Smoldering multiple myeloma

INTRODUCTION — Smoldering multiple myeloma (SMM) is diagnosed in persons who meet the following criteria (table 1) [1,2]:

●Serum monoclonal (M) protein ≥3 g/dL and/or 10 to 59 percent bone marrow clonal plasma cells.

●Absence of lytic lesions, anemia, hypercalcemia, and kidney impairment (end-organ damage) that can be attributed to the plasma cell proliferative disorder and the absence of biomarkers associated with near inevitable progression to end-organ damage (≥60 percent clonal plasma cells in the marrow; involved/uninvolved free light chain [FLC] ratio of ≥100 with involved FLC >100 mg/dL; or more than one focal bone lesion on magnetic resonance imaging [MRI]).

SMM is distinguished from multiple myeloma (MM) based on the lack of myeloma-defining events; it is distinguished from monoclonal gammopathy of undetermined significance (MGUS) based on the size of the M protein and the percentage of plasma cells in the bone marrow (table 2 and algorithm 1 and table 3).

The clinical course and management of patients with SMM will be discussed here. The diagnosis of this and other plasma cell dyscrasias, the recognition of serum or urinary M proteins, and the management of symptomatic MM are presented separately.

●(See "Multiple myeloma: Overview of management".)

●(See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

●(See "Diagnosis of monoclonal gammopathy of undetermined significance".)

●(See "Clinical course and management of monoclonal gammopathy of undetermined significance".)

●(See "Laboratory methods for analyzing monoclonal proteins".)

DEFINITIONS

●Smoldering multiple myeloma – Smoldering multiple myeloma (SMM) is defined as a monoclonal (M) protein ≥3 g/dL and/or 10 to 59 percent bone marrow plasma cells but no end-organ damage (lytic lesions, anemia, kidney disease, or hypercalcemia) that can be attributed to the underlying plasma cell disorder or other myeloma-defining events, and no amyloidosis (table 1) [1,2].

Thus, for the diagnosis of SMM, patients should not have any of the following myeloma-defining events:

•End-organ damage (lytic lesions, anemia, kidney disease, or hypercalcemia) that can be attributed to the underlying plasma cell disorder.

•≥60 percent clonal plasma cells in the bone marrow [3,4].

•Involved/uninvolved free light chain (FLC) ratio ≥100 with involved FLC >100 mg/dL [5-7].

•MRI with more than one focal lesion >5 mm (involving bone or bone marrow) [8-11].

Asymptomatic patients with one or more of the myeloma-defining events listed above are considered to have multiple myeloma (MM) rather than SMM because they have a risk of progression with complications of greater than 80 percent within two years [1]. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnostic criteria'.)

●Differentiation from MGUS – SMM is differentiated from monoclonal gammopathy of undetermined significance (MGUS) based on the size of the M protein and the level of bone marrow involvement (table 2 and table 3). It is considered a separate premalignant entity because the risk of progression is much higher than with MGUS especially during the first five years (10 percent per year for the first five years versus 1 percent per year, respectively). As a result, patients with SMM need more frequent follow-up compared with patients with MGUS, at least during the first five years.

●Differentiation from MM – SMM is differentiated from MM based on either the presence of end-organ damage or on the presence of at least one of the three biomarkers described above that accurately identify a subset of patients who are at imminent risk of developing end-organ damage (table 2 and table 1). If there are doubts about the differentiation of MGUS/SMM from MM and whether to begin treatment, one should re-evaluate in two or three months. Importantly, to be considered a criterion for the diagnosis of MM, the end-organ damage must be due to the plasma cell disorder. Examples of comorbidities that may mimic end-organ damage include kidney impairment related to hypertension or diabetes and anemia due to iron or vitamin deficiency. This is discussed in more detail separately. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnostic criteria'.)

The management of MM and indications for treatment are presented in more detail separately. (See "Multiple myeloma: Overview of management", section on 'Verify the diagnosis'.)

EPIDEMIOLOGY — There are limited data regarding the epidemiology of smoldering multiple myeloma (SMM) since it is an asymptomatic condition without a routine screening program.

The best data come from the iStopMM population-based study from Iceland in which >75,000 asymptomatic adults over age 40 were screened with serum protein electrophoresis and serum free light chain assay [12]. Bone marrow biopsy was used to evaluate those with monoclonal paraprotein detected.

The prevalence of SMM in this population was 0.5 percent overall (95% CI 0.49-0.57 percent). Rates were higher in males (0.7 percent, 95% CI 0.62-0.73 percent) than in females (0.4 percent, 95% CI 0.35-0.43 percent), and increased with age from <0.25 percent in those under 50 years to >1 percent in those over 80 years.

Among the 193 individuals with SMM, median age was 70 years (range 44 to 92 years), and 60 percent were male. The mean M protein concentration was 0.62 g/dL (range 0.01 to 3.5 g/dL) and 73 percent had 11 to 20 percent bone marrow plasma cell infiltration.

CLINICAL COURSE — The natural history of patients with smoldering multiple myeloma (SMM) is variable. Patients progress to symptomatic myeloma or AL amyloidosis at approximate rates of (table 4) [13]:

●10 percent per year for the first five years

●3 percent per year for the next five years

●1 to 2 percent per year for the following 10 years

As such, most patients with SMM will progress with a median time to progression of 4.8 years. A simple risk stratification schema can identify those patients who are more or less likely to progress over the next two years and can guide therapy (algorithm 2). (See 'Risk stratification' below.)

MANAGEMENT

Risk stratification — We risk stratify individuals with smoldering multiple myeloma (SMM) using the Mayo 2018/International Myeloma Working Group (IMWG) risk stratification system (also called the 20/2/20 criteria), which takes into consideration the following three risk factors for progression [14]:

●Bone marrow plasma cells >20 percent

●Monoclonal (M) protein >2 g/dL

●Involved/uninvolved free light chain (FLC) ratio >20

In one analysis of 417 patients with SMM diagnosed according to 2014 diagnostic criteria and followed without intervention, these risk factors were able to stratify patients into three risk groups with distinctly different patterns of progression [1,14]:

●High risk (two or three factors present) – Estimated median time to progression (TTP) 29 months; estimated risk of progression of 24 percent per year during the first two years, 11 percent per year for the next three years, and 3 percent per year for the next five years.

●Intermediate risk (one factor present) – Estimated median TTP 68 months; estimated rate of progression of 15 percent per year during the first two years, 7 percent per year for the next three years, and 4 percent per year for the next five years.

●Low risk (no factors present) – Estimated median TTP of 110 months; estimated rate of progression of 5 percent per year during the first 10 years.

The 20/2/20 criteria were validated in a retrospective analysis of 1151 patients with SMM [15]. The estimated progression rates at two years were 6, 18, and 44 percent among those with low-risk, intermediate-risk, and high-risk disease, respectively.

Additional risk factors for progression that have been identified in some, but not all, studies include (table 5):

●Immunoglobulin A (IgA) isotype [13].

●Immunoparesis with reduction of two uninvolved immunoglobulin isotypes [13,16,17].

●Abnormal plasma cell immunophenotype with immunoparesis (reduction of ≥1 uninvolved immunoglobulin isotypes) [17,18]. In contrast, an MGUS-like immunophenotype on flow cytometry may be associated with a lower risk of progression [19].

●Increased circulating plasma cells by immunofluorescence [20] or flow cytometry [21].

●Detection of lesions on MRI of the spine and pelvis [22], evolving pattern of M-spike [23,24].

●Presence of Bence Jones proteinuria in IgG or IgA SMM [25].

●PET/computed tomography (CT) with focal lesion with increased uptake without underlying osteolytic bone destruction [26,27].

While initial studies suggest genetic features may impact prognosis (table 6), these results must be validated and compared with clinical features before they can be routinely applied to clinical practice.

In one study, TTP and overall survival (OS) were shorter in patients with t(4;14) when compared with those with t(11;14) [28]. A trend toward shorter TTP has also been seen in patients with deletion 17p, gain 1q21, and hyperdiploidy [28,29].

The impact of genetic changes on prognosis appears to be strongest in patients with a low tumor burden. In a prospective study of 179 patients with SMM, those with a high-risk gene expression profile signature had a higher rate of progression to symptomatic multiple myeloma (MM) at two years (51 versus 12 percent) [30].

Management of low- or intermediate-risk SMM — Observation with deferral of treatment until disease progression is standard for patients with low-risk SMM (algorithm 2). For patients with intermediate-risk SMM, we also suggest close observation rather than treatment. A clearly increasing level of the M protein in the serum or urine suggests that therapy will be needed in the near future.

Some patients with low-risk or intermediate-risk SMM can remain stable without treatment over extended periods of time, and it is not clear that treatment with available therapies improves outcomes [2,31-34]. In randomized studies that compared melphalan-based therapy at diagnosis versus deferral of chemotherapy until progression, early treatment delayed progression, but did not improve OS, and was associated with an increase in acute leukemia [32]. In addition, a subgroup analysis of the randomized trial comparing single-agent lenalidomide versus observation in SMM did not demonstrate a progression-free survival (PFS) or OS benefit in those with low-risk or intermediate-risk SMM [35]. (See 'Management of high-risk SMM' below.)

Monitoring for progression — Our approach to monitoring individuals with low- or intermediate-risk SMM is similar to that suggested by the IMWG [1,36,37]. At the time of diagnosis, we perform the following to rule out end-organ damage and other findings that are diagnostic of MM:

●Laboratory studies should include a serum protein electrophoresis (SPEP), complete blood count (CBC), serum creatinine, serum calcium, urine protein electrophoresis (UPEP) with immunofixation, FLC ratio, and bone marrow biopsy.

●Cross-sectional imaging with either low-dose whole-body CT without contrast or whole-body combined fluorine-18-labeled fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT), followed by a whole-body MRI or MRI of the spine and pelvis. Conventional skeletal surveys are no longer a preferred imaging modality. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Choice of modality'.)

Two to three months after this testing, we again measure the SPEP, CBC, creatinine, calcium, FLC ratio, UPEP, and urine immunofixation. If the results of these tests are stable, the span of time between testing can be lengthened to every four to six months for one year, then to every 6 to 12 months. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Evaluation'.)

Follow-up imaging studies must balance the potential cost and toxicity with the risk of progression [37].

●For patients with SMM and no lesions on initial CT (or PET/CT) and MRI, we perform annual MRI to monitor for the development of asymptomatic bone lesions.

●For patients with SMM whose initial imaging demonstrated one focal lesion on MRI, we image every six months, alternating whole-body MRI and whole-body low-dose CT or PET/CT.

Other patients who may warrant imaging every six months include those with diffuse infiltration of the bone marrow on initial MRI and those with equivocal findings on initial imaging. In patients with otherwise asymptomatic myeloma, the identification of more than one focal bone lesion on MRI is diagnostic of MM and an indication for therapy. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnostic criteria'.)

The importance of monitoring M protein and hemoglobin levels was illustrated in a single-center retrospective study of 190 patients with SMM, which identified those with two to three of the following risk factors as having a high risk of progression within two years, thereby potentially meriting further work-up and/or therapy [24]:

●An evolving monoclonal protein level (eMP) defined as an increase in the M protein level of ≥25 percent within the first 12 months (minimum increase ≥0.5 g/dL) and/or a ≥10 percent increase within the first six months of diagnosis in patients with a baseline M protein ≥3 g/dL.

●An evolving change in hemoglobin (eHb) defined as decrease in hemoglobin concentration by ≥0.5 g/dL within 12 months of diagnosis.

●Bone marrow plasma cells ≥20 percent.

The median time to progression was 12, 5, 2, and 1 years among patients with zero, one, two, and three risk factors respectively. The two-year progression risk was 82 percent in individuals who demonstrated both eMP and eHb, and 91 percent in those with all three risk factors. (See 'Management of high-risk SMM' below.)

Monitoring for complications — Patients with SMM are at increased risk for complications, including:

●Osteoporosis – Patients with SMM should be evaluated for osteoporosis with a dual energy x-ray absorptiometry (DEXA) scan and have their vitamin D and calcium intake optimized. If osteoporosis is present, treatment with bisphosphonates may be considered at the same dosing and schedule used for osteoporosis in patients without SMM. Analogs of PTH (eg, teriparatide) and PTH-related protein (eg, abaloparatide) are generally avoided due to their tendency to exacerbate hypercalcemia. (See "Multiple myeloma: The use of osteoclast inhibitors", section on 'Use in smoldering MM, MGUS, or solitary plasmacytoma'.)

●Thromboembolism – There is an increased incidence of venous thromboembolic disease (VTE) and arterial thrombosis in patients with plasma cell dyscrasias, including SMM [38-40]. While the mechanisms involving this increased incidence are unclear, a hypercoagulable state secondary to an ongoing clonal plasma cell activity has been suggested [40,41]. Despite this, SMM itself is not an indication for VTE prophylaxis or specific avoidance of medications that increase risk for VTE. (See "Multiple myeloma: Prevention of venous thromboembolism".)

●Infections – Patients with plasma cell dyscrasias have an increased risk of developing bacterial and viral infections over that seen in the general population. There are limited data regarding the magnitude of this risk, but it likely falls between that of monoclonal gammopathy of undetermined significance (MGUS; approximately twofold increased risk [42,43]) and that of symptomatic MM (approximately sevenfold increased risk [44]). For most patients, we follow standard age-based vaccine recommendations that do not differ from the general population. For patients who begin myeloma-directed therapy, we follow an approach similar to that used for patients treated for MM. (See "Infections in patients with multiple myeloma".)

●Second cancers – Persons with MGUS, SMM, and MM also have a higher incidence of developing second cancers [45]. We recommend that patients with SMM be encouraged to participate in age-appropriate cancer screening programs. No additional cancer screening has been recommended for this population. (See "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Second malignancies'.)

Management of high-risk SMM — For patients with high-risk SMM by the Mayo 2018/IMWG 20/2/20 criteria, we recommend treatment with single-agent lenalidomide or lenalidomide plus dexamethasone rather than observation, as this approach has been shown to prevent end-organ damage (algorithm 2). Clinical trials are evaluating other approaches such as single-agent daratumumab and more intensive combination regimens [46,47]; such approaches should be reserved for clinical trials. Patients who want to delay therapy need close observation with evaluation for progression every three to four months, and treatment if there is evidence of progression or an evolving pattern (rising M protein or FLC level). Those with baseline abnormalities on MRI (diffuse infiltration, solitary focal lesion, or equivocal lesions) should have a repeat MRI in three to six months.

Lenalidomide-based therapy should mimic one of the protocols used in the randomized trials described below. Options include:

●Lenalidomide 25 mg on the first 21 days of each 28-day cycle, continued as tolerated for up to two years [35].

●Lenalidomide 25 mg on the first 21 days of each 28-day cycle plus dexamethasone 40 mg weekly [18]. After nine cycles, reduce the lenalidomide dose to 10 mg and discontinue dexamethasone. Continue as tolerated for up to two years.

Adjustments are needed for those with kidney dysfunction, and routine antithrombotic prophylaxis is warranted for all. Lenalidomide is myelosuppressive and we advise stem cell collection after four cycles in transplant-eligible patients. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Immunomodulatory drugs'.)

Two randomized trials have compared lenalidomide-based therapy versus observation in high-risk SMM [18,35,48,49]. The trials differed in selection criteria, the definition used for high-risk SMM, and in the treatment regimen. Both demonstrated an 80 to 90 percent risk reduction in end-organ damage. One demonstrated an improvement in OS [18,48,49].

A multicenter randomized trial compared single-agent lenalidomide versus observation in 182 patients with SMM [35]. SMM diagnosis was made using 2014 IMWG criteria and required cross sectional imaging. All patients were risk stratified using the Mayo 2018/IMWG (20/2/20) criteria. Progression was defined as the development of symptomatic MM as evidenced by biochemical disease progression or related end-organ damage. After a median follow-up of 35 months, the following were noted:

●Lenalidomide improved PFS in the entire study population (93 versus 76 percent at two years; HR 0.28, 95% CI 0.12-0.62). In the lenalidomide arm, there were fewer progression events due to end-organ damage, including fewer cases of kidney failure (0 versus 3 events) and bone lesions (3 versus 11 events).

●On subgroup analysis, the PFS benefit was clear in patients with high-risk SMM (HR 0.09, 95% CI 0.02-0.44) but did not reach statistical significance in those with intermediate-risk SMM (HR 0.52, 95% CI 0.15-1.85).

●Longer follow-up is needed to evaluate OS. There were two deaths in the lenalidomide arm and four deaths in the observation arm (HR for death 0.46, 95% CI 0.08-2.53).

●Most toxicities were managed with dose modifications. Approximately 20 percent of patients stopped lenalidomide early due to toxicities.

Another multicenter randomized trial compared immediate treatment with lenalidomide plus dexamethasone (Rd) for nine cycles followed by single-agent lenalidomide to complete a total treatment duration of two years versus observation until progression in 119 patients with SMM at high risk of progression [18,48,49]. SMM diagnosis was made based on the absence of end-organ damage and did not incorporate modern biochemical diagnostic criteria or cross-sectional imaging. In this study, high-risk SMM was defined as:

●≥10 percent clonal bone marrow plasma cells plus presence of a monoclonal component (serum IgG ≥3 g/dL, IgA ≥2 g/dL, or Bence-Jones proteinuria >1 g/24 hours); or

●One of the two criteria above plus aberrant plasma cell immunophenotype in >95 percent of clonal plasma cells and immunoparesis (reduction in one or more uninvolved immunoglobulins by more than 25 percent compared with normal)

At a median follow-up of 12.5 years, immediate treatment with Rd resulted in:

●Improved PFS (median 9.5 years versus 2.1 years; HR 0.28; 95% CI 0.18-0.44).

●Improved OS (median not reached versus 8.5 years; HR 0.57; 95% CI 0.34-0.95).

●One treatment-related death (a respiratory infection). Severe (grade 3/4) toxicities included infection (6 percent), asthenia (6 percent), neutropenia (5 percent), rash (3 percent), and more second primary malignancies (6 versus 1).

Interpretation of this study can be limited by the method used to define high-risk SMM, which required flow cytometric assessment of plasma cell immunophenotype in approximately 50 percent of patients, although the classic Mayo Model was also used, and 45 percent of the patients met its criteria for the definition of high-risk. The median age of the control group was higher than the treatment group.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple myeloma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●(See "Patient education: Multiple myeloma (The Basics)".)

SUMMARY AND RECOMMENDATIONS

●Definition and distinction from other entities – Smoldering multiple myeloma (SMM) is defined as a monoclonal (M) protein ≥3 g/dL and/or 10 to 59 percent bone marrow plasma cells but no end-organ damage (lytic lesions, anemia, renal disease, or hypercalcemia) that can be attributed to the underlying plasma cell disorder or other myeloma-defining events, and no amyloidosis (table 1). Patients with SMM are distinguished from those with monoclonal gammopathy of undetermined significance (MGUS) by the size of the M protein and the level of bone marrow involvement, and from multiple myeloma (MM) by the absence of any myeloma-defining event (table 2 and algorithm 1 and table 3). (See "Multiple myeloma: Overview of management", section on 'Verify the diagnosis' and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Diagnosis'.)

●Natural history – The natural history of patients with SMM is variable. Patients with SMM will progress to symptomatic MM or AL amyloidosis at an approximate rate of 10 percent per year for the first five years, 3 percent per year for the next five years, and 1 to 2 percent per year for the following 10 years. As such, most patients with SMM will progress with a median time to progression of 4.8 years. (See 'Clinical course' above.)

●Risk stratification – We risk stratify individuals with SMM using the Mayo 2018/IMWG risk stratification system (also called the 20/2/20 criteria). Individuals with two or three of the following risk factors are considered to have high-risk SMM (see 'Risk stratification' above):

•Bone marrow plasma cells >20 percent

•M protein >2 g/dL

•Involved/uninvolved free light chain (FLC) ratio >20

●Management of low- and intermediate-risk SMM – Observation with deferral of treatment is standard for patients with low-risk SMM (algorithm 2). For patients with intermediate-risk SMM, we suggest observation rather than treatment (Grade 2B). Some patients with low-risk or intermediate-risk SMM can remain stable without treatment over extended periods of time, and it is not clear that treatment with available therapies improves outcomes. (See 'Monitoring for progression' above.)

Prompt initiation of therapy is indicated in patients with MM. The following findings, if attributable to the underlying plasma cell disorder, are diagnostic of MM (table 1): anemia, hypercalcemia, kidney impairment, lytic bone lesions, and extramedullary plasmacytoma. In addition, the following are diagnostic biomarkers of MM in the absence of symptoms: ≥60 percent clonal plasma cells in the marrow; involved/uninvolved FLC ratio ≥100; or more than one focal bone lesion on MRI. (See "Multiple myeloma: Overview of management", section on 'Verify the diagnosis'.)

●Management of high-risk SMM – For patients with high-risk SMM, we recommend treatment with single-agent lenalidomide or lenalidomide plus dexamethasone rather than observation (algorithm 2) (Grade 1B). In this population, early treatment prevents end-organ damage and may improve overall survival. More intensive regimens should be reserved for clinical trials. (See 'Management of high-risk SMM' above.)