in Google Scholar

Alexander DD, Mink PJ, Adami HO, et al. Multiple myeloma: a review of the epidemiologic literature. Int J Cancer 2007;120:40–61.AlexanderDDMinkPJAdamiHOMultiple myeloma: a review of the epidemiologic literatureInt J Cancer20071204061Search in Google Scholar

Sergentanis TN, Zagouri F, Tsilimidos G, et al. Risk factors for multiple myeloma: a systematic review of meta-analyses. Clin Lymphoma Myeloma Leuk 2015;15:563–77.SergentanisTNZagouriFTsilimidosGRisk factors for multiple myeloma: a systematic review of meta-analysesClin Lymphoma Myeloma Leuk20151556377Search in Google Scholar

Landgren O, Zeig-Owens R, Giricz O, et al. Multiple myeloma and its precursor disease among firefighters exposed to theworld trade center disaster. JAMA Oncol 2018;4:821–7.LandgrenOZeig-OwensRGiriczOMultiple myeloma and its precursor disease among firefighters exposed to theworld trade center disasterJAMA Oncol201848217Search in Google Scholar

Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM. A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009;113:5418–22.WeissBMAbadieJVermaPHowardRSKuehlWMA monoclonal gammopathy precedes multiple myeloma in most patientsBlood2009113541822Search in Google Scholar

Kyle RA, Kumar S. The significance of monoclonal gammopathy of undetermined significance. Haematologica 2009;94:1641–4.KyleRAKumarSThe significance of monoclonal gammopathy of undetermined significanceHaematologica20099416414Search in Google Scholar

Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature 2011;471:467–72.ChapmanMALawrenceMSKeatsJJInitial genome sequencing and analysis of multiple myelomaNature201147146772Search in Google Scholar

Ghobrial I, Cruz CH, Garfall A, et al. Immunotherapy in multiple myeloma: accelerating on the path to the patient. Clin Lymphoma Myeloma Leuk 2019;19:332–44.GhobrialICruzCHGarfallAImmunotherapy in multiple myeloma: accelerating on the path to the patientClin Lymphoma Myeloma Leuk20191933244Search in Google Scholar

Egan JB, Shi CX, Tembe W, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood 2012;120:1060–6.EganJBShiCXTembeWWhole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tidesBlood201212010606Search in Google Scholar

Anderson K, Lutz C, van Delft FW, et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 2011;469:356–61.AndersonKLutzCvan DelftFWGenetic variegation of clonal architecture and propagating cells in leukaemiaNature201146935661Search in Google Scholar

Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer 2012;12:335–48.MorganGJWalkerBADaviesFEThe genetic architecture of multiple myelomaNat Rev Cancer20121233548Search in Google Scholar

Kuehl WM, Bergsagel PL. Early genetic events provide the basis for a clinical classification of multiple myeloma. Hematology Am Soc Hematol Educ Program 2005;2005:346–52.KuehlWMBergsagelPLEarly genetic events provide the basis for a clinical classification of multiple myelomaHematology Am Soc Hematol Educ Program2005200534652Search in Google Scholar

Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012;120:1067–76.KeatsJJChesiMEganJBClonal competition with alternating dominance in multiple myelomaBlood2012120106776Search in Google Scholar

Brioli A, Melchor L, Cavo M, Morgan GJ. The impact of intra-clonal heterogeneity on the treatment of multiple myeloma. Br J Haematol 2014;165:441–54.BrioliAMelchorLCavoMMorganGJThe impact of intra-clonal heterogeneity on the treatment of multiple myelomaBr J Haematol201416544154Search in Google Scholar

Katodritou E, Papadaki S, Konstantinidou P, Terpos E. Is it possible to cure myeloma without allogeneic transplantation? Transfus Apher Sci 2016;54:63–70.KatodritouEPapadakiSKonstantinidouPTerposEIs it possible to cure myeloma without allogeneic transplantation?Transfus Apher Sci2016546370Search in Google Scholar

Maura F, Bolli N, Rustad EH, Hultcrantz M, Munshi N, Landgren O. Moving from cancer burden to cancer genomics for smoldering myeloma: a review. JAMA Oncol 2020;6:425–32.MauraFBolliNRustadEHHultcrantzMMunshiNLandgrenOMoving from cancer burden to cancer genomics for smoldering myeloma: a reviewJAMA Oncol2020642532Search in Google Scholar

Prideaux SM, Conway O’Brien E, Chevassut TJ. The genetic architecture of multiple myeloma. Adv Hematol 2014;2014:864058.PrideauxSMConway O’BrienEChevassutTJThe genetic architecture of multiple myelomaAdv Hematol20142014864058Search in Google Scholar

Landgren O. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: biological insights and early treatment strategies. Hematology Am Soc Hematol Educ Program 2013;2013:478–87.LandgrenOMonoclonal gammopathy of undetermined significance and smoldering multiple myeloma: biological insights and early treatment strategiesHematology Am Soc Hematol Educ Program2013201347887Search in Google Scholar

Landgren O, Kyle RA, Rajkumar SV. From myeloma precursor disease to multiple myeloma: new diagnostic concepts and opportunities for early intervention. Clin Cancer Res 2011;17:1243–52.LandgrenOKyleRARajkumarSVFrom myeloma precursor disease to multiple myeloma: new diagnostic concepts and opportunities for early interventionClin Cancer Res201117124352Search in Google Scholar

Landgren O. Shall we treat smoldering multiple myeloma in the near future? Hematology Am Soc Hematol Educ Program 2017;2017:194–204.LandgrenOShall we treat smoldering multiple myeloma in the near future?Hematology Am Soc Hematol Educ Program20172017194204Search in Google Scholar

Chauhan D, Singh AV, Brahmandam M, et al. Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell 2009;16:309–23.ChauhanDSinghAVBrahmandamMFunctional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic targetCancer Cell20091630923Search in Google Scholar

Mahnke K, Ring S, Johnson TS, et al. Induction of immunosuppressive functions of dendritic cells in vivo by CD4+CD25+ regulatory T cells: role of B7-H3 expression and antigen presentation. Eur J Immunol 2007;37:2117–26.MahnkeKRingSJohnsonTSInduction of immunosuppressive functions of dendritic cells in vivo by CD4+CD25+ regulatory T cells: role of B7-H3 expression and antigen presentationEur J Immunol200737211726Search in Google Scholar

Neri P, Bahlis NJ, Lonial S. New strategies in multiple myeloma: immunotherapy as a novel approach to treat patients with multiple myeloma. Clin Cancer Res 2016;22:5959–65.NeriPBahlisNJLonialSNew strategies in multiple myeloma: immunotherapy as a novel approach to treat patients with multiple myelomaClin Cancer Res201622595965Search in Google Scholar

Ray A, Das DS, Song Y, et al. Targeting PD1-PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells. Leukemia 2015;29:1441–4.RayADasDSSongYTargeting PD1-PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cellsLeukemia20152914414Search in Google Scholar

Rutella S, Locatelli F. Targeting multiple-myeloma-induced immune dysfunction to improve immunotherapy outcomes. Clin Dev Immunol 2012;2012:196063.RutellaSLocatelliFTargeting multiple-myeloma-induced immune dysfunction to improve immunotherapy outcomesClin Dev Immunol20122012196063Search in Google Scholar

Kyle RA, Larson DR, Therneau TM, et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N Engl J Med 2018;378:241–9.KyleRALarsonDRTherneauTMLong-term follow-up of monoclonal gammopathy of undetermined significanceN Engl J Med20183782419Search in Google Scholar

Kyle RA, Durie BGM, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010;24:1121–7.KyleRADurieBGMRajkumarSVMonoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and managementLeukemia20102411217Search in Google Scholar

Kyle RA, San-Miguel JF, Mateos MV, Rajkumar SV. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Hematol Oncol Clin North Am 2014;28:775–90.KyleRASan-MiguelJFMateosMVRajkumarSVMonoclonal gammopathy of undetermined significance and smoldering multiple myelomaHematol Oncol Clin North Am20142877590Search in Google Scholar

Watanaboonyongcharoen P, Nakorn TN, Rojnuckarin P, Lawasut P, Intragumtornchai T. Prevalence of monoclonal gammopathy of undetermined significance in Thailand. Int J Hematol 2012;95:176–81.WatanaboonyongcharoenPNakornTNRojnuckarinPLawasutPIntragumtornchaiTPrevalence of monoclonal gammopathy of undetermined significance in ThailandInt J Hematol20129517681Search in Google Scholar

Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006;354:1362–9.KyleRATherneauTMRajkumarSVPrevalence of monoclonal gammopathy of undetermined significanceN Engl J Med200635413629Search in Google Scholar

Landgren O, Graubard BI, Kumar S, et al. Prevalence of myeloma precursor state monoclonal gammopathy of undetermined significance in 12372 individuals 10–49 years old: a population-based study from the National Health and Nutrition Examination Survey. Blood Cancer J 2017;7:e618.LandgrenOGraubardBIKumarSPrevalence of myeloma precursor state monoclonal gammopathy of undetermined significance in 12372 individuals 10–49 years old: a population-based study from the National Health and Nutrition Examination SurveyBlood Cancer J20177e618Search in Google Scholar

Therneau TM, Kyle RA, Melton LJ, et al. Incidence of monoclonal gammopathy of undetermined significance and estimation of duration before first clinical recognition. Mayo Clin Proc 2012;87:1071–9.TherneauTMKyleRAMeltonLJIncidence of monoclonal gammopathy of undetermined significance and estimation of duration before first clinical recognitionMayo Clin Proc20128710719Search in Google Scholar

Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Melton LJ. Long-term follow-up of 241 patients with monoclonal gammopathy of undetermined significance: The original Mayo Clinic series 25 years later. Mayo Clin Proc 2004;79:859–66.KyleRATherneauTMRajkumarSVLarsonDRPlevakMFMeltonLJLong-term follow-up of 241 patients with monoclonal gammopathy of undetermined significance: The original Mayo Clinic series 25 years laterMayo Clin Proc20047985966Search in Google Scholar

Batko K, Malyszko J, Jurczyszyn A, et al. The clinical implication of monoclonal gammopathies: monoclonal gammopathy of undetermined significance and of renal significance. Nephrol Dial Transplant 2019;34:1440–52.BatkoKMalyszkoJJurczyszynAThe clinical implication of monoclonal gammopathies: monoclonal gammopathy of undetermined significance and of renal significanceNephrol Dial Transplant201934144052Search in Google Scholar

Blade J, Lopez-Guillermo A, Rozman C, et al. Malignant transformation and life expectancy in monoclonal gammopathy of undetermined significance. Br J Haematol 1992;81:391–4.BladeJLopez-GuillermoARozmanCMalignant transformation and life expectancy in monoclonal gammopathy of undetermined significanceBr J Haematol1992813914Search in Google Scholar

Cesana C, Klersy C, Barbarano L, et al. Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. J Clin Oncol 2002;20:1625–34.CesanaCKlersyCBarbaranoLPrognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myelomaJ Clin Oncol200220162534Search in Google Scholar

Baldini L, Guffanti A, Cesana BM, et al. Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy. Blood 1996;87:912–8.BaldiniLGuffantiACesanaBMRole of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathyBlood1996879128Search in Google Scholar

Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005;106:812–7.RajkumarSVKyleRATherneauTMSerum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significanceBlood20051068127Search in Google Scholar

Landgren O, Hofmann JN, McShane CM, et al. Association of immune marker changes with progression of monoclonal gammopathy of undetermined significance to multiple myeloma. JAMA Oncol 2019;5:1293–301.LandgrenOHofmannJNMcShaneCMAssociation of immune marker changes with progression of monoclonal gammopathy of undetermined significance to multiple myelomaJAMA Oncol201951293301Search in Google Scholar

Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009;113:5412–7.LandgrenOKyleRAPfeifferRMKatzmannJACaporasoNEHayesRBMonoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective studyBlood200911354127Search in Google Scholar

Rajan AM, Rajkumar SV. Diagnostic evaluation of monoclonal gammopathy of undetermined significance. Eur J Haematol 2013;91:561–2.RajanAMRajkumarSVDiagnostic evaluation of monoclonal gammopathy of undetermined significanceEur J Haematol2013915612Search in Google Scholar

Mouhieddine TH, Weeks LD, Ghobrial IM. Monoclonal gammopathy of undetermined significance. Blood 2019;133:2484–94.MouhieddineTHWeeksLDGhobrialIMMonoclonal gammopathy of undetermined significanceBlood2019133248494Search in Google Scholar

Melton LJ, Rajkumar SV, Khosla S, Achenbach SJ, Oberg AL, Kyle RA. Fracture risk in monoclonal gammopathy of undetermined significance. J Bone Miner Res 2004;19:25–30.MeltonLJRajkumarSVKhoslaSAchenbachSJObergALKyleRAFracture risk in monoclonal gammopathy of undetermined significanceJ Bone Miner Res2004192530Search in Google Scholar

Bida JP, Kyle RA, Therneau TM, et al. Disease associations with monoclonal gammopathy of undetermined significance: a population-based study of 17,398 patients. Mayo Clin Proc 2009;84:685–93.BidaJPKyleRATherneauTMDisease associations with monoclonal gammopathy of undetermined significance: a population-based study of 17,398 patientsMayo Clin Proc20098468593Search in Google Scholar

van de Donk NWCJ, Palumbo A, Johnsen HE, et al. The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network. Haematologica 2014;99:984–96.van de DonkNWCJPalumboAJohnsenHEThe clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma NetworkHaematologica20149998496Search in Google Scholar

Pepe J, Petrucci MT, Mascia ML, et al. The effects of alendronate treatment in osteoporotic patients affected by monoclonal gammopathy of undetermined significance. Calcif Tissue Int 2008;82:418–26.PepeJPetrucciMTMasciaMLThe effects of alendronate treatment in osteoporotic patients affected by monoclonal gammopathy of undetermined significanceCalcif Tissue Int20088241826Search in Google Scholar

Lomas OC, Mouhieddine TH, Tahri S, Ghobrial IM. Monoclonal gammopathy of undetermined significance (MGUS) – not so asymptomatic after all. Cancers (Basel) 2020;12:1554.LomasOCMouhieddineTHTahriSGhobrialIMMonoclonal gammopathy of undetermined significance (MGUS) – not so asymptomatic after allCancers (Basel)2020121554Search in Google Scholar

Kristinsson SY, Björkholm M, Andersson TML, et al. Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance: a population-based study. Haematologica 2009;94:1714–20.KristinssonSYBjörkholmMAnderssonTMLPatterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance: a population-based studyHaematologica200994171420Search in Google Scholar

Gregersen H, Madsen KM, Sørensen HT, Schønheyder HC, Ibsen JS, Dahlerup JF. The risk of bacteremia in patients with monoclonal gammopathy of undetermined significance. Eur J Haematol 1998;61:140–4.GregersenHMadsenKMSørensenHTSchønheyderHCIbsenJSDahlerupJFThe risk of bacteremia in patients with monoclonal gammopathy of undetermined significanceEur J Haematol1998611404Search in Google Scholar

Gregersen H, Ibsen JS, Mellemkjær L, Dahlerup JF, Olsen JH, Sørensen HT. Mortality and causes of death in patients with monoclonal gammopathy of undetermined significance. Br J Haematol 2001;112:353–7.GregersenHIbsenJSMellemkjærLDahlerupJFOlsenJHSørensenHTMortality and causes of death in patients with monoclonal gammopathy of undetermined significanceBr J Haematol20011123537Search in Google Scholar

Schütt P, Brandhorst D, Stellberg W, et al. Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections. Leuk Lymphoma 2006;47:1570–82.SchüttPBrandhorstDStellbergWImmune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infectionsLeuk Lymphoma200647157082Search in Google Scholar

Leung N, Bridoux F, Hutchison CA, et al. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood 2012;120:4292–5.LeungNBridouxFHutchisonCAMonoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificantBlood201212042925Search in Google Scholar

iStopMM. Int Myeloma Found 2020.iStopMMInt Myeloma Found2020Search in Google Scholar

Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009;23: 3–9.KyleRARajkumarSVCriteria for diagnosis, staging, risk stratification and response assessment of multiple myelomaLeukemia20092339Search in Google Scholar

International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders. Br J Haematol 2003;121:749–57.International Myeloma Working GroupCriteria for the classification of monoclonal gammopathies, multiple myeloma and related disordersBr J Haematol200312174957Search in Google Scholar

Ravindran A, Bartley AC, Holton SJ, et al. Prevalence, incidence and survival of smoldering multiple myeloma in the United States. Blood Cancer J 2016;6:e486.RavindranABartleyACHoltonSJPrevalence, incidence and survival of smoldering multiple myeloma in the United StatesBlood Cancer J20166e486Search in Google Scholar

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30.SiegelRLMillerKDJemalACancer statistics, 2016CA Cancer J Clin201666730Search in Google Scholar

Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007;356:2582–90.KyleRARemsteinEDTherneauTMClinical course and prognosis of smoldering (asymptomatic) multiple myelomaN Engl J Med2007356258290Search in Google Scholar

Lomas OC, Ghobrial IM. Clinical controversies in the management of smoldering multiple myeloma. Am Soc Clin Oncol Educ Book 2020;40:1–6.LomasOCGhobrialIMClinical controversies in the management of smoldering multiple myelomaAm Soc Clin Oncol Educ Book20204016Search in Google Scholar

Kazandjian D, Mailankody S, Korde N, Landgren O. Smoldering multiple myeloma: pathophysiologic insights, novel diagnostics, clinical risk models, and treatment strategies. Clin Adv Hematol Oncol 2014;12:578–87.KazandjianDMailankodySKordeNLandgrenOSmoldering multiple myeloma: pathophysiologic insights, novel diagnostics, clinical risk models, and treatment strategiesClin Adv Hematol Oncol20141257887Search in Google Scholar

Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood 2008;111:785–9.DispenzieriAKyleRAKatzmannJAImmunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myelomaBlood20081117859Search in Google Scholar

Pérez-Persona E, Vidriales MB, Mateo G, et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 2007;110:2586–92.Pérez-PersonaEVidrialesMBMateoGNew criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cellsBlood2007110258692Search in Google Scholar

Pérez-Persona E, Mateo G, García-Sanz R, et al. Risk of progression in smouldering myeloma and monoclonal gammopathies of unknown significance: comparative analysis of the evolution of monoclonal component and multiparameter flow cytometry of bone marrow plasma cells. Br J Haematol 2010;148:110–4.Pérez-PersonaEMateoGGarcía-SanzRRisk of progression in smouldering myeloma and monoclonal gammopathies of unknown significance: comparative analysis of the evolution of monoclonal component and multiparameter flow cytometry of bone marrow plasma cellsBr J Haematol20101481104Search in Google Scholar

Neben K, Jauch A, Hielscher T, et al. Progression in smoldering myeloma is independently determined by the chromosomal abnormalities del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor load. J Clin Oncol 2013;31:4325–32.NebenKJauchAHielscherTProgression in smoldering myeloma is independently determined by the chromosomal abnormalities del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor loadJ Clin Oncol201331432532Search in Google Scholar

Bolli N, Maura F, Minvielle S, et al. Genomic patterns of progression in smoldering multiple myeloma. Nat Commun 2018;9:3363.BolliNMauraFMinvielleSGenomic patterns of progression in smoldering multiple myelomaNat Commun201893363Search in Google Scholar

Dhodapkar MV, Sexton R, Waheed S, et al. Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood 2014;123:78–85.DhodapkarMVSextonRWaheedSClinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120)Blood20141237885Search in Google Scholar

van Laar R, Farmer P, Bender RA, et al. The 70-gene MyPRSR prognostic risk score signature predicts increased risk of progression from MGUS to multiple myeloma requring treatment. Blood 2016;128:3275.van LaarRFarmerPBenderRAThe 70-gene MyPRSR prognostic risk score signature predicts increased risk of progression from MGUS to multiple myeloma requring treatmentBlood20161283275Search in Google Scholar

Hillengass J, Kilk K, Listl K, et al. Over 30% of smoldering myeloma patients have tumor cell bone marrow infiltration patterns similar to multiple myeloma: a large (n=544) clinical study using whole-body MRI. Blood 2012;120:2911.HillengassJKilkKListlKOver 30% of smoldering myeloma patients have tumor cell bone marrow infiltration patterns similar to multiple myeloma: a large (n=544) clinical study using whole-body MRIBlood20121202911Search in Google Scholar

Rajkumar SV. MGUS and smoldering multiple myeloma: update on pathogenesis, natural history, and management. Hematology Am Soc Hematol Educ Program 2005;2005:340–5.RajkumarSVMGUS and smoldering multiple myeloma: update on pathogenesis, natural history, and managementHematology Am Soc Hematol Educ Program200520053405Search in Google Scholar

Hillengass J, Fechtner K, Weber MA, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 2010;28:1606–10.HillengassJFechtnerKWeberMAPrognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myelomaJ Clin Oncol201028160610Search in Google Scholar

Koppula B, Kaptuch J, Hanrahan CJ. Imaging of multiple myeloma: usefulness of MRI and PET/CT. Semin Ultrasound CT MRI 2013;34:566–77.KoppulaBKaptuchJHanrahanCJImaging of multiple myeloma: usefulness of MRI and PET/CTSemin Ultrasound CT MRI20133456677Search in Google Scholar

Mena E, Choyke P, Tan E, Landgren O, Kurdziel K. Molecular imaging in myeloma precursor disease. Semin Hematol 2011;48:22–31.MenaEChoykePTanELandgrenOKurdzielKMolecular imaging in myeloma precursor diseaseSemin Hematol2011482231Search in Google Scholar

Lonial S, Jacobus S, Fonseca R, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol 2020;38:1126–37.LonialSJacobusSFonsecaRRandomized trial of lenalidomide versus observation in smoldering multiple myelomaJ Clin Oncol202038112637Search in Google Scholar

Joseph NS, Dhodapkar MV, Lonial S. The role of early intervention in high-risk smoldering myeloma. Am Soc Clin Oncol Educ Book 2020;40:355–63.JosephNSDhodapkarMVLonialSThe role of early intervention in high-risk smoldering myelomaAm Soc Clin Oncol Educ Book20204035563Search in Google Scholar

Biran N, Vesole DH, Donato ML, et al. Treatment of smoldering myeloma: problems with study design as well as biological and clinical implications. J Clin Oncol 2020;38:1367–8.BiranNVesoleDHDonatoMLTreatment of smoldering myeloma: problems with study design as well as biological and clinical implicationsJ Clin Oncol20203813678Search in Google Scholar

Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood 2015;125:3069–75.RajkumarSVLandgrenOMateosMVSmoldering multiple myelomaBlood2015125306975Search in Google Scholar

Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I – a randomized study. Eur J Haematol 1993;50:95–102.HjorthMHellquistLHolmbergEMagnussonBRödjerSWestinJInitial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I – a randomized studyEur J Haematol19935095102Search in Google Scholar

Barlogie B, van Rhee F, Shaughnessy JD, et al. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood 2008;112:3122–5.BarlogieBvan RheeFShaughnessyJDSeven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic diseaseBlood200811231225Search in Google Scholar

Rajkumar SV, Gertz MA, Lacy MQ, et al. Thalidomide as initial therapy for early-stage myeloma. Leukemia 2003;17:775–9.RajkumarSVGertzMALacyMQThalidomide as initial therapy for early-stage myelomaLeukemia2003177759Search in Google Scholar

Witzig TE, Laumann KM, Lacy MQ, et al. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia 2013;27:220–5.WitzigTELaumannKMLacyMQA phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myelomaLeukemia2013272205Search in Google Scholar

Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 2013;369:438–47.MateosMVHernándezMTGiraldoPLenalidomide plus dexamethasone for high-risk smoldering multiple myelomaN Engl J Med201336943847Search in Google Scholar

Korde N, Roschewski M, Zingone A, et al. Treatment with carfilzomiblenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol 2015;1:746–54.KordeNRoschewskiMZingoneATreatment with carfilzomiblenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myelomaJAMA Oncol2015174654Search in Google Scholar

Hill E, Dew A, Kazandjian D. State of the science in smoldering myeloma: should we be treating in the clinic? Semin Oncol 2019;46:112–20.HillEDewAKazandjianDState of the science in smoldering myeloma: should we be treating in the clinic?Semin Oncol20194611220Search in Google Scholar

Mateos MV, Martinez-Lopez J, Rodriguez-Otero P, et al. Curative strategy (GEM-CESAR) for high-risk smoldering myeloma (SMM): carfilzomib, lenalidomide and dexamethasone (KRd) as induction followed by HDT-ASCT, consolidation with Krd and maintenance with Rd. Blood 2019;134:781.MateosMVMartinez-LopezJRodriguez-OteroPCurative strategy (GEM-CESAR) for high-risk smoldering myeloma (SMM): carfilzomib, lenalidomide and dexamethasone (KRd) as induction followed by HDT-ASCT, consolidation with Krd and maintenance with RdBlood2019134781Search in Google Scholar

Mateos MV, Landgren O. MGUS and smoldering multiple myeloma: diagnosis and epidemiology. Cancer Treat Res 2016;169:3–12.MateosMVLandgrenOMGUS and smoldering multiple myeloma: diagnosis and epidemiologyCancer Treat Res2016169312Search in Google Scholar

Zavidij O, Haradhvala NJ, Mouhieddine TH, et al. Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma. Nat Cancer 2020;1:493–506.ZavidijOHaradhvalaNJMouhieddineTHSingle-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myelomaNat Cancer20201493506Search in Google Scholar

Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood 2017;130:2594–602.MikkilineniLKochenderferJNChimeric antigen receptor T-cell therapies for multiple myelomaBlood20171302594602Search in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo