World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website http://www.wjon.org

Review

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
	MGUS	SMM	Multiple 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
	And	And/or	And/or
Clonal bone marrow plasma cells	< 10%	≥ 10%	≥ 10%
	And	And	And
CRAB	Absent	Absent	Present

Table 1. IMWG Diagnostic Criteria for SMM, MGUS and sy-MM

MGUS

SMM

Multiple 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

And

And/or

Clonal bone marrow plasma cells

< 10%

≥ 10%

And

CRAB

Absent

Present

**Table 2.** Risk Stratification of SMM Patients According to Mayo Clinic Criteria
	M-protein size	Bone marrow plasma cells	Time 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 2. Risk Stratification of SMM Patients According to Mayo Clinic Criteria

M-protein size

Bone marrow plasma cells

Time to progression (years)

SMM: smoldering multiple myeloma.

Group 1

≥ 3 g/dL

≥ 10%

Group 2

< 3 g/dL

≥ 10%

Group 3

≥ 3 g/dL

< 10%

**Table 3.** Updated Risk Stratification Model for SMM Incorporating Revised IMWG Diagnostic Criteria Using (20/2/20) Parameter
Risk factor	Number of Subjects (n)	Hazard ratio	P value	2-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.
0	424		Not available	21 (5%)
1	312	2.25 (1.68 - 3.01)	Significant	53 (17%)
2	415	5.63 (4.34 - 7.29)	Significant	190 (46%)

Table 3. Updated Risk Stratification Model for SMM Incorporating Revised IMWG Diagnostic Criteria Using (20/2/20) Parameter

Risk factor

Number of Subjects (n)

Hazard ratio

P value

2-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.

424

Not available

21 (5%)

312

2.25 (1.68 - 3.01)

Significant

53 (17%)

415

5.63 (4.34 - 7.29)

Significant

190 (46%)

**Table 4.** Summary of Prognostic Factors for Progression of SMM to MM
Investigators	Risk factors	Progression
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 MRI	Normal 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 disease	Evolving type: TTP 1.3 years; non-evolving type: TTP 3.9 years
Wang et al (2003) [25]	Abnormal MRI	Normal 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 C	Group 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 immunoglobulins	0 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 > 8	1 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/L	Both 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 ≥ 100	FLCr < 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 cells	Absent: 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 lesions	Risk 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 ASPM	Gene 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 MM	Static 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 model	Intermediate risk (1) and high risk (> 2) had a significantly high risk for progression in 2 years: 17% and 46% respectively

Table 4. Summary of Prognostic Factors for Progression of SMM to MM

Investigators

Risk factors

Progression

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 MRI

Normal 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 disease

Evolving type: TTP 1.3 years; non-evolving type: TTP 3.9 years

Wang et al (2003) [25]

Abnormal MRI

Normal 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 C

Group 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 immunoglobulins

0 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 > 8

1 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/L

Both 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 ≥ 100

FLCr < 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 cells

Absent: 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 lesions

Risk 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 ASPM

Gene 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 MM

Static 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 model

Intermediate 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
Investigators	Study	Treatment	TTP	OS
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]	RCT	Initial versus delayed MP	12 months	No difference
Grignani et al (1996) [31]	RCT	MP versus observation		No treatment: 58 months; treatment: 54 arms
Riccardi et al (2000) [32]	RCT	Initial versus delayed MP	13 months	Initial MP: 64 months; delayed MP: 71 months
Rajkumar et al (2001) [33]	Single arm phase 2 trial	Thalidomide	35 months	Treatment: 49 months; observation: 86 months
Barlogie et al (2008) [34]	Single arm phase 2 trial	Thalidomide and pamidronate	4-year EFS 60%	4-year OS 91%
Musto et al (2003) [36]	RCT	Pamidronate versus observation	Treatment: TTP 16 months; observation: TTP 17.4 months	OS not reported
Musto et al (2008) [37]	RCT	Zoledronate versus observation	Treatment: TTP 67 months; observation: TTP 59 months	OS not reported
Witzig et al (2013) [38]	RCT	Thalidomide and zoledronate versus zoledronate	Thalidomide/zolendronate: TTP 2.4 years; zolendronate: TTP 1.2 years	OS > 70% after 6 years in both arms (no difference)
Mateos et al (2013) [39]	RCT	Lenalidomide and dexamethasone versus observation	Treatment: TTP NR; observation: TTP 21 months	5-year OS; treatment: 94 months, observation: 78 months
Lonial et al (2019) [40]	RCT	Lenalidomide versus observation	Treatment arm of PFS 91% versus 66% in the observation arm	OS not reported

Table 5. Summary of Completed Clinical Trials in SMM Patients

Investigators

Study

Treatment

TTP

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]

RCT

Initial versus delayed MP

12 months

No difference

Grignani et al (1996) [31]

RCT

MP versus observation

No treatment: 58 months; treatment: 54 arms

Riccardi et al (2000) [32]

RCT

Initial versus delayed MP

13 months

Initial MP: 64 months; delayed MP: 71 months

Rajkumar et al (2001) [33]

Single arm phase 2 trial

Thalidomide

35 months

Treatment: 49 months; observation: 86 months

Barlogie et al (2008) [34]

Single arm phase 2 trial

Thalidomide and pamidronate

4-year EFS 60%

4-year OS 91%

Musto et al (2003) [36]

RCT

Pamidronate versus observation

Treatment: TTP 16 months; observation: TTP 17.4 months

OS not reported

Musto et al (2008) [37]

RCT

Zoledronate versus observation

Treatment: TTP 67 months; observation: TTP 59 months

OS not reported

Witzig et al (2013) [38]

RCT

Thalidomide and zoledronate versus zoledronate

Thalidomide/zolendronate: TTP 2.4 years; zolendronate: TTP 1.2 years

OS > 70% after 6 years in both arms (no difference)

Mateos et al (2013) [39]

RCT

Lenalidomide and dexamethasone versus observation

Treatment: TTP NR; observation: TTP 21 months

5-year OS; treatment: 94 months, observation: 78 months

Lonial et al (2019) [40]

RCT

Lenalidomide versus observation

Treatment arm of PFS 91% versus 66% in the observation arm

OS not reported

**Table 6.** Summary of Ongoing Clinical Trials in SMM
Treatment	Study	Primary 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 group	Proportion 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 group	High-risk SMM patient who received IRd combination therapy, progression free at 2 years
Ibrutinib [49]	Open label, phase II, single group	High-risk SMM; efficacy of ibrutinib to prevent progression to symptomatic MM in 1 year
Personalized vaccine [50]	Early phase I, single group	Feasibility and safety of personalized vaccine
Carfilzomib, lenalidomide, and dexamethasone [43]	Open label, phase II, single group	Response 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, nonrandomized	Safety 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 group	Proportion 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 label	Stringent 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, RCT	Overall survival, assess health related quality of life
Carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone [54]	Open label, phase II, RCT	Progression-free survival until 5 years

Table 6. Summary of Ongoing Clinical Trials in SMM

Treatment

Study

Primary 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]