Smoldering Multiple Myeloma (SMM): Observation versus Control versus Cure

INTRODUCTION

Monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM) are part of a spectrum of clonal plasma cell proliferative disorders.¹ MGUS is a classic pre-malignancy and does not require intervention, while MM at the other end of the spectrum is a clear malignancy that is fatal without therapy. SMM is an is an asymptomatic, intermediate, clinically defined entity comprised of a heterogeneous mix of patients, approximately two-thirds with MGUS (premalignancy) and one-third with MM (malignancy). Due to significant overlap in cytogenetic and molecular features it is not easy to differentiate SMM who have MGUS versus MM using clinical or laboratory tests. Several risk stratification models have been developed to identify the subset of patients with SMM in whom malignant transformation has likely occurred (high risk SMM) to enable appropriate counseling and patient care. While observation is the standard of care in low/intermediate risk SMM which is enriched for patients likely in the MGUS (premalignant) stage, early intervention studies have targeted high risk SMM in an attempt to delay progression (control) or to eradicate the clone (cure). In this article, diagnostic criteria, risk stratification models, and the various approaches to manage SMM (observation, control, and cure) are discussed.

DIAGNOSTIC CRITERIA AND CLINICAL FEATURES

MGUS, SMM, and MM are differentiated from each other using the criteria listed in Table 1.² MGUS present in 5% of the general population over the age of 50,^3–5 with a 1% per year risk of progression to malignancy.^6,7 SMM is present in approximately 0.5% of the population above the age of 40 years,⁸ and is associated with a risk of progression to symptomatic malignancy of approximately 10% per year for the first 5 years following diagnosis, 3% per year over the next 5 years, and 1.5% per year thereafter.⁹ Although both disorders are asymptomatic, it is important to keep the categories separate for clinical reasons since the risk of progression of SMM is 10 times higher than MGUS in the first 5 years following diagnosis.¹⁰ This affects patient counseling and follow up as well as the intensity of intervention strategies. In MGUS, the lifetime risk of progression to MM is only approximately 10% after adjusting for competing causes of death, whereas the risk of progression in SMM is 50% within 2 years in the high risk SMM subset. Intervention strategies in which the risk of progression is very low (MGUS) should differ markedly from ones in which the risk is considerable.

Table 1.

International Myeloma Working Group Diagnostic Criteria for MGUS, SMM, and Multiple Myeloma and Related Plasma Cell Disorders

Disorder	Disease Definition
IgM Monoclonal gammopathy of undetermined significance (IgM MGUS)	All 3 criteria must be met:  • Serum IgM monoclonal protein <3gm/dL  • Bone marrow lymphoplasmacytic infiltration <10%  • No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder.
Non-IgM monoclonal gammopathy of undetermined significance (MGUS)	All 3 criteria must be met:  • Serum monoclonal protein (non-IgM type) <3gm/dL  • Clonal bone marrow plasma cells <10%*  • Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) that can be attributed to the plasma cell proliferative disorder
Light Chain MGUS	All criteria must be met:  • Abnormal free light chain (FLC) ratio (<0.26 or >1.65)  • Increased level of the appropriate involved light chain (increased kappa FLC in patients with ratio > 1.65 and increased lambda FLC in patients with ratio < 0.26)  • No immunoglobulin heavy chain expression on immunofixation  • Absence of end-organ damage that can be attributed to the plasma cell proliferative disorder  • Clonal bone marrow plasma cells <10% Urinary monoclonal protein <500 mg/24h
Smoldering multiple myeloma	Both criteria must be met:  • Serum monoclonal protein (IgG or IgA) ≥3gm/dL, or urinary monoclonal protein ≥500 mg per 24h and/or clonal bone marrow plasma cells 10–60%  • Absence of myeloma defining events or amyloidosis
Multiple Myeloma	Both criteria must be met:  • Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma  • Any one or more of the following myeloma defining events:   ○ Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:    • 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)    • Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177 μmol/L (>2 mg/dL)    • Anemia: hemoglobin value of >2 g/dL below the lower limit of normal, or a hemoglobin value <10 g/dL    • Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography-CT (PET-CT)   ○ Clonal bone marrow plasma cell percentage ≥60%   ○ Involved: uninvolved serum free light chain (FLC) ratio ≥100 (involved free light chain level must be ≥100 mg/L and urine monoclonal protein level at least 200 mg per 24 hours on urine protein electrophoresis)   ○ >1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5mm in size)

Modified from 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-e548.

^*A bone marrow can be deferred in patients with low risk MGUS (IgG type, M protein <1.5 gm/dL, normal free light chain ratio), in patients with uncomplicated suspected IgM MGUS <1.5 gm/dl, and in patients with serum FLC ratio <8, in whom there are no clinical features concerning for myeloma, macroglobulinemia, or amyloidosis.

Although SMM is asymptomatic, as with MGUS, related paraprotein clinical disorders such as monoclonal gammopathy associated peripheral neuropathy or monoclonal gammopathy associated renal disorders can occur and coexist.^11,12 Similarly, as with MGUS, symptoms secondary to these paraprotein related disorders do not qualify as myeloma defining events even though myeloma-like treatments may be used to control them. MM is a malignancy diagnosed using the criteria listed in Table 1. During follow up of SMM, progression to MM (malignancy) must be differentiated from and treated differently than progression or association with paraprotein related disorders that occur independent of malignant transformation based solely on the nature of the M protein.

Baseline laboratory studies in SMM should include complete blood count, serum creatinine, serum calcium, whole body low dose computed tomography (CT) or positron emission tomography-computed tomography (PET-CT), serum protein electrophoresis (SPEP), serum immunofixation (IFE), 24 hour urine protein electrophoresis (UPEP), urine IFE, and serum free light chain (FLC) assay.¹³ Bone marrow examination with fluorescent in situ hybridization (FISH) studies to detect high risk cytogenetic abnormalities (del 17p, t(4;14), gain 1q, del 13) and plasma cell immunophenotyping by multiparametric flow cytometry is needed. If no myeloma defining events are present on the above evaluation, patients with suspected high risk SMM should also preferably have an MRI of the spine and pelvis (or whole body MRI) to ensure that focal myeloma defining lesions are not missed.¹⁴

RISK STRATIFICATION

The goal of risk stratification is to differentiate patients with SMM in whom the underlying clonal plasma cell population has already undergone malignant transformation (high risk SMM) from those in whom the underlying clone is premalignant (low/intermediate risk SMM). High risk SMM has a 50% risk of progression to MM in 2 years and requires consideration of early intervention strategies, whereas low/intermediate risk SMM has a risk of progression of approximately 5% per year and is mostly managed with observation alone. A number of prognostic factors have been identified, and these variables have been used in combination to create multiple risk stratification models for clinical use.^9,15–22

The earliest prognostic markers identified were the size and type of monoclonal protein, and the extent of bone marrow involvement.⁹ Numerous prognostic factors have since been identified, and these include simple blood-based biomarkers as well as imaging studies and bone marrow abnormalities. A reduction in the level of uninvolved immunoglobulins is associated with increased risk of progression.^9,15 The serum FLC ratio is also particularly valuable, and has been incorporated into risk stratification models.¹⁶ Imaging provides valuable information on prognosis at baseline and during follow up. Thus, the presence of one focal non-osteolytic lesion or presence of diffuse (non-focal) abnormalities on MRI are associated with an increased risk of progression to MM, and suggest the need for more close follow up and repeat imaging in 3–6 months.²³ Similarly increased uptake on PET-CT without bone destruction is indicative of a higher risk of progression.²⁴

Bone marrow immunophenotyping with multiparametric flow cytometry can be used to distinguish and quantitate bone marrow plasma cells with malignant potential (aberrant) from normal plasma cells.²⁵ The median time to progression is significantly shorter when the proportion of aberrance bone marrow plasma cells is ≥95%. Cytogenetic abnormalities detected on bone marrow examination of clonal plasma cells, t(4;14), del(17p), and gain(1q) are associated with a higher risk of progression.^18,19,26

Multiple risk-stratification models have been developed over the years and the main goal with these models is to identify patients with the highest risk of progression for early intervention.^9,15–22 Essentially, these models attempt to identify patients in whom malignant transformation has already occurred, and they do so with either a combination of laboratory and imaging variables, genomics, or both. In clinical practice, we need to accurately identify patients with at least a 50% risk of progression within 2 years, since they are most likely to benefit from early intervention. The Mayo 2018 criteria, also referred to as the 20–2-20 criteria uses three high risk factors: serum free light chain ratio >20, serum M protein level >2gm/dL, bone marrow clonal plasma cells >20%.²⁷ Presence of 2 or 3 of these factors is considered high risk SMM (Table 2) and have been validated in a separate cohort by the IMWG (Table 2).¹⁰ However, the IMWG validation study provides a scoring system for more accurate estimation of prognosis and is preferable if data on the variables is available at the point of care.

Table 2.

Risk Stratification of Smoldering Multiple Myeloma (SMM)

Mayo 2018 Criteria (20–2-20 criteria)
High Risk SMM (2-year risk of progression 50%)
Any 2–3 of the following high risk factors:
Serum monoclonal protein > 2gm/dL
Serum free light chain ratio (involved/uninvolved) >20
Bone marrow plasma cells >20%
Intermediate risk SMM
Any 1 high risk factor
Low risk SMM
No high risk factor
International Myeloma Working Group (IMWG) Scoring System for SMM*
Risk Factor Scores
Serum Free Light Chain Involved/Uninvolved Ratio
0–10: 0
11–25: 2
26–40: 3
>40: 5
Serum monoclonal protein level (g/dL)
0–1.5: 0
1.6–2.9: 3
≥ 3: 4
Bone marrow plasma cell percentage
0–15: 0
16–20: 2
21–30: 3
31–40: 5
>40: 6
High Risk FISH abnormalities (del 17p, gain 1q, t(4;14), or del 1)
Absent: 0
Present: 2
Risk Stratification using IMWG Score
High Risk SMM (2-year risk of progression, 75%)
Score >12
High-Intermediate Risk SMM (2-year risk of progression, 50%)
Score 9–12
Low-Intermediate Risk SMM (2-year risk of progression, 25%)
Score 5–8
Low Risk SMM (2-year risk of progression, 5%)
Score 1–4

FISH, Fluorescent in situ hybridization.

Derived from Lakshman A, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J 2018;8:59; and Mateos MV, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J 2020;10:102.

Besides baseline prognostic factors, a change in one or more of the above parameters over time is of critical importance.²⁸ In one study, an evolving change in monoclonal protein (0.5 gm/dl increase in M-protein) along with an evolving change in hemoglobin (0.5 g/dl decrease in hemoglobin) over a 12 month period was associated with high risk of progression.²⁹ Among patients with bone marrow plasma cells ≥20%, evolving M protein and evolving hemoglobin were independent predictors of progression; the 2-year progression rate was 90.5% in patients who had both an evolving M protein and evolving hemoglobin. Importantly, a recent study has found the Mayo 2018 high risk criteria can be used in follow up and patients who are initially diagnosed as low risk SMM can be later reclassified based on changes in M protein, serum FLC ratio, and/or bone marrow involvement.

Current risk stratification models are not perfect, but they are readily available around the world. But it is important to continue to develop better models. One caveat at the present time is that none of the models are very sensitive, and so only a proportion of patients at high risk are identified by each model. By combining models, we can probably capture more patients at risk, and our estimate on the risk of progression will be more precise. In the future modern genomic sequencing methods may be able to separate patients who need immediate intervention from those who can be followed. However, these studies are not standardized and are not widely available, with methods and techniques varying across laboratories. Further even patients who are considered not to have malignancy by genomic methods can always have a malignant transformation at some point in the future and hence such studies can neither fully reassure a patient nor do they negate the need for follow up even in patients not considered to have malignant transformation.

APPROACH TO TREATMENT

Observation

Observation without therapy every 3–4 months is the standard of care for patients with low and intermediate risk SMM. After 5 years, the interval between follow up visits can be extended. In general, serum M protein, serum FLC levels, complete blood count, serum calcium, and serum creatinine should be monitored.³⁰ Bone imaging and bone marrow biopsies are recommended if clinical suspicion for progression occurs. If during follow up, low risk SMM patients have increases in M protein, bone marrow plasma cells, serum free light chain levels, or changes in other relevant parameters that meet high risk criteria, then they should be managed according to the high risk SMM pathway.²⁹ In patients with MRI showing diffuse infiltration, solitary focal lesion, or equivocal lesions, follow-up radiographic examination in 3–6 months is recommended.²³

In high risk SMM, some investigators continue to recommend observation alone instead of early intervention. However, there are many problems with this approach. First, it may not be possible to intervene in time before serious end-organ damage even with close follow up. Second, as discussed below early intervention in high risk SMM is associated with 90% reduction in risk of progression with concurrent end-organ damage. Third, the treatment duration and intensity are not indefinite and there is no data from current trials to suggest any adverse effect on response to future lines of therapy or overall survival. In fact, overall survival benefit has been seen with early intervention in the Spanish trial. Observation alone was reasonable prior to availability of effective therapy, prior to evidence from randomized trial, and prior to good risk stratification models to identify the subset of SMM most likely to benefit from intervention. This is not the case anymore, and hence we do not prefer observation alone for high risk SMM. If a decision is made not to offer treatment to patients with newly diagnosed high risk SMM, patients should have a clear discussion on the pros and cons. In many parts of the world lenalidomide is inexpensive and cost is not a barrier to initiation of therapy.

Control

Our current approach to management of SMM mirrors the control approach, and is provided in Figure 1.³⁰ This approach has been tested in randomized trials and provides important clinical benefit.^31,32 The control approach consists of limited duration intervention and is only recommended for patients with newly diagnosed high risk SMM who have a 50% risk of progression by reliable risk stratification models. We recommend therapy with either lenalidomide or lenalidomide plus dexamethasone (Rd) for two years, or enrollment in a clinical trial testing early therapy. This recommendation is based on two randomized trials with lenalidomide in high risk SMM have shown benefit. In the Spanish randomized trial, time to progression to MM with end organ damage was significantly longer in patients treated with Rd compared with observation, median TTP not reached versus 21 months, P<0.001.^25,31 Overall survival was also longer, 3-year survival rate 94% vs. 80%, respectively, P=0.03. Importantly, early intervention with Rd did not affect the impact of subsequent therapy after progression or survival after progression, arguing against any long-term deleterious effect of early intervention. In the randomized trial conducted by the Eastern Cooperative Oncology Group (ECOG), early therapy with lenalidomide prolonged time to symptomatic MM with end-organ damage in patients with high risk SMM.³³ Among patients meeting Mayo 2018 high risk criteria, both the Spanish trial and the ECOG trial found a striking 90% reduction in time to end-organ damage. Between lenalidomide and Rd, the choice should be made taking into account the patients age, comorbidities, and tolerance to dexamethasone. Patients with high risk SMM who are treated with lenalidomide or Rd should have peripheral blood stem cells collected for cryopreservation after approximately 4–6 cycles of therapy.^34,35 Besides lenalidomide, other myeloma agents are also being tested in high risk SMM including daratumumab. A randomized trial of daratumumab versus observation (NCT03301220) has completed accrual and is awaiting analysis.

Figure 1. Approach to the management of smoldering multiple myeloma.

Footnote for Figure 1: SMM, smoldering multiple myeloma; MM, multiple myeloma; Rd, lenalidomide plus dexamethasone

Can we control SMM better using a triple regimen as is used in the treatment of MM rather than lenalidomide alone or Rd? This is an important question and is the subject of randomized trials. A randomized trial testing daratumumab, lenalidomide, dexamethasone (DRd) versus Rd is ongoing (NCT03937635), and we are awaiting its results. Another randomized trial is testing isatuximab, lenalidomide, dexamethasone (IxaRd) versus Rd(NCT04270409). These trials are not meant to cure SMM but provide better disease control and prolong time to end organ damage and improve overall survival. Addition of a third drug carries other risks, and hence the need to wait for long term data from randomized trials before recommending such therapy in asymptomatic patients. Nevertheless, there is a small subset of patients with high risk SMM in whom the risk of progression in 2 years approaches that used to revise the diagnostic criteria for MM, and in such patients careful consideration to MM like therapy may not be unreasonable.

The role of bisphosphonates to delay bone events in SMM is not fully settled. In a randomized trial, a reduction in skeletal-related events (SRE) has been seen with pamidronate (once a month for 12 months) compared with observation.³⁶ However, no improvement in time to progression or survival was seen. In another randomized trial, a reduction in SREs was noted with zoledronic acid (once a month for 12 months), 56% versus 78%, respectively, P=0.04.³⁷ We recommend once-yearly bisphosphonate similar to that used for the treatment of osteoporosis for patients with SMM who have osteopenia or osteoporosis.

Cure

It is possible that MM is not a curable disease because we are starting intervention too late, when the disease is already advanced. One hypothesis is that MM can be cured if we use intense therapy at the early asymptomatic high risk SMM stage when the clonal cells are not cytogenetically advanced and are more susceptible to therapy. Patients with high risk SMM are good candidates for clinical trials testing intensive therapy with curative intent.³⁸ Two such trials, CESAR and ASCENT(NCT02415413, NCT03289299), have completed accrual and await long term analysis to determine if a plateau exists and to see if early aggressive intervention at the SMM stage can be curative. The cure approach is of academic interest but is still investigational and is not recommended outside of clinical trials.

FUTURE DIRECTIONS

We await results of randomized trials testing whether a standard myeloma therapeutic triplet will be superior to prophylactic doublet therapy with lenalidomide plus dexamethasone in patients with high risk SMM. We also await long term results of cure trials to determine if such an intense approach may be of value in selected patients. Importantly we are pursuing continuous development of risk stratification models including genomics to more accurately identify patients for intervention.

Key Points.

• Smoldering multiple myeloma is a clonal plasma cell proliferative disorder that has a 10% per year risk of progression to myeloma in the first five years following diagnosis

• Smoldering multiple myeloma can be risk stratified using common laboratory and imaging variables into high risk versus low/intermediate risk subtypes

• Patients with high risk smoldering multiple myeloma are candidates for early intervention

Synopsis.

Smoldering multiple myeloma (SMM) is an intermediate clinical stage in the spectrum of monoclonal plasma cell disorders. It represents a heterogeneous clinically defined condition in which some patients (approximately 50%) have monoclonal gammopathy of undetermined significance (pre-malignancy), and some (approximately 50%) have multiple myeloma (biologic malignancy). Using specific prognostic factors, patients with SMM, in whom malignant transformation has already likely occurred, can be identified. These patients are considered to have high risk SMM. Patients with newly diagnosed high risk SMM are candidates for early intervention with lenalidomide or lenalidomide plus dexamethasone (Rd) for two years, or enrollment in clinical trials. Observation every 3–4 months is the standard of care for patients with low risk SMM.

Clinics Care Points.

• Following diagnosis of smoldering multiple myeloma, patients should be risk-stratified to identify patients with high risk disease needing early intervention

• The best defined early intervention is lenalidomide or lenalidomide plus dexamethasone for two years

• Patients with SMM should be considered for enrollment in clinical trials testing early intervention