World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access
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Volume 11, Number 2, April 2020, pages 45-54

Recent Advances in the Management of Smoldering Multiple Myeloma


Table 1. IMWG Diagnostic Criteria for SMM, MGUS and sy-MM
MGUSSMMMultiple myeloma
MGUS: monoclonal gammopathy of undetermined significance; SMM: smoldering multiple myeloma; sy-MM: symptomatic multiple myeloma; CRAB: hypercalcemia, renal insufficiency, anemia, bone lesion; Ig: immunoglobulin; IMWG: International Myeloma Working Group.
Serum monoclonal protein (IgG or IgA)< 3 g/dL≥ 3 g/dL≥ 3 g/dL
Clonal bone marrow plasma cells< 10%≥ 10%≥ 10%


Table 2. Risk Stratification of SMM Patients According to Mayo Clinic Criteria
M-protein sizeBone marrow plasma cellsTime to progression (years)
SMM: smoldering multiple myeloma.
Group 1≥ 3 g/dL≥ 10%2
Group 2< 3 g/dL≥ 10%8
Group 3≥ 3 g/dL< 10%19


Table 3. Updated Risk Stratification Model for SMM Incorporating Revised IMWG Diagnostic Criteria Using (20/2/20) Parameter
Risk factorNumber of Subjects (n)Hazard ratioP value2-year progression (n (%))
Serum M-protein (2 g/dL); involved to uninvolved serum-free light chain ratio (20); and marrow plasma cells % (20%). SMM: smoldering multiple myeloma; IMWG: International Myeloma Working Group.
0424Not available21 (5%)
13122.25 (1.68 - 3.01)Significant53 (17%)
24155.63 (4.34 - 7.29)Significant190 (46%)


Table 4. Summary of Prognostic Factors for Progression of SMM to MM
InvestigatorsRisk factorsProgression
SMM: smoldering multiple myeloma; MM: multiple myeloma; TTP: time to progression; BPMC: bone marrow plasma cell; MRI: magnetic resonance imaging; M: monoclonal; FLCr: free light chain ratio; NR: not reached; FISH: fluorescent in situ hybridization; PCs: plasma cells; PET: positron emission tomography; CT: computed tomography; CI: confidence interval.
Moulopoulos et al (1995) [23]Abnormal MRINormal MRI: TTP 43 months; abnormal MRI: TTP 16 months; variegated pattern: TTP 22 months; diffuse pattern: TTP 16 months; focal pattern: TTP 6 months
Rosinol et al (2003) [13]Evolving diseaseEvolving type: TTP 1.3 years; non-evolving type: TTP 3.9 years
Wang et al (2003) [25]Abnormal MRINormal MRI: TTP 5 years; abnormal MRI: TTP 1.5 years
Kyle et al (2007) [6]M-protein ≥ 3 g/dL, BMPC ≥ 10%: Group A; M-protein < 3 g/dL, BMPC ≥ 10%: Group B; M-protein ≥ 3 g/dL, BMPC < 10%: Group CGroup A: TTP 2 years; Group B: TTP 8 years; Group C: TTP 19 years
Perez-Persona et al (2007) [16]95% aberrant BMPC (absence of CD19 and/or CD45 expression, overexpression of CD56, or weak expression of CD38); immunoparesis of the uninvolved immunoglobulins0 risk factor: 5-year TTP of 4%; 1 risk factor: 5-year TTP of 46%; 2 risk factors: 5-year TTP of 72%
Dispenzieri et al (2008) [15]M-protein ≥ 3 g/dL; BMPC ≥ 10%; abnormal FLCr < 0.125 or > 81 factor: 5-year TTP of 25% (TTP 10 years); 2 factors: 5-year TTP of 51% (TTP 5.1 years); 3 factors: 5-year TTP of 76% (TTP 1.9 years)
Hillengass et al (2009) [26]Focal lesion on whole body MRI≤ 1 focal lesion: 2-year TTP of 20% (TTP NR); > 1 focal lesion: 2-year TTP of 70% (TTP 13 months)
Neben et al (2012) [20]High-risk FISHs: t (4:14), deletion 17p or 11q21; high tumor burden: M-protein of 20 g/LBoth absent: 3-year TTP of 8%; high-risk FISH only: 3-year TTP of 30%; high tumor load only: 3-year TTP of 40%; both present: 3-year TTP of 59%
Larsen et al (2013) [29]Involved/uninvolved FLCr of ≥ 100FLCr < 100: TTP 55 months; FLCr ≥ 100: TTP 15 months
Bianchi et al (2013) [18]> 5,000 × 106/L PCs and/or > 5% cytoplasmic immunoglobulin positive PCs per 100 peripheral mononuclear cellsAbsent: 5-year TTP of 25% (TTP 57 months); present: 5-year TTP of 71% (TTP 12 months)
Zamagni et al (2016) [28]Number of focal lesionsRisk of progression with positive PET/CT was 3.00 (95% CI 1.58 - 5.69, P = 0.001), with a median TTP of 1.1 versus 4.5 years for PET/CT-negative patients; median TTP of 2.2 years versus 7 years with negative PET/CT (1)
Khan et al (2015) [21]Gene signature from foure genes (GEP4): the top genes in the GEP4 model includes RRM2 expression, DTL, implicated in oncogenesis via a role in apoptosis and cell cycle control, and ASPMGene signature binary cutoff > 9.28 associated with a 2-year risk of therapy 85.7%
Bolli et al (2018) [22]Whole-genome sequence of 11 patients with SMM progressed to MMStatic progression model: clonal architecture retained, progression occurs with accumulation of enough disease burden; spontaneous evolution model: via accumulation of new mutations progress to MM
Miguel et al (2019) [19]M-protein (2 g/dL), involved to uninvolved FLCr (20), and marrow plasma cell % (20%); 20/2/20 risk modelIntermediate risk (1) and high risk (> 2) had a significantly high risk for progression in 2 years: 17% and 46% respectively


Table 5. Summary of Completed Clinical Trials in SMM Patients
SMM: smoldering multiple myeloma; TTP: time to progression; OS: overall survival; RCT: randomized controlled trial; MP: melphalan-prednisone; NR: not reached; PFS: progression-free survival.
Hjorth et al (1993) [30]RCTInitial versus delayed MP12 monthsNo difference
Grignani et al (1996) [31]RCTMP versus observationNo treatment: 58 months; treatment: 54 arms
Riccardi et al (2000) [32]RCTInitial versus delayed MP13 monthsInitial MP: 64 months; delayed MP: 71 months
Rajkumar et al (2001) [33]Single arm phase 2 trialThalidomide35 monthsTreatment: 49 months; observation: 86 months
Barlogie et al (2008) [34]Single arm phase 2 trialThalidomide and pamidronate4-year EFS 60%4-year OS 91%
Musto et al (2003) [36]RCTPamidronate versus observationTreatment: TTP 16 months; observation: TTP 17.4 monthsOS not reported
Musto et al (2008) [37]RCTZoledronate versus observationTreatment: TTP 67 months; observation: TTP 59 monthsOS not reported
Witzig et al (2013) [38]RCTThalidomide and zoledronate versus zoledronateThalidomide/zolendronate: TTP 2.4 years; zolendronate: TTP 1.2 yearsOS > 70% after 6 years in both arms (no difference)
Mateos et al (2013) [39]RCTLenalidomide and dexamethasone versus observationTreatment: TTP NR; observation: TTP 21 months5-year OS; treatment: 94 months, observation: 78 months
Lonial et al (2019) [40]RCTLenalidomide versus observationTreatment arm of PFS 91% versus 66% in the observation armOS not reported


Table 6. Summary of Ongoing Clinical Trials in SMM
TreatmentStudyPrimary objectives
Most studies are in high-risk SMM unless specified. SMM: smoldering multiple myeloma; IRd: revlimid (lenalidomide), dexamethasone; MM: multiple myeloma; HDACi: histone deacetylase inhibitor; MGUS: monoclonal gammopathy of undetermined significance; ASCENT: Aggressive Smoldering Curative Approach Evaluating Novel Therapies and Transplant; MRD: minimal residual disease; RCT: randomized controlled trial.
Denosumab [47]Open label, phase II, single groupProportion of patients with decreased risk of progression of SMM within 1 year
Trial of Combination of Ixazomib and Lenalidomide and Dexamethasone [48]Open label, phase II, single groupHigh-risk SMM patient who received IRd combination therapy, progression free at 2 years
Ibrutinib [49]Open label, phase II, single groupHigh-risk SMM; efficacy of ibrutinib to prevent progression to symptomatic MM in 1 year
Personalized vaccine [50]Early phase I, single groupFeasibility and safety of personalized vaccine
Carfilzomib, lenalidomide, and dexamethasone [43]Open label, phase II, single groupResponse rate at 8 months, progression-free survival and duration of response
PVX-410, a multi-peptide cancer vaccine, and citarinostat (CC-96241), a HDACi with and without lenalidomide [51]Open label, phase I, nonrandomizedSafety and tolerability of this vaccine regimen in 2 years
Daratumumab in patients with high-risk MGUS and low-risk SMM [52]Open label, phase II, single groupProportion of patients in deep response at 2 years
Carfilzomib, lenalidomide, daratumumab, and dexamethasone in subjects with high-risk SMM ASCENT trial [29]Multicenter, phase II, open labelStringent complete response, deep MRD, and potentially achieving cure or long-term disease quiescence
Lenalidomide and dexamethasone work with or without daratumumab [53]Open label, phase III, RCTOverall survival, assess health related quality of life
Carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone [54]Open label, phase II, RCTProgression-free survival until 5 years