Smoldering myeloma (SMM) is a clinically heterogeneous disease, with some patients having a slow clinical progression similar to monoclonal gammoplasmosis of undetermined significance (MGUS) and others having a more aggressive course described as “early stage myeloma”. There are no molecular markers to detect risk factors associated with disease progression, and currently the recommended treatment remains follow-up or voluntary enrollment of patients in clinical trials. However, the International Myeloma Working Group (IMWG) agreed on a new definition of active multiple myeloma that may change the timing of SMM treatment. Based on the available data on patient treatment, the recommended treatment for SMM patients will become an increasingly hot topic. Ghobrial et al. of the Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA, reviewed the existing cognitive and disease-progression-related risk factors for this disease, while detecting molecular biological insights and alterations in clonal tumor cells and the bone marrow stromal microenvironment. Finally, results related to clinical trials in patients with SMM are reviewed and recommendations for follow-up of patients with this unique disease are presented. and was published in BLOOD on November 27, 2014. Although effective targeted therapy for multiple myeloma (MM) has been available for the past decade, the clinical utility of targeted therapy has been hampered by drug resistance, clonal evolution, and disease progression, requiring us to further explore this elusive disease. However, the controversial view is that starting treatment when MM is symptomatic is equivalent to treating solid tumors when they metastasize. Therefore, even with the clinical application of the current best drug combination regimen, most patients are still not cured. Therefore, most people are beginning to explore the question of whether treatment is needed in the prodromal asymptomatic phase of MM, with the ultimate goal of halting disease progression and achieving cure. MM can progress continuously from the prodromal state MGUS and SMM, which indicates that the tumor load remains a continuously progressive process in the absence of symptoms or signs of end-organ damage. The authors review what is known about SMM today, including the clinical risk factors that can contribute to disease progression. The recommended treatment for most patients now remains long-term follow-up observation or clinical registration trials. However, the definition of active MM and indications for treatment were recently agreed upon by the IMWG. Based on the available data for the treatment of SMM, long-term and sustained remission has shown significant improvements in progression-free survival (PFS) and overall survival (OS). Based on the above reasonable presentation, it gives us reason to believe that treatment of SMM will become a hot topic in the near future. Case description A 42-year-old pediatrician presented to the clinic with a blood test that revealed the presence of monoclonal protein in the serum. Routine laboratory tests revealed an elevated protein level of 9.5 g/dL (reference range: 6.0-8.0 g/dL). Serum protein electrophoresis showed immunoglobulin (Ig) A κ light chain of 3.5 g/dL. There was no bone pain, fever, or weight loss. Serum creatinine level and calcium ion concentration were within normal range. κ light chain was elevated and κ/λ ratio was 30. serum IgG and IgM levels were decreased. Further examination did not reveal osteolytic lesions, and MRI did not show focal damage. Bone marrow biopsy revealed 30% plasma cells in a single, clustered, sheet-like distribution. Abnormal plasma cells could be isolated by immunophenotyping 95% of these abnormal plasma cells expressed CD38, CD138, CD56 by flow cytometry, with cytoplasmic overproduction of κ light chains and abnormal staining. Cytogenetics and fluorescence in situ hybridization showed an increased long arm of one chromosome 1. How to diagnose patients with SMM and initial evaluation SMM is a clinically heterogeneous disease with a higher risk of disease progression than MGUS, and the timing of treatment is unclear because of the lack of end-organ damage that meets diagnostic criteria for MM. In 2003, the IMWG formed a unified definition of MGUS and SMM, with MGUS defined as serum M protein <3 g/dL along with <10% monoclonal plasma cells in the bone marrow, while SMM was defined as serum M protein ≥3 g/dL or ≥10% monoclonal cells in the bone marrow (Table I), both without end-organ damage. Criteria for end-organ damage CRAB definition: hypercalcemia (serum calcium ≥11.5 mg/dL), renal failure (creatinine ≥1.95, excluding other causes), anemia (hemoglobin ≤10 g/dL or more than 2 g/dL below the low limit of normal), bone damage (osteolytic changes, pathologic fractures, spinal cord compression). tests required for grading SMM patients are analogous to those required for MM diagnosis ( Table II), the diagnosis of SMM requires an adequate tumor cell load and monoclonal protein in the bone marrow, but lacks symptoms or signs of end-organ damage. Recent recommendations include spine and pelvis MRI or low-dose CT for more timely prediction of disease (see SMM imaging studies section for details). Recently expanded criteria for clinical diagnosis and early treatment of MM with significant progression include bone marrow plasma cells ≥ 60%, an involved free light chain (FLC) to non-involved light chain ratio ≥ 100, and/or focal bone marrow lesions seen by functional imaging such as PET-CT and/or MRI ≥ 2. One of the SMM imaging study CARB criteria defining symptomatic MM requires the presence of osteolytic damage, previously MRI can provide the actual tumor load. When SMM patients present with ≥2 focal bone marrow lesions, they can progress to active MM in a very short period of time, making it a new criterion for starting treatment for MM. In addition, CT can detect bone damage earlier, and low-dose CT has been used in some studies as a means of detecting end-organ damage. In addition to this, functional techniques include such as PET (PET-CT or PET-MRI), dynamic-enhanced MRI, and diffusion-weighted imaging MRI, which can provide functional disease activity information. SMM follow-up, assessment of risk factors and chance of progression The incidence and prevalence of SMM is unclear and is estimated to account for 8% to 20% of MM. In a recent review of 2494 myeloma patients in the Swedish myeloma registry from 2008 to 2011, 360 (14.4%) were eligible for SMM. 104 (28.8%) of these SMM patients were of high-risk type (defined as M protein ≥3 g/dL and plasma cell infiltration ≥10%), representing 4.2% of all myeloma patients. Using the world population as a reference, the age-standardized incidence of SMM was 0.44 cases/100,000 and the incidence of the high-risk type was 0.14 cases/100,000. Based on the Mayo Clinic retrospective study, the overall risk of SMM progressing to MM is 10%/year for the first 5 years, 3%/year for the next 5 years, and 1%/year for the last 10 years, above showing a high biological and clinical heterogeneity of SMM as currently defined. The frequency of follow-up of these SMM patients depends on the above mentioned risk factors for disease progression, and the 2010 IMWG guidelines suggest that SMM patients should be tested every 2 to 3 months for the first year, followed by 4 to 6 months per year, and eventually 6 to 12 months if clinically stable. The authors of this article recommend that patients with high-risk SMM should be followed more intensively (at least every 3 months if they are not receiving treatment). Indeed, SMM is a heterogeneous clinical disease, meaning that some patients are in a very inert process, similar to the MGUS-like stage, yet others have a more aggressive clinical process, i.e. patients with myeloma described as early-stage myeloma or CRAB-negative myeloma. There are currently no molecular factors that distinguish these two clinically to biologically distinct subgroups, and further studies are needed to determine the hallmarks of these progressive patients. Current risk factors associated with disease progression are based primarily on the level of tumor load in SMM patients through analysis of the extent of tumor cell involvement in the bone marrow and quantification of peripheral blood monoclonal proteins. Both of these factors are widely used for risk stratification by the Mayo Clinic and by the Spanish Programapara et Tratamiento de Hemopatias Malignas (PETHEMA) study group. The Mayo Clinic based mainly on serum protein marker levels (serum protein electrophoresis and FLC analysis) and percentage of plasma cells in the bone marrow. the PETHEMA study group risk stratification focused on applying bone marrow multiparametric flow cytometry to quantify the ratio of abnormal plasma cells in the bone marrow, and the reduction of uninvolved globulins. However, there were significant differences between the two organizations' assessments, i.e., many patients had one criterion suggesting high risk and the other suggesting low risk. Other detectable risk factors include IgA (vs IgG type) phenotype, proteinuria, peripheral blood plasma cell count, high rate of plasma cell proliferation in the bone marrow, and abnormal MRI presentation. Recent studies have shown that plasma cell chromosomal abnormalities are also a key factor in SMM progression. Two studies have shown that 17q deletion or t(4;14) is associated with the shortest time to progression (TTP), while triploidy is also a risk factor for progression. increased mutations in chromosome 1q21 can also increase the risk of progression in patients with SMM. Therefore, patients diagnosed with SMM should first be risk stratified (applying both Mayo criteria and PETHEMA criteria). In addition, other high-risk progression factors such as cytogenetics, peripheral plasma cell counts, changes in serum protein electrophoresis M peak and MRI imaging changes should be taken into account. Clearly, the old classification of "ultra-high risk" should be reclassified as MM with a significant risk of progression requiring clinical intervention. These patients include: bone marrow plasma cells ≥ 60%, abnormal FLC ratio ≥ 100 (κ chain involvement) or < 0.01 (λ chain involvement), and/or focal bone lesions ≥ 2 on PET-CT and/or MRI imaging. The patient mentioned above was diagnosed as high-risk according to Mayo Clinic and PETHEMA evaluation criteria. Therefore, this patient may have a more rapid clinical progression with a 5-year progression incidence of 70% to 80%. Choosing a treatment option for SMM: observation or early treatment The standard treatment today for patients diagnosed with SMM is a watchful waiting strategy. However, clinical trials showing different PFS and OS in patients with SMM have led to a possible change in this standard of care. The SMM patient mentioned above showed rapid progression after one year of follow-up, with a bone marrow biopsy suggesting 70% plasma cells. Based on CRAB criteria, this patient showed no other evidence of symptomatic MM, but needed to be started on treatment based on the current redefinition of high-risk SMM patients as myeloma with a "myeloma-defining event (MDE)" with a significant risk of progression. Therefore, the latest classification change treats patients who meet the criteria for MDE as symptomatic MM. Such patients should be excluded from future SMM clinical trial studies. The idea that early interventional therapy can significantly improve outcomes has been tested for many years. There are two main ideas for interventional therapy, the first is to stop disease progression; the second is etiologic therapy, which attempts to eradicate subclonal cells at an early stage of the disease to achieve complete remission or even a cure. The main obstacle to early intervention is the definition of the patient population that would really benefit from early treatment. In fact, if SMM is a mixture of early-stage myeloma and MGUS-like myeloma, early-stage MM is the only patient who really needs intervention. Unfortunately, there are no biological markers to suggest SMM disease progression, except for tumor load indicators in risk stratification. The first application of marfalan and prednisone to test the early intervention treatment hypothesis in the 1990s did not show an advantage in terms of survival. Subsequent SMM studies in which bisphosphonates were applied (including 2 randomized controlled studies) showed no improvement in OS or time to progression, but a reduction in bone-related events. The next drug in the trial was thalidomide. The thalidomide/zoledronic acid group significantly improved PFS compared to the zoledronic acid-only group, 29 and 14 months, respectively, but there was no difference in PFS (49 and 40 months, respectively) or OS (6-year OS, 70%) between the two groups as defined by CRAB events. The results of the most important study on SMM, the PETHEMA Study Group, which designated lenalidomide and dexamethasone as the intervention treatment group and compared it with the observation group, ignited great interest. dexamethasone), with the treatment group having higher 3-year progression-free survival (77%, 30%, respectively) and OS (94%, 80%, respectively). However, enrollment required meeting 1 or more of 2 sets of high-risk disease definition (Mayo Clinic or PETHEMA risk stratification criteria) criteria. However, there are some concerns about the generalized findings of this trial, and care needs to be taken to compare different clinical trials and trial results. Therefore, every effort should be made to collect information on all risk factors for disease progression. In addition, this study was inadequate in that it did not clarify the asymptomatic biological progression in both groups, the transient OS in the dropout group, and the salvage treatment in the dropout group. For these reasons, further studies are needed before implementing treatment criteria for high-risk SMM interventions. However, this study was challenging enough to inspire the development of many clinical trials investigating the treatment of high-risk SMM. Many drugs have been tested, including carfilzomib/lenalidomide in combination with dexamethasone, the latest immunotherapies such as targeting 7-elotuzumab, a member of the signaling lymphocyte activating molecule family, CD38-targeting antibodies, and programmed cell death-1 targeting antibodies. Recommendations Based on the current definition of SMM, SMM is not a unique biological disease, but a step in the ongoing clonal evolution and progression of tumor cells in the bone marrow microenvironment that eventually leads to symptomatic MM. However, by understanding SMM, it gives us to understand the biological steps of disease progression, so that disease progression or even cure can be halted/delayed by targeted attacks on tumor cells and thus interventional therapy before significant clonal heterogeneity occurs, immune disorders and abnormal regulation of the bone marrow microenvironment. Previous attempts by scientists to test the hypothesis of early intervention to halt progression or cure myeloma have failed. It was not until lenalidomide in combination with dexamethasone showed promising findings that early intervention has a survival advantage. However, more pilot studies are needed before this finding can be adopted clinically.The biggest practice change in SMM today is the reclassification of a subset of high-risk SMM patients as MM with MDE at significant risk of progression, and the treatment of these patients should be equivalent to that of symptomatic patients. For all other patients with SMM, the authors suggest that they should also be carefully monitored or enrolled in clinical trials to better assess the role of early intervention in this disease. We believe that a more meaningful molecular profile could be used to identify patients with early stage myeloma who are at high risk of progression to symptomatic MM and MGUS-like stages that do not benefit from treatment. Although formal testing and confirmation are still needed, we speculate that early stage myeloma is less genetically unfavorable and that some patients can achieve cure with the application of available effective drugs. Ongoing and future studies are expected to provide answers to these questions.