High-risk smoldering myeloma versus early detection of multiple myeloma: current models, goals of therapy, and clinical implications

Abstract

Multiple myeloma, a bone marrow cancer, is preceded by precursor stages called monoclonal gammopathy of unknown significance and smoldering multiple myeloma. Over the past few years, highly effective and safe therapies have been made available to treat multiple myeloma. This represents a major breakthrough and has major therapeutic implications. Treatment for multiple myeloma has evolved to include treatment of precursor stages (early treatment) as these therapies are shown to be safe and effective also in smoldering myeloma. Randomized studies have shown that early treatment can delay the onset of multiple myeloma and even improve overall survival compared to observation in smoldering myeloma. The best therapeutic course and selection of patients with smoldering myeloma to treat is still a matter of debate. In this manuscript, we review the definition, management, clinical implications of smoldering myeloma and early detection of myeloma in the current context and with up-to-date data.

Introduction

Smoldering multiple myeloma (SMM) is usually defined as an asymptomatic precursor stage that lies between full blown multiple myeloma (MM) and the more indolent monoclonal gammopathy of unknown significance (MGUS) [1]. SMM is heterogeneous with some patients having a low risk of progression to MM of about 5% per year, whereas others have a risk as high as 50% risk within 2 years of diagnosis [2,3].

Several factors have been found to be significant in determining the risk to evolve to full blown MM. There is currently a lot of interest in the early treatment of myeloma which is twofold; one: to delay the evolution to MM preventing organ dysfunction and two: to induce deep and durable remissions that may result in cure. In 2013, the first randomized study comparing lenalidomide/dexamethasone to observation in patients with high-risk SMM showed improved progression free survival (PFS) and overall survival (OS) for the treatment arm. Because this study included some patients that met the definition of full-blown MM the standard of care of observation did not change [4].

This review will focus on the current definition of SMM, current models to define high-risk SMM, treatment and clinical guidance.

Definition of multiple myeloma and smoldering multiple myeloma

The origins of the term smoldering multiple myeloma

The definition of SMM has changed over time. This term was first described in 1980 in six patients whose blood and bone marrow (BM) plasma cell percentage satisfied MM criteria, however the patients did not have anemia, lytic lesions, hypercalcemia, and/or renal failure after 5 years of follow-up [5]. In 2003 the international myeloma working group (IMWG) defined SMM in patients whose monoclonal protein (M-protein) was ≥ 3 g/dL and who had a monoclonal BM plasma cell percentage ≥ 10% without MM related organ damage (CRAB: hypercalcemia, renal failure, anemia, and bone lesions) [6].

SMM: disease heterogeneity

The definition of SMM was then widely applied to all patients who met the 2003 criteria. It has been published that the rate of progression to MM varies over time. For example, a study of SMM indicated that the rate of progression to MM was 10% per year in first 5 years, 3% per year in the next 5 years, and 1% per year thereafter [2]. However, patients whose M-protein was ≥ 3 g/dL and plasma cell BM percentage was ≥ 10% had the worse prognosis whereas patients with M-protein ≥ 3 g/dL but BM plasma cell percentage was ≥ 10% had better prognosis. The median time to myeloma (TTM) was 2, 8, and 19 years in patients with ≥10% BM plasma cells and ≥3 g/dL, ≥10% BM plasma cells and <3 g/dL, and <10% BM plasma cells and ≥3 g/dL, respectively. This was used to divide SMM into risk category groups depicted in Table and Figure 1.

Table 1:

Selected smoldering myeloma risk categories [17, 18]

	Incidence	Median TTP (months)	2-year TTP (%)	Rate of progression to MM per year within 10 years
Ultra-high risk SMM (Currently classified as MM requiring treatment)	15%	12	80%	40%
High-risk SMM	30%	30	50% (98% at 5 years)	25% in first 2 years then 11% during years 3 – 5, and 3% thereafter
Intermediate-risk SMM	25%	68	26%	13% in first 2 years then 7% during years 3 – 5, and 4% thereafter
Low-risk SMM	30%	110	10%	Constant at 5%

^*Abbreviations: MM, multiple myeloma; SMM, smoldering multiple myeloma; TTP, time to progression to multiple myeloma

Figure 1:

Smoldering multiple myeloma heterogeneity and risk group categories

Myeloma requiring treatment: definition

During the early 2010s, the term ultra-high risk SMM was coined to refer to patients who met the SMM definition (at the time: 10% BM plasma cell percentage and/or had a M protein in blood of ≥3 g/dL and/or M-protein in urine of ≥ 500 mg) but who had a very high risk of developing organ dysfunction from myeloma. These patients were identified in retrospective studies to have at least one of the following risk factors: involved: uninvolved (i:u)serum free light chain (SFLC) ratio ≥ 100, bone lesions on magnetic resonance imaging (MRI) > 1 lesion, and BM plasma cell % ≥ 60%. Having these risk factors showed in these studies a high-risk of organ dysfunction of at least 75 – 80% within 2 years of diagnosis.

For example, 90 out of 586 SMM patients (15%) that had i:u SFLC ratio ≥ 100 progressed to MM within 15 months compared with 55 months in patients who had i:u SFLC ratio < 100 (p<0.0001) [7]. Additionally, seventy-two percent of patients with i:u sFLC ratio ≥ 100 progressed to MM within 2 years of diagnosis. Other studies have shown similar results, including a retrospective cohort study of 96 SMM patient. In this study, patients with i:u sFLC ratio ≥ 100 and BM plasma cell % ≥ 60% had a median time to myeloma (TTP) of 13 and 15 months, respectively [8]. Unfavorable TTP in patients who had focal lesions in BM detected by whole body or spine MRI was reported. Patients with > 1 focal lesion had worse TTP compared to those with one or less focal lesions. The 2-year TTP was 70% and median TTP was 13 months versus not reached in patients with focal lesions > 1 versus ≤ 1 lesion(s) (p<0.001) [9]. Another study that used spine MRI showed similar results with patients that had more than one focal lesion. These patients progressed to MM at a rate of 70% within 2 years of diagnosis. A limitation of this study is that spine MRI missed around 10% of non-axial lesions [10].

The revised 2014 IMWG MM definition criteria added some SMM patients who either had i:u sFLC ≥ 100 or > one focal lesion on MRI or had ≥ 60% infiltration of the bone marrow by monoclonal plasma cells as these patients were thought to have high risk of progression to organ dysfunction of around 80% within two years of diagnosis [11]. Current MM and SMM criteria are in table 2.

Table 2:

Diagnostic criteria for plasma cell disorder according to International Myeloma Working Group 2003 and 2014

	Monoclonal gammopathy of undetermined significance	Smoldering multiple myeloma	Multiple myeloma
2003 criteria [56]	- Serum monoclonal protein <30 g/l - Bone marrow clonal plasma cells ≥10% - No evidence of other B-cell proliferative disorders - No end-organ damage*	- Serum monoclonal protein > 30 g/l and/or - Bone marrow clonal plasma cells ≥ 10% - No end-organ damage*	- Serum monoclonal protein in serum and/or urine - Bone marrow clonal plasma cells or plasmacytoma - End-organ damage*
2014 criteria [11]	- Serum monoclonal protein (non-IgM type) <30 g/L - Clonal bone marrow plasma cells <10% - Absence of end-organ damage or amyloidosis that can be attributed to the plasma cell proliferative disorder	Both criteria must be met: – Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10–60% – Absence of myeloma defining events or amyloidosis	- Bone marrow clonal plasma cells >10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events: - Myeloma defining events: • Evidence of end-organ damage* that can be attributed to the underlying plasma cell proliferative disorder, specifically:  √ Hypercalcaemia: 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 min or serum creatinine >177 μmol/L (>2 mg/dL)  √ Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin value <100 g/L  √ Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT • Any one or more of the following biomarkers of malignancy:  √ Bone marrow clonal plasma cells percentage >60%  √ Involved:uninvolved serum free light chain ratio >100  √ >1 focal lesions on MRI studies

^*End-organ damage as detailed in 2014 criteria

PET/CT to define MM requiring treatment

Positron emission tomography/computed tomography (PET/CT) has been used successfully to identify lytic lesions as a factor to initiate treatment in patients with MM. The identification of bone marrow FDG-avid lesions without underlying osteolysis has been proposed as a risk factor to identify patients with SMM at higher risk of progression to myeloma. In a study evaluating this, 19 patients out of 120 patients (16%) had PET/CT positive lesions with both a focal and diffuse pattern without underlying osteolytic lesions [9]. These patients had a poorer median TTP (1.1 years) than PET/CT negative patients (4.5 years). Two-year TTP of PET/CT positive patients was 58% versus 33% in PET/CT negative patients. The TTP was shorter with an increasing number of lesions. Another study in 122 SMM patients also confirmed the shorter TTP in PET/CT positive SMM [10]. Nine patients with focal lesions in PET/CT had 2-year TTP of 61%, while only 30% of PET/CT negative patients progressed to MM within 2 years of diagnosis. The limited number of patients included in these studies precluded the analysis for the cutoff to optimize the number of lesions to predict 80% progression to MM within 2 years [10]. Thus, FDG avid bone marrow lesions were not included in the current MM definition of biomarkers of malignancy.

Biomarkers of malignancy controversy

The current MM definition includes biomarkers of malignancy and recommends treatment in patients who have monoclonal gammopathy who additionally have i:u sFLC ratio ≥ 100, > 1 BM focal lesion on MRI and/or have ≥ 60% plasma cell involvement in the bone marrow, in the absence of CRAB criteria. This was based on retrospective studies as reviewed previously. A Danish study reported a 2-year TTP of only 30.4% in patients with i:u sFLC ratio ≥ 100 [13]. Another US-based study reported similar results in a cohort of 273 SMM patients [14]. Patients with i:u sFLC ratio ≥ 100 or BM plasma cell % ≥ 60% had a median TTP of 40 months (2-year TTP 44%) and 31 months (2-year TTP 41%), respectively. Moreover, 44% and 27% of patients who had either i:u SFLC ratio ≥ 100 or BM plasma cell ≥ 60%, respectively, did not progress to symptomatic MM during the 74 months of follow-up time. This has created some controversy specifically around the i:u sFLC ratio as a biomarker of malignancy to initiate treatment for MM with some patients opting for a wait and watch approach versus treatment.

High-risk smoldering multiple myeloma: current models and other factors

Widely used models to identify high-risk smoldering multiple myeloma

Several models are available to identify patients with high-risk SMM. The MAYO 2008, PETHEMA, and SWOG models have been widely used for this purpose over the past 15 years approximately [15, 16, Dhodapkar, 2014 #25]. Immunoparesis (reduction in 1 or 2 uninvolved immunoglobulin levels) and having ≥ 95% of aberrant plasma cells of all plasma cells by flow cytometry were identified by the PETHEMA group to discriminate between SMM patients. This classified patients into low, intermediate and high-risk categories. High-risk patients who had both parameters would have short time to progression to MM with a median TTP of 23 months [15]. The MAYO group have also explored the factors predicting risk of progression to MM. The MAYO 2008 model is described in table 3 and is widely used in the clinic. The International Myeloma Foundation (IMF) and MAYO group with international collaborators have also developed a new 2019 model. The data was obtained through retrospective review of thousands of patients with SMM in an international effort. The 20/2/20 model (IMF 2019) consists of BM plasma cell % > 20%, M-protein > 2 g/dL, and i:u sFLC ratio > 20 [17, 18]. In this model, high-risk patients have 5.63 times the risk of developing MM vs low-risk patients. The 2-year progression rate for high-risk patients is 46% [17]. Although, the MAYO 2008/IMF 2019 and PETHEMA models can identify high-risk SMM but they are highly discordant [19]. The Southwest Oncology Group (SWOG) was the first group to incorporate gene expression profiling (GEP) into the model to progression in SMM patients. The use of sFLC values, serum M-spike, and bone marrow GEP-70 predicted a 2-year progression rate at 66.7%, 21.9%, and 3.4% in patients with 2-3, 1, and 0 risk factors, respectively. Amongst all investigated clinical models during the SWOG analysis, the model that incorporated GEP was the one with better prediction capability and thus selected [20]. Selected models to identify high-risk SMM are in table 3.

Table 3:

Selected models that classify SMM based on risk of progression to MM

	Criteria	Median TTP (months)
PETHEMA criteria [15]
High-risk	Two risk factors are met   (1) Immunoparesis   (2) ≥ 95% aberrant plasma cells of all plasma cells by flow cytometry	23
Intermediate	One risk factor is met	73
Low	No risk factors	Not reached
SWOG criteria [20]
High-risk	Two out of three risk factors are met   (1) Involved SFLC > 25 mg/dL   (2) M-Protein ≥ 3 g/dL   (3) GEP > −0.26	Median 6; 2-year TTP 66.7%
Intermediate	One risk factor is met	Median not reached; 2-year TTP 21.9%
Low	No risk factors	Median not reached; 2-year TTP 3.4%
MAYO 2008 criteria [16]
High-risk	Three out of three risk factors are met   (1) Bone marrow plasma cell % ≥ 10%   (2) M-protein ≥ 3 g/dL   (3) I:u sFLC ratio > 8	23
Intermediate	Two out of three risk factors are met	45
Low	One out of three risk factors are met	110
IMF 2019 criteria [17]
High-risk	Two out of three risk factors are met   (1) Bone marrow plasma cell % ≥ 20%   (2) M-protein > 2 g/dL   (3) I:u sFLC ratio > 20	30
Intermediate	One out of three risk factors are met	68
Low	No risk factors	110
MAYO 2018 criteria with FISH [17]
High-risk	Two out of three risk factors are met   (1) Bone marrow plasma cell % ≥ 20%   (2) High-risk FISH   (3) I:u sFLC ratio > 20	23.6
Intermediate	One out of three risk factors are met	83.1
Low	No risk factors	Not reached

FISH=fluorescence in situ hybridization

Other risk factors to identify high-risk SMM

As we have described, risk factors associated to tumor burden have been used in several risk models to identify high-risk SMM. Other factors including plasma cell biology, genetics and disease distribution by imaging have also been investigated and are described in table 4.

Table 4:

Selected variables described in the literature to identify high-risk SMM

Type of measurement	Parameter	Reference
Tumor burden	M-protein level	[2, 15, 17]
	Bone marrow plasma cell percentage	[2, 17]
	Involved: uninvolved serum free light chain ratio	[16, 17]
	Blood circulating plasma cells	[29, 30]
Immunology Biology Genetics	Serum immunoparesis	[2, 15]
	Percentage of aberrant plasma cells of all plasma cells in bone marrow aspirate	[15]
	Evolving disease: evolving M-protein, evolving hemoglobin, evolving sFLC	[21–24, 57]
	Cytogenetics	[27, 28]
	Gene expression profiling	[20, 58]
	FISH	[27, 28]
Imaging	MRI	[31]
	PET/CT	[59]

Abbreviations: FISH, Fluorescence in situ hybridization; MRI, Magnetic resonance imaging; PET/CT, positron emission tomography – computed tomography; sFLC, serum free-light chain ratio

The evolving pattern of M-protein has been described by the Spanish group since the early 2000s. In a study of 53 SMM patients, 22 of them (42%) had increasing M-protein level of at least 10% within the first 6 months after diagnosis. These patients had worse TTP of 1.3 versus 3.9 years (p=0.007) when compared to those with a non-evolving M-protein pattern [21]. Thereafter, several studies confirmed the importance of the evolving pattern [14, 22–24]. Interestingly, patients with an evolving M-protein had similar genetic changes as those with newly diagnosed MM. For example, patients with an evolving pattern had a higher incidence of gain of chromosome 1q and deletion of chromosome 13q and 16q[25]. The genomic heterogeneity that characterizes MM is also found in SMM [20, 26]. In a prospective study of SMM patients, the incorporation of gene expression profiling (GEP) 4 into the SWOG model was better than MAYO 2008 model at predicting the risk of progression to MM. However, GEP is not widely available in the clinic [27]. Genetic abnormalities that define high-risk M such as t(4;14), 17p deletion, and gain chromosome 1q also are associated with an increased risk of progression to MM in SMM [27, 28]. In a study where FISH was added to the IMF 2019 20/2/20 model, the M-protein level lost statistical significance in multivariate analysis and only 3 parameters: BM plasma cell % > 20%, sFLC ratio > 20, and high-risk FISH were associated with increased risk of progression (Table 3) [17]. The median TTP for high-risk SMM patients in this model was 23 months. This suggests that genetic information is important for predicting risk in SMM and future models may need to integrate this to increase prediction power.

Circulating plasma cells in patients with MM has also been investigated to predict progression to MM [29, 30]. In a study, SMM with circulating plasma cells > 150 cells per 150,000 events by multicolor flow cytometry had median TTP of 9 months compared with not reached in those who had less than 150 circulating plasma cells (p< 0.001) [30]. The number of bone marrow lesions detected by MRI and PET/CT can also help determine the risk of progression to MM. For example, patients with previously normal MRI, who later on have bone marrow focal lesions identified, have been seen to have a shorter TTP than patients with persistent normal MRI pattern [31].

Goals of therapy for SMM patients

The initial treatment studies for SMM patients included any patients that met SMM definition without risk stratification. In that context, several studies were conducted. For example, melphalan-prednisolone versus observation in SMM patients showed only TTP benefit in treatment arm without OS benefit [32, 33]. Moreover, 2 out of 25 patients in melphalan-prednisolone arm developed acute leukemia. Given the concern of secondary malignancies and lack of OS benefit, observation was deemed the best option still for SMM patients at the time [32]. Later on, thalidomide plus zoledronic acid was compared with zoledronic acid alone in a phase 3 randomized controlled trial [34]. The thalidomide containing arm showed better TTP 2.4 versus 1.2 years with better overall response rate (ORR) of 37% (34% partial response, 3% very good partial response) versus 0%, respectively. However, there was no OS benefit and high toxicity from thalidomide. Again, observation was deemed the best option for SMM outside of clinical trials.

The first phase 3 study in high-risk SMM is the QuiRedex study which was published by the PETHEMA group in 2013. This study compared lenalidomide and dexamethasone (Rd) with observation in high-risk SMM. This showed an ORR of 79% (≥ complete remission [CR] 21%) after initial therapy and improved TTP and OS benefit in treatment arm [4] (Table 5). Despite the favorable outcome, this study screened patients with plan x-rays. This may have missed up to 30% of patients with lytic lesions and thus may have included MM patients instead of true SMM patients in both the treatment and observation arms. It also included patients that have biomarkers of malignancy as per the new diagnosis criteria of MM, thus again with the possibility of including patients with a diagnosis of MM instead of SMM by IMWH criteria [35]. Therefore, after this study, patients with SMM continued to be managed with observation outside of clinical trials.

Table 5:

Selected smoldering multiple myeloma treatment studies

Studies/number of patients	Treatments	Risk stratification	MRD (yes/no)/Method and sensitivity	ORR* (CR/MRD negative) (%)	PFS/OS	Adverse events (≥ grade 3)
Myeloma-like regimen
2015, Korde and 2017, Mailankody N=18 [38, 39]	Initial Therapy: 28 day-cycle [C1-8]: Carfilzomib 20/36 mg/m 2 i.v. days 1,2, 8, 9, 15, 16 + lenalidomide 25 mg p.o. days 1–21 + dex 20mg (C1 – 4) and 10 (C5 – 8) p.o. or i.v. days 1, 2, 8, 9, 15, 16 then Maintenance: 28 day-cycle [C1 – 24] Lenalidomide 25 mg days 1 – 21 for up to 2 years (n=18)	Risk stratification by: MAYO 2008 (low/intermediate/high): 83/17% PETHEMA (low/intermediate/high): 11/89%	Yes/MFC 10−5	After initial treatment: 100(89/83) At 2 years after maintenance: 100(89/63)	No progression to symptomatic MM 3-, 4-year PFS 94%, 70.6% 3-, 4- year OS: 100%	- Lymphopenia 39% - Neutropenia 28% - anemia 22% - diarrhea 17% - lung infection 17% - Hypophosphatemia 11% - Thrombocytopenia 11% - 1 patient developed CHF after 6th cycle
GEM-CESAR [60] 2017, Mateos (ASH 2019) NCT02415413 Ongoing study N=90	Induction: 28 day-cycle [C1-6]: Carfilzomib 20/36 mg/m 2 i.v. days 1,2, 8, 9, 15, 16 + lenalidomide 25 mg p.o. days 1–21 + dex 40 mg days 1, 8, 15, 22 ASCT Melphalan 200 mg/m2 Consolidation: KRD as induction for 2 cycles Maintenance: 28 day-cycle Lenalidomide 10 mg days 1 – 21 + Dex 20 mg days 1, 8, 15, 22 for 2 years (N=60)	High-risk by MAYO 2008 or PETHEMA: MAYO 21% PETHEMA 52% Both 27%	Yes/MFC	After induction (n=60): 95(40/28) After ASCT (n=55): 95(64/58) After consolidation (n=55): 100(78/65) After maintenance (n=40) 100 (85/68)	At 30 months PFS 93% (5 patients have biological progression)	After induction: -Infection 10% -Neutropenia 3% -Thrombocytopenia 5%
2019, Bustoros ASH 2019) [42] NCT02916771 Ongoing study	Induction: 28 day-cycle [C1-9]: Ixazomib 4 mg p.o. days 1, 8, 15 + lenalidomide 25 mg p.o. days 1–21 + dex (40 mg p.o. days 1, 8, 15, 22 Maintenance: 28 day-cycle [C10-24]: Ixazomib 4 mg p.o. days 1, 8, 15 + lenalidomide 15 mg p.o. days 1–21 (n=45)	IMF 2019 criteria: 53.4% are high-risk	Yes/cfDNA and CTCs	- At least 1 cycles of treatment: 91(31/ongoing) - At least 9 cycles: 97(42.4, ongoing)	Ongoing	- Hypophosphatemia 4.2% - Hypertension 6.3% - neutropenia 4.4% - Thrombocytopenia 4.4%
2018, Liu (ASH 2017) NCT02279394 N= 50 [43] Ongoing study	Induction: 28 day-cycle [C1-2] Elotuzumab 10 mg/kg i.v. days 1, 8, 15, 22 + lenalidomide 25 mg p.o. days 1–21 + dex 40 mg p.o. days 1, 8, 15, 22 [C3-8]: Elotuzumab 10 mg/kg i.v. days 1, 15 + lenalidomide as 25 mg p.o. days 1–21 + dex 40 mg p.o. days 1, 8, 15 Maintenance: 28 day-cycle [C9-24] Elotuzumab 10 mg/kg i.v. days 1 + lenalidomide 25 mg p.o. days 1–21 (n=50)	High-risk by MAYO 2008 or PETHEMA	No	84(6/NA)	3-year PFS 95%	- Hypophosphatemia 34% - neutropenia 26% - Lymphopenia 22% - 1 patient had DKA sepsis and death
2019, Mailankody NCT02697383 Ongoing study	Induction: 28 day-cycle [C1-12] Ixazomib + dexamethasone Maintenance: 28 day-cycle [C1-24] Ixazomib (n=14)	High-risk by MAYO 2008 or PETHEMA: MAYO 2008: 14% PETHEMA: 79% Both: 7%	NA	After induction: 64(0/NA)	On going	- Gastrointestinal event 21% - Lung infection 14%
Lenalidomide alone of with dexamethasone regimen
QuiReDex [4, 61] Lenalidomide/dex vs observation 2013, Mateos 2015, Mateos N=119	Induction: 28 day-cycle [C1 - 9] Lenalidomide 25 mg p.o. days 1–21 + dex 20mg p.o. days 1-4, 12-15 then Maintenance: 28 day-cycle [C1 - 24] Lenalidomide 10 mg days 1 – 21 (n=57)	High-risk by MAYO 2008 or PETHEMA: MAYO 2008: 18% PETHEMA: 40% Both: 42%	No	After induction: 79(14/NA) After maintenance: 90(26/NA)	Median time to progression NR 3-year PFS 77% 3-, 5-year OS 94%, 88%	- Infection 6% - Asthenia 6% - Neutropenia 5% - Skin rash 3% - Thrombocytopenia 2% - Anemia 2% - Diarrhea 2%
	Observe (n=62)	MAYO 2008: 13% PETHEMA: 39% Both: 48%		0	Median time to progression 23 months, HR 0.18, p<0.001 3-year PFS 30%, p<0.001 3-year OS 80%, 71%, p= 0.03	None
2019, Lonial	[C1 – progressive disease]: 28 day-cycle Lenalidomide 25 mg p.o. days 1–21 (n=90)	Risk by IMF 2019 (low/intermediate/high): 34/38/28%	No	50 (0/NA)	3-year PFS: 91%	- Neutropenia 14% - Infection 10% - Hypertension 9% - Skin 6%
	Observe (n=92)	29/37/34%		0	3-year PFS: 66 HR 0.28, p=0.002% HR for high-risk patient 0.09,
Immunotherapy
2019, Brighton [54] Phase 2 RCT N=85	[C1-progressive disease]: Siltuximab 15 mg/kg i.v. in 2 hour q 4 week (n=43)	NA but included UHR 23%	No	NA	1-year PFS: 84.5% Median PFS: NR	-Infections (5 patients in siltuximab and 6 patients in placebo group) -renal and urinary disorders (1 patient in the siltuximab group and 3 pts in the placebo group)
	Observation (n=42)	NA but included UHR 41%		NA	1-year PFS: 74.4% Median PFS: 23.5 months HR 0.5, p=0.0597
2019, Manasanch N= 13 [51]	[C1-8] Pembrolizumab 200 mg i.v. in 30 minutes q 21 days	Intermediate to high risk by either PETHEMA, MAYO 2008 or SWOG criteria	Yes/NGS	8(8/8)	2/13 patients progress to symptomatic MM at 24 months of follow-up time	-Transaminitis (3 patients)
2019, Manasanch (ASH 2019) N=24 [49]	Isatuximab 20 mg/kg i.v. in 4 week cycle [C1]every 1 week; [C2-6] every other week; [C7-30] every 4 week (n=24)	All patients are high-risk by PETHEMA criteria	Yes/MFC	Best response 63(5/5)	Ongoing	- Infusion reaction 8% - Headache 4% - Neutropenia 5% - Urinary tract infection 5%
CENTAURUS study [47] 2017, Craig C Hofmeister (ASH 2017) NCT02316106 N=93 Ongoing study	Daratumumab. 16 mg/kg IV in 8-wk cycles Long intensity (n=41): [C1]every 1 week; [C2-3] every other week; [C4-7] every 4 week; [C8-20] every 8 week	Intermediate or high-risk smoldering multiple myeloma	No	Interim at 6 months after enrollment last case: 56(2/NA)	1-year PFS: 98%	- infusion related toxicity 2% - Hypertension 5% - Hyperglycemia 2%
	Intermediate intensity (n=41): [C1]every 1 week and [C2-20] every 8 week			51(0/NA)	1-year PFS: 93%
	Short intensity (n=41): [C1]every 1 week			15(0/NA)	1-year PFS: 89%
2018, Jagannath N=31 [46]	[C1] Elotuzumab 20 mg/kg i.v. days 1, 8 then [C2-progressive disease] Elotuzumab monthly q 4 week	MAYO 2008 (intermediate): 93%	No	Comparable both group: 10%(NA/NA)	Comparable both group: 2-year PFS 69%	Total grade 3-4: 47% -Upper respiratory tract infection 7%
	[C1] Elotuzumab 10 mg/kg i.v. days 1, 8, 15, 22 [C2-progressive disease] Elotuzumab monthly q 2 week	MAYO 2008 (intermediate): 94%				Total grade 3-4: 38% -Fatigue 6% -Diarrhea 6% -Insomnia 6%

Abbreviation: C, cycle; cfDNA, cell-free DNA; CTC, circulartory tumor cells; MFC, multicolor flow cytometry; NA, not available; OS, overall survival; PFS, progression free survival

^*PFS in all studies is measured as time from study entry to progression to MM with CRAB criteria or death, except 2019 Lonial ECOG study and CENTAURUS with PFS there being time from study entry until death or progression to MM with SLiM-CRAB criteria. (SLiM-CRAB (S=sixty, Li=light chains, M=MRI, C=calcium [elevated], R=renal failure, A=anemia, B=bone lesions)

Another phase III study in SMM patients comparing lenalidomide alone versus observation was published in 2019. This ECOG study in 182 SMM patients (92 and 90 patients in lenalidomide and observation arms, respectively) showed a PFS benefit favoring the lenalidomide arm [45]. This study included patients at low-, intermediate- and high-risk of progression to MM according to the MAYO 2008 criteria. Importantly, this study used advance imaging (PET/CT or whole body or spine MRI) and defined the end point as MM requiring treatment which including symptomatic MM with CRAB criteria or biomarkers of malignancy [11]. At a median follow-up of 35 months, 50% of patients in the lenalidomide arm after a median of 23 cycles had at least a PR (CR 0%) compared with 0% response in observation arm. Lenalidomide single agent resulted in a 72% reduction in the risk of transformation to MM in all patients. Twenty-five high-risk SMM patients by MAYO 2018 criteria treated with lenalidomide had a 91% risk reduction to MM compared to the observation arm.

Patients in the lenalidomide-based arms of both studies, QuiReDex and ECOG, had higher second primary malignancies rates of 6% and 5.2% compared with the observation arms at 3% and 3.5%, respectively. As of January 2020, these studies have not led to the specific approval of lenalidomide for the treatment of SMM by any regulatory agency.

Numerous efforts are underway to investigate the best therapeutic approach for patients with SMM. These efforts seems to correspond to two distinct schools of thought. One, which would treat myeloma early. As such, patients with SMM receive the same treatment as newly diagnosed MM, they just receive the treatment earlier on (before development of CRAB criteria or biomarkers of malignancy). Two, by treating SMM patients with lower intensity or immunotherapy treatment approaches. Both are currently under investigation with the goals to reduce tumor burden, delay the time to progression to myeloma and ultimately, provide a cure to MM [36, 37].

Treatment of early myeloma with myeloma-like regimens

A pivotal study of 18 SMM patients using myeloma-like regimen carfilzomib-Rd (KRd) for 8 cycles followed by 2 years of lenalidomide maintenance without autologous stem cell transplantation (ASCT) is the first study that demonstrated persistent MRD negativity in SMM patinets which aimed to induce deep responses and evaluate the possibility of cure [38, 39]. SMM patients in this study showed consistently higher rates of ORR, CR and MRD negativity when compared to a parallel cohort of newly diagnosed MM patients. 83% of patients achieved MRD negativity after initial therapy and at a median follow-up time of 43.3 months, 63% of the patients continued to be MRD negative with 71% PFS and 100% OS. The GEM-CESAR phase II study used initial therapy with KRd then autologous stem cell transplant (ASCT), consolidation and maintenance in 90 patients with SMM. This therapy had a 100% ORR and MRD negativity rate of 56% after ASCT [40, 41]. This MRD negativity rate met the primary goal of the study to have an MRD negative rate of more than 50% after ASCT. The 30-month PFS was 93% with only 5 patient having biochemical relapse.

The lenalidomide plus dexamethasone (Rd) backbone has been studied in combination with elotuzumab or ixazomib in two phase 2 studies [42, 43]. Both studies demonstrated high ORR at 89% (CR 19%) and 86% (CR 6%) in ixazomib-Rd and elotuzumab-Rd, respectively. Most side effects were manageable, except for one patient in the elotuzumab-Rd that passed away from diabetes ketone acidosis and sepsis [42, 43]. Another study combined ixazomib with dexamethasone in 14 high-risk SMM [44]. The ORR was 64% after 12 cycles of initial therapy (Table 5).

Low-intensity or novel immunotherapy approach

Monoclonal antibody monotherapy with agents like elotuzumab (targeting SLAMF7), pembrolizumab (targeting PD-1), daratumumab and isatuximab (targeting CD38) has been investigated in the treatment of SMM.

The CENTAURUS study investigated daratumumab monotherapy in 93 SMM patients with either intermediate or high-risk SMM with 3 different intensity schedules, detailed in table 5 [47, 48]. The long and intermediate intensity groups treated patients for a maximum of 3 years. The ORR for these groups was 56% (2% CR) and 51% (0% CR) with 1-yeat PFS at 98% and 93%, respectively. Isatuximab can also induce deep responses in selected SMM patients.

Isatuximab single agent was investigated in a phase II study of 24 high-risk SMM patients selected by PETHEMA criteria. The best ORR was 64% with 1 patient achieving a CR MRD negative by advanced flow cytometry at 10⁻⁵ [49]. At a median follow up of 12 months, 2 out of 24 patients progressed to MM. No deaths were reported. Patients reported improved quality of life with treatment. Quality of life scores were higher after treatment when compared to baseline.

Elotuzumab single agent in high-risk SMM was evaluated in 31 SMM patients and showed comparable response rates between the 20 mg and 10 mg per kg dose of 10% ORR and a 2-year PFS of 69% [46]. The expression of programmed cell death-ligand 1 (PD-L1) on aberrant plasma cells in asymptomatic monoclonal gammopathy patients has been associated with an increased risk of progression to MM [50]. The anti-PD1 antibody pembrolizumab was investigated to treat 13 intermediate- and high-risk SMM patients. The ORR was 8% (1/13) ORR. The responder had an extraordinary response. This patient had baseline high-risk SMM in both FISH (gain CKS1B and 17p deletion) and GEP 70. This would also signal that the patient would evolve to high-risk MM, which represents a treatment challenge. After only 3 cycles of the treatment, this patient achieved a CR with MRD negativity at 10⁻⁴ level by next-generation sequencing. Correlative analysis revealed that the responder had a preexisting immune response with both a high level of PD-1 expression and increased interferon-gamma gene signature, a main driver for PD-L1 expression on tumor cells and host cells similar to that found in solid tumors [51] [52]. This patient has an ongoing response and remains in remission even after 3 years of treatment. Anti-PD-1/PD-L1 drug development in SMM has been halted by the FDA due to a higher rate of deaths in the pembrolizumab arm of two phase 3 studies, the KEYNOTE-183 and KEYNOTE-185, and in the nivolumab arm in the CHECKMATE study [53]. Despite this, a portion of SMM patients may have a pre-existing immune response and immunotherapy approaches may be of value in this subset.

Interleukin-6 is a cytokine important in the development of MM. Siltuximab, an anti-interleukin 6 monoclonal antibody, was tested as monotherapy in high-risk SMM compared to observation [54]. This study included 30% of patients that would be defined as MM per 2014 IMWG criteria. Siltuximab showed prolonged PFS however this did not reach statistical significance (HR 0.5, p=0.597).

Clinical implications

SMM is a widely heterogeneous precursor stage and varies widely in risk of progression to MM from 5% per year to 50% in 2 years in most published models. Most studies that have been conducted to evaluate clinical and genomic risk factors of progression are retrospective or single center. In 2019, more than 2000 patients were included in an international retrospective study to evaluate clinical risk factors (IMF 2019). This big effort did however not include genetic or immunologic information on the risk of progression, which have been shown in other studies to be important. It is likely that many individual factors predict progression to MM and that these factors may be different patient to patient making it exceedingly difficult to determine with exact precision the individual risk of progression of a particular SMM patient to MM. Indeed, well conducted prospective studies with validation in multiple cohorts are needed to best estimate the individual risk of progression.

It is encouraging that already two randomized studies (even with their limitations) showed improved PFS and in one instance OS when compared to observation. The 2019 ECOG study that compared lenalidomide single agent to observation also treated patients with low-, intermediate- and high-risk of progression and all the subgroups seemed to benefit from treatment. This challenges the idea that only high-risk SMM should be treated and it remains to be seen if it will carry over in other studies. The higher rate of second primary malignancies in randomized studies of lenalidomide is a concern, however this did not preclude the favorable PFS (and OS) reported by the studies.

A randomized phase III registration study of isatuximab, lenalidomide and dexamethasone compared to lenalidomide and dexamethasone in high-risk SMM is planned and could lead to an approval for treatment of SMM. Other randomized phase III studies are ongoing for treatment of SMM including a combination of daratumumab, lenalidomide, dexamethasone compared to lenalidomide and dexamethasone.

Given data from the ECOG 2019 study some SMM patients may elect to be treated with lenalidomide single agent after a thorough risk/benefit conversation with their physician and discussion of informed consent. It is likely however that most patients and physicians will elect to continue with an observation approach. Our recommendation for the overall management of SMM is to enroll patients on treatment clinical trials if feasible so that we may establish an excellent alternative to the wait and watch approach. Ideally this treatment needs to be highly efficacious with low toxicity and able to maintain deep remissions throughout time.

Summary

SMM is a vastly heterogeneous precursor of MM. Models that estimate the individual risk of progression as well as treatment options for these patients are an area of ongoing and very active research. Fortunately for these patients and despite limitations, two randomized studies have shown clinical benefit of lenalidomide with our without dexamethasone compared to observation. It is unknown whether this will receive regulatory approval. When treated with myeloma-like newly diagnosed regimens (such as KRd), patients with SMM have higher response rates and higher rates of MRD negativity that are sustained in time and could lead to a cure in some patients. When treated with single agent CD38 antibodies high ORR are seen (about 50-60% of patients) with almost non-existent toxicity. Combination therapies including CD38 antibodies are planned in large randomized phase III studies which could result in deep remissions without severe toxicity and could lead to an approval for the treatment of SMM.

Practice points.

• High-risk SMM has an overall rate of progression to MM of about 50% within 2 years of diagnosis

• To prevent organ damage, early treatment with lenalidomide single agent in SMM has been seen to improve PFS when compared to observation

• Current clinical models that predict the individual risk of MM progression in SMM are highly discordant and this is an intensive area of research

• Single agent CD38 antibodies are very well tolerated and results in high responses in a subset of patients with SMM

• Large randomized studies in SMM are planned or ongoing which could lead to a change in practice for these patients

Research Agenda.

• Well-designed prospective studies focusing on the genomic and immune markers that may drive progression are needed

• Prospective screening studies in monoclonal gammopathies are ongoing and are needed to prove a benefit for screening individuals to diagnose SMM early on and offer close follow up or potential treatment before progression to MM

• Participation of SMM patients in clinical trials is essential to establish the best treatment for these patients

Abbreviations

ASCT

autologous stem cell transplantation

BM

bone marrow

CR

complete remission

FISH

Fluorescence in situ hybridization

GEP

gene expression profiling

IMWG

international myeloma working group

KRd

carfilzomib-lenalidomide-dexamethasone

mAb

Monoclonal antibody

MGUS

monoclonal gammopathy of unspecified significant

MM

multiple myeloma

MRD

minimal residual disease

MRI

magnetic resonance imaging

ORR

overall response rate

OS

overall survival

PD-L1

programmed cell death-ligand 1

PET/CT

positron emission tomography/computed tomography

Rd

lenalidomide plus dexamethasone

SFLC

serum free light chain

SMM

smoldering multiple myeloma

SWOG

Southwest Oncology Group

TTP

time to progression to MM