To treat or not to treat: a state-of-the-art overview of smoldering multiple myeloma

Smoldering multiple myeloma (SMM) is a plasma cell disorder characterized by an elevated monoclonal protein and increased bone marrow plasma cells (BMPC) without end-organ damage. It is an intermediate stage on the spectrum of plasma cell disorders, between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic (active) multiple myeloma (MM). While most patients remain asymptomatic for years, a high-risk subset progresses rapidly. Traditional “watch-and-wait” strategy while avoiding toxicities associated with unnecessary therapy, can potentially delay treatment in those at increased risk for progression to MM associated with painful bone lesions, anemia, kidney failure and hypercalcemia. Hence, selection of the appropriate patient for treatment by accurate determination of individual risk of progression is vital in improving outcomes while avoiding toxicity. This review discusses the risk-stratification methods and evaluate various clinical therapeutic interventions for high-risk SMM, including immunomodulatory drugs, monoclonal antibodies, bispecific antibodies, and Chimeric Antigen Receptor- T cell (CAR-T) therapies along with their outcomes, safety profiles and limitations. We also discuss the importance of shared decision-making between clinicians and patients, tailoring monitoring and treatment to individual preferences to ensure that each patient receives maximum benefit and minimum harm.

1 Introduction

1.1 Natural history and prevalence of smoldering multiple myeloma

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell dyscrasia characterized by elevated levels of monoclonal protein in the blood and/or urine, clonal plasma cells in the bone marrow, and the absence of myeloma-defining events that cause end-organ damage (1).

In 1980, Kyle and Greipp introduced the concept of SMM for the first time as an asymptomatic plasma cell disorder characterized by monoclonal plasma cell accumulation in the bone marrow. SMM represents an intermediate stage in the spectrum of plasma cell disorders between monoclonal gammopathy of undetermined significance (MGUS) and overt multiple myeloma (MM) (2). Between 1988 and 2003, the lack of standardized diagnostic criteria for SMM led to variable definitions across studies, making the diagnosis and interpretation of clinical outcomes challenging (3–9).

As diagnostic definitions have become more standardized over time, more reliable data on the epidemiology of SMM has become available. A recent nationwide screening study (N = 80,759) from Iceland (iStopMM) reported a prevalence of SMM of 0.53% among individuals aged 40 years and older, with higher rates observed in men (0.67%) compared to women (0.39%), and an increase in prevalence with advancing age (10). SMM represents a precursor condition to MM or AL amyloidosis in a subset of patients, depending on their individual risk of progression, while others may remain stable for many years without developing symptomatic disease (11). According to data from a Scandinavian population-based study, approximately 14% of all newly diagnosed myeloma cases originate from SMM (12).

Until recently, the standard of care for SMM consisted primarily of active monitoring. However, over the past decade, the therapeutic landscape has begun to shift as emerging evidence from multiple clinical trials, particularly in high-risk SMM, suggests potential benefit from early intervention. Given these developments, it is increasingly important to synthesize contemporary data to guide clinical decision-making. In this review, we aim to provide an updated and comprehensive overview of SMM, including current diagnostic criteria, risk-stratification models, and the evolving evidence supporting early treatment approaches.

1.2 Definition of smoldering multiple myeloma

SMM can be differentiated from MGUS and active MM based on monoclonal protein levels, BMPC infiltration, and the presence or absence of end-organ damage (12). The diagnostic criteria for SMM were first defined by the International Myeloma Working Group (IMWG) in 2003 as a serum M protein level of ≥30 g/L and/ or ≥10% BMPC, with no evidence of myeloma-defining events indicative of end organ damage (i.e. CRAB criteria: hypercalcemia, renal failure, anemia, or lytic bone lesions) (13). However, the 2003 IMWG definition was subsequently updated as data from large prospective cohorts identified a subset of “high-risk” SMM patients with biomarkers that predicted a ≥ 80% of progression to active MM within two years (14–16). In 2014, the IMWG added three such “SLiM” biomarkers- S: ≥ 60% clonal BMPC; Li: serum involved / uninvolved free light-chain ratio ≥ 100; and M: more than one focal lesion on magnetic resonance imaging (MRI), to the traditional CRAB criteria in its updated diagnostic framework, collectively known as the SLiM-CRAB criteria, which led to reclassification of 10-15% of patients formerly labeled as SMM as having active MM (15).

Advances in imaging including low-dose whole body CT, MRI, 18 F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) with increased sensitivity have improved the detection of extramedullary disease that necessitated revisions to the diagnostic criteria (17).

Therefore, the 2014 revised diagnostic criteria developed by the IMWG defined SMM as follows:

● Serum monoclonal protein (IgG or IgA) ≥ 30 g/L or urinary monoclonal protein ≥ 500 mg/24 h, and/or

● Clonal BMPC 10-60%,

● Absence of any myeloma-defining event (CRAB or SLiM) or amyloidosis

Both laboratory thresholds must be met to classify a patient as SMM, with a new BMPC cutoff of 60% being added to the old criteria to differentiate SMM from MM (15).

2 Pathophysiology, cytogenetics and risk stratification of smoldering multiple myeloma

2.1 Pathophysiology: role of the bone marrow stromal microenvironment

The progression from MGUS to SMM and eventually MM, is driven by a series of interactions between the bone marrow microenvironment and the plasma cells. Early in disease evolution, the immune microenvironment (IME) effectively maintains plasma cell dormancy via immune surveillance mechanisms, involving natural killer (NK) cells, CD8⁺ T cells, and antigen-presenting cells. However, the malignant plasma cells evade this surveillance by downregulating NK cell activating receptors (such as CD226) and expanding immunosuppressive cell populations, including regulatory T cells and monocytes (18, 19).

As SMM advances, plasma cells interact more extensively with bone marrow stromal components, particularly mesenchymal stem cells, which in turn, overproduce chemokine C-X-C motif ligand 12 (CXCL12), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and other proinflammatory cytokines, while both conventional dendritic cells (via CD28-CD80/CD86 interactions and interleukin-6 (IL-6)) and plasmacytoid dendritic cells (via IL-6 and type I interferons) promoting plasma cell proliferation, chemotaxis, drug resistance and disease persistence (20–27).

Apart from the above immune components, the non-immune stroma undergoes structural changes as well. Osteoclast activity increases while osteoblast function is suppressed, resulting in bone destruction and a more permissive niche for tumor cells. Extrinsic factors such as gut dysbiosis (for example, the overgrowth of Prevotella heparinolytica) can stimulate interleukin-17 (IL-17) producing helper T-17 (Th17) cells, which in turn activate IL-6 producing eosinophils that promote inflammation and MM progression (28). Additionally, increased angiogenesis and extracellular matrix remodeling further stabilize the niche and facilitate clonal plasma cell expansion (21, 23). Together, these cumulative changes enable the bone marrow microenvironment to eventually lead to the transition from MGUS to SMM and eventually MM.

2.2 Cytogenetics

Various factors influence disease progression as revealed by the cytogenetic and genetic abnormalities. Primary events (trisomies and immunoglobulin heavy chain (IgH) translocations) initiate plasma cell abnormalities in MGUS, while secondary mutations (alterations in the mitogen-activated protein kinase pathway (MAPK), DNA repair pathways (deletion 17p, Tumor Protein 53 (TP53), and Ataxia Telangiectasia Mutated (ATM) single nucleotide variants (SNVs)) and myelocytoma viral oncogene homolog (MYC) dysregulation) increase the risk for progression of SMM to MM (29). Analysis of whole genomes from paired SMM-MM samples revealed that the mutational and structural landscape at the smoldering stage closely mirrors MM, with two patterns of progression observed: a “static model,” in which sub clonal structure remains stable as disease burden increases, and a “spontaneous evolution model,” in which new subclones emerge over time (30).

A study of 82 patients using targeted sequencing showed that SMM with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations is associated with shortened time to progression (TTP) (Hazard Ratio (HR): 3.5, p = 0.001) (31). Another study of 351 SMM patients identified distinct molecular cytogenetic subtypes, revealing trisomies, IgH translocations, and monosomy13/del(13q) with prognostic significance. Median TTP was 28 months for t (4, 14) (high-risk), 34 months for trisomies (intermediate-risk), 55 months for t (11, 14), v-maf musculoaponeurotic fibrosarcoma oncogene homolog (MAF) translocations and those with both trisomies and IgH translocations (standard-risk), and no TTP reached for patients with no detectable abnormalities (low-risk), p=0.001. Shorter TTP was associated with deletion 17p (24 months), while overall survival (OS) was significantly worse in patients with t (4, 14) compared to those with t (11;14) (105 vs. 147 months, P = 0.036) (32).

Several cytogenetic abnormalities have been consistently recognized as high-risk indicators for disease progression in both clinical trials and prognostic models. Gain or amplification of 1q, t (4;14), t (14;16), deletion 17p, and deletion or monosomy 13q are integrated into the IMWG revision of the Mayo 2/20/20 model and are strongly linked with more aggressive disease behavior (33). However, not all clinical trials stratify patients based on cytogenetic risk, and inclusion criteria often vary depending on trial design and therapeutic goals. For example, the B-PRISM trial identifies high-risk SMM based on these cytogenetic abnormalities whereas, the Immuno-PRISM trial focuses on 1q gain and t (4;14) as key cytogenetic criteria (34, 35). The ASCENT trial incorporates a composite score that includes these and other high-risk FISH abnormalities (36). Together, these lesions signify underlying genomic instability and serve as major determinants of rapid progression from SMM to active MM.

2.3 Evolving evidence and clinical considerations in the treatment of smoldering multiple myeloma

Advances in understanding the natural and differential course of SMM have led to questioning the traditional “watch and wait” approach. Historically, it was believed that patients could be safely monitored until clinical signs of end-organ damage occurred, at which point therapy was initiated (37–39). This strategy helped spare the patients from the toxic adverse effects associated with treatments that could adversely impact their quality of life (QOL).

However, growing clinical evidence now supports early intervention in patients with high-risk SMM patients who rapidly progress to symptomatic myeloma (often associated with serious complications, including but not limited to irreversible kidney damage, spinal cord compression, pathological fractures, persistent bone pain and higher mortality rate exceeding 10%) in a short time frame (40). Early intervention in these individuals has been shown to delay disease progression, avert end organ damage, improve OS, and reduce the need for more aggressive treatment later in the disease. Moreover, the novel treatment options have a better toxicity profile compared to the traditional treatments, further supporting the recommendation of early intervention.

2.4 Risk stratification

Risk stratification is essential for identifying high-risk SMM patients, predicting progression to active MM, and selecting individuals who may benefit from early therapeutic intervention using models based on laboratory and clinical parameters (See Table 1). Among these, the Mayo Clinic 2018 (2/20/20) model and the International Myeloma Working Group (IMWG) 2020 update are the most widely applied in clinical trials due to their reliance on routine, reproducible laboratory values (33, 41). The IMWG model extends the Mayo framework by incorporating cytogenetic abnormalities such as t (4,14), t (14;16), +1q and del(13q)/monosomy 13 (41, 42). In addition, the revised IMWG criteria reclassified approximately 10-15% of patients who were formerly diagnosed with SMM as having MM, based on the presence of “SLiM-CRAB” criteria (41). Together, these models have provided a standardized foundation for identifying “high-risk” SMM, enabling consistent patient selection in multicenter studies such as ECOG-E3A06, which defined eligibility using these parameters (43–45).

Table 1

Table 1. Risk stratification models for smoldering multiple myeloma.

The Spanish PETHEMA group (Programa de Estudio y Tratamiento de las Hemopat í as Malignas) model involves stratifying patients into low, intermediate, and high-risk groups based on: a) the presence of ≥95% aberrant BMPC as determined by flow cytometry, where aberrancy is defined by CD38⁺ cells showing absence or under expression of CD19 and/or CD45, or overexpression of CD56; and/or b) immunoparesis, which is identified by a reduction in one or more uninvolved immunoglobulin heavy chains. Patients with neither risk factor are considered low, intermediate or high-risk which correlates strongly with progression-free survival (PFS) at five years (42).

The PANGEA model is a dynamic risk stratification tool that incorporates patient’s evolving clinical and laboratory biomarkers to predict disease progression. Two versions of the model were developed based on whether the data regarding BMPC% was included, making it convenient for use in various individuals where bone marrow data is unavailable. The key parameters used in the model include age, involved/uninvolved free light chain ratio, M-spike concentration, creatinine level, hemoglobin trajectory with or without BMPC%. The model stratified patients into four risk groups based on predicted progression probabilities: low, intermediate-low, intermediate-high, and high (46).

When compared collectively, the existing risk stratification models vary in practicality, biological depth, and applicability to clinical research. Importantly, although the IMWG criteria enhance prognostic precision by incorporating high-risk FISH abnormalities, FISH testing is not universally available across clinical settings. Due to this limitation, the Mayo 2/20/20 model and its IMWG update are the most frequently employed in clinical trials because they rely on standardized, widely available laboratory measurements, facilitating consistent application across centers. The IMWG refinement enhances prognostic accuracy by incorporating cytogenetic abnormalities to risk assessment. In contrast, the PETHEMA model needs flow cytometry that lacks uniform implementation since it is not available everywhere. PANGEA model includes changes in patient’s hemoglobin over time thereby improving the precision of individual risk assessment and the version without the need for BM assessment makes it applicable even in settings with limited resources.

3 Therapeutic interventions in high-risk smoldering myeloma

3.1 Immunomodulators

Recently, clinical trials investigating early treatment with novel agents for patients with high-risk SMM have shown significant benefit in terms of delaying progression to symptomatic myeloma (47)(See Table 2). The earliest evidence supporting early intervention came from studies using immunomodulatory drugs in combination with corticosteroids. In 2013, the Spanish Myeloma Group randomly assigned participants with high-risk SMM to receive lenalidomide (a second-generation immunomodulatory drug (IMiD) that acts by modulation of the CRL4^CRBN E3 ubiquitin ligase) plus dexamethasone (Rd) regimen or observation. High-risk SMM was defined according to the Spanish PETHEMA (GEM) flow-cytometry risk model. The primary endpoint was TTP to MM (48, 49).

Table 2

Table 2. Summary of clinical trials evaluating early therapeutic intervention in high-risk smoldering multiple myeloma.

After a median follow-up of 12.5 years (ranging from 10.4 to 13.6 years), the median TTP to MM was 2.1 years in the observation cohort compared to 9.5 years in the Rd treatment cohort (HR: 0.28, 95% CI: 0.18-0.44, p < 0.0001). This study had several limitations: it compared lenalidomide and dexamethasone (Rd) to inadequate care, as some control patients eventually required treatment, and it was a phase 2 trial underpowered to assess OS, potentially leading to exaggerated results. Additionally, the combination regimen used made it difficult to isolate the specific contribution of lenalidomide. Modern imaging techniques like MRI and PET scans were not used at randomization, raising concerns about enrolling patients with symptomatic myeloma. In addition, the multiparametric flow cytometry criteria for defining high-risk SMM were not widely accessible outside the trial centers, limiting the generalizability of the results (43, 50–53).

Lenalidomide was evaluated in patients with intermediate- or high-risk SMM, requiring participants to have ≥10% bone marrow plasma cells (or sheets of plasma cells) along with an abnormal serum free light chain ratio, initially defined as <0.26 or >1.65. Early in the study, enrollment criteria were narrower and restricted participation to individuals diagnosed with high-risk SMM within the prior year and those with more pronounced free light chain abnormalities (<0.125 or >8). However, these criteria were relaxed in a protocol amendment implemented in December 2013, after the first 21 patients had enrolled, to facilitate improved accrual. The study compared lenalidomide monotherapy with observation. The primary endpoint was progression-free survival (PFS), defined as the TTP to MM requiring both end-organ damage and biochemical progression (43).

After a median follow-up of 35 months, half of the patients in the lenalidomide cohort showed response to therapy (95% CI, 39% to 61%), whereas none did in the observation cohort. Lenalidomide monotherapy improved PFS compared to observation with 1-, 2-, and 3-year PFS rates of 98%, 93%, and 91%, compared to 89%, 76%, and 66% in the observation group (HR:0.28; 95% CI, 0.12 to 0.62; P = .002).

The benefit was most pronounced in high-risk SMM compared to intermediate-risk disease. Nearly half of the patients on lenalidomide discontinued therapy due to toxicity, emphasizing the importance of patient selection by age, comorbidity, and fitness. The 3-year cumulative incidence of second primary malignancies (SPM) was 5.2% in the lenalidomide arm versus 3.5% in observation, and that needs to be discussed while making informed decision regarding early treatment for SMM.

A multi-drug regimen involving a combination of proteasome inhibitor (PI), IMiD and steroids was tested in high-risk SMM, including induction therapy, ASCT, consolidation, and maintenance, with the goal of achieving sustained minimal residual disease (MRD) negativity at 5 years (54). High-risk SMM patients were defined according to either the Mayo 2008 model or the GEM-Pethema model. Induction therapy involved six cycles of carfilzomib, lenalidomide, and dexamethasone (KRd) followed by intensification with high dose melphalan and ASCT. Patients then received consolidation with two additional cycles of KRd before transitioning to maintenance with Rd for up to two years. The primary endpoint was rate of MRD negativity by next-generation flow cytometry (NGF) following induction and ASCT, with an aim to increase the MRD negative rate from 34% to 50% following ASCT. The trial’s primary endpoint was achieved in more than half of the patients reaching MRD negativity post-ASCT [31% post-induction] as measured by NGF. After a median follow-up of 17 months, almost all the patients were alive and progression-free (54).

Despite these promising outcomes, several limitations of this trial warrant consideration. Its use of the Spanish/PETHEMA model, lack of mandatory MRI at baseline to rule out focal bone lesions and inclusion of patients who, by the current Mayo 2/20/20, would be diagnosed with MM due to myeloma-defining biomarkers, limits the generalizability of its findings to contemporary high-risk SMM populations. The absence of a control arm also prevents accurate assessment of the absolute benefit offered by early intervention and risk of toxicity. Notably, 4.4% of patients died from non-myeloma-related causes, and only 28% of patients maintained MRD-negativity at four years, questioning the curative benefit of intensive treatment in an asymptomatic population. Moreover, the absence of QOL assessments undermines the potential physical, emotional, and financial burdens of treatment in a population among which some may not progress to active disease (41, 54, 55).

3.2 Monoclonal antibodies

The role of daratumumab, an anti-CD38 monoclonal antibody, was investigated in intermediate- or high-risk SMM defined as 10-60% BMPC infiltration plus at least one of the following: serum M-protein ≥3 g/dL (or IgA ≥2 g/dL), urine M-protein >500 mg/24 h, abnormal free light chain ratio (<0.126 or >8) with serum M-protein between 1 and <3 g/dL or involved free light chain level ≥100 mg/L (with an abnormal ratio but not ≤0.01 or ≥100). Patients were assigned to intense, intermediate, or short dosing schedules. The co-primary endpoints included CR rate and the progressive disease (PD)/death rate (DR) per patient-year. After a median follow-up of 25.9 months, the CR rates were 4.9%, 9.8%, and 0% for the intense, intermediate, and short groups, respectively. The PD/DR were 0.059 (80% CI: 0.025-0.092) for the intense regimen, 0.107 (80% CI: 0.058-0.155) for the intermediate regimen, and 0.150 (80% CI: 0.089-0.211) for the short regimen. Pharmaco-kinetic analysis showed sustained exposure without new safety concerns that supported further investigation in a phase 3 study (56).

Dimopoulos et al. compared subcutaneous daratumumab versus active monitoring in high-risk SMM. It was defined by clonal BMPC% ≥10 plus at least one of the following: serum M-protein ≥30 g/L, IgA subtype smoldering myeloma, reduction of two uninvolved immunoglobulins (immunoparesis), an involved: uninvolved free light chain ratio ≥8 to <100, or clonal BMPC% >50 to <60 with measurable disease. Screening also included centralized review of CT and MRI imaging to assess for focal or lytic lesions prior to enrollment. Treatment continued for 39 cycles over 36 months, or until disease progression. The primary endpoint was PFS. With median follow-up of 65.2 months, daratumumab reduced risk of progression or death by half (HR 0.49; 95% CI, 0.27–0.98; P < 0.001). OS was 93% in the daratumumab arm and 86.9% in the active-monitoring group (HR 0.52; 95% CI, 0.36–0.67; P < 0.001) (44, 45). This study led to the approval of subcutaneous daratumumab for the treatment of high-risk SMM. Daratumumab, with its favorable toxicity profile and efficacy analysis, seems to be a feasible and beneficial option for this patient population. Also, the fixed treatment duration is another appealing feature given the parenteral route of administration and the travel to the infusion center it would involve for the patients.

Daratumumab has also been investigated as a fixed-duration quadruplet regimen with carfilzomib, lenalidomide and dexamethasone (Dara-KRd) for high-risk SMM. In this trial, high-risk SMM was defined by the Mayo 20/2/20 model or the IMWG 2020 risk score. The treatment regimen consisted of three phases with a total of 24 treatment cycles, each lasting 28 days (57). The primary endpoint was stringent complete response (sCR) at the end of maintenance. With a median follow-up of 25.8 months (95% CI, 21.3-29.1), the best ORR was 97%, with 37% achieving a sCR. It is of note that grade 3 or higher non-hematological toxicity was seen in half of the patients in this study and 15% experienced hematological toxicity. Hence, even though this combination treatment resulted in high responses that were deep including sustained MRD negativity, making it a potential treatment strategy in high-risk SMM, patient selection is very important given the high rate of toxicities (36).

A combination of daratumumab with bortezomib, lenalidomide, and dexamethasone (Dara-VRD) was tested in patients with high-risk SMM, defined by the Mayo 2018 2/20/20 model and additional features such as immunoparesis, evolving disease pattern, or high-risk cytogenetics including t(4;14), t(14;16), t(14;20), +1q, and del 17p. Treatment was administered over 24 four-week cycles spanning two years, with PBSC collection after six cycles. The primary objective of the study is the rate of sustained MRD negativity at two years. MRD negativity was achieved in 50% and 25% of evaluable patients at two years at thresholds of 10^-5 and 10^-6, respectively. These results highlight the potential of D-RVD regimen to delay progression to symptomatic MM (34). The absence of a control arm, small sample size and unknown long-term outcomes are some of the limitations of this study.

Ongoing studies are further exploring the role of daratumumab-based therapy in high-risk SMM, including phase 3 evaluations of Rd with or without daratumumab-hyaluronidase. The primary objective is to compare OS; secondary objectives include PFS, response rates, safety, toxicity and stem cell mobilization failure and early stem cell mobilization feasibility (NCT03937635) (58).

Isatuximab, another anti-CD38 IgG1 monoclonal antibody, has also been evaluated in high-risk SMM. This phase 2 (NCT02960555) is a multicenter, single-arm trial in which patients with high-risk SMM (per PETHEMA and Mayo criteria) received intravenous isatuximab for up to 30 cycles, initially as monotherapy and, in a second stage, in combination with lenalidomide. The primary endpoint was ORR. The ORR (≥PR) was 62.5%, including 5% CR (MRD negativity at 10^-5) (59).

Building on the above, there is an ongoing phase 3 trial that randomizes patients with high-risk SMM (per Mayo 2/20/20 and/or updated PETHEMA model criteria) to receive isatuximab plus lenalidomide and dexamethasone (Isa-Rd) versus Rd for up to 36 cycles of 28 days. The safety run-in part of the study showed a favorable safety profile for Isa-Rd with an ORR of 100%. It is of note that nearly half the patients had grade ≥3 treatment-emergent adverse events (TEAE). These findings suggest that isatuximab-based triplet therapy is highly active in high-risk SMM, although long-term PFS and OS data, as well as formal comparison with the Rd arm, are still awaited (50).

Other monoclonal antibodies such as elotuzumab (Elo), a humanized IgG1 antibody targeting Signaling Lymphocyte Activation Molecule (SLAMF7/CS1) have also been explored in SMM. In a phase 2 study, patients with high-risk SMM (per 2010 IMWG criteria) received elotuzumab monotherapy at either 20 mg/kg or 10 mg/kg in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was the correlation between baseline bone-marrow CD56^dim NK-cell proportion and maximal M-protein reduction. At 28-month follow-up, elotuzumab monotherapy was well tolerated and safe but had minimal activity in this setting (60).

Another study used Elo in combination with Rd in patients with high-risk SMM (per the Mayo or the Spanish criteria), with the primary endpoint being 2-year PFS. At 48 months, PFS was 88.7% (90% confidence interval [CI], 81.2%–96.9%), and OS was 95.6% (90% CI, 90.6%–100%). Grade 3–5 TEAEs including neutropenia, lymphocytopenia and hypophosphatemia were seen in more than 20% of the patients. These findings suggest that while SLAMF7-directed therapy alone may offer limited benefit, combination regimens such as Elo-Rd can achieve high response rates and prolonged disease control in high-risk SMM (61).

3.3 Bispecific antibodies

Teclistamab (TEC), is a bispecific antibody targeting B-cell maturation antigen (BCMA) that binds to both MM cells and T-cells, helping the immune system recognize and destroy myeloma cells (57). The Immuno-PRISM trial is an ongoing, randomized, phase 2 trial evaluating the efficacy of TEC, a bispecific antibody, against a control arm of Rd in high-risk SMM patients defined by either meeting two of the Mayo 2/20/20 criteria or by achieving a total score ≥9 on a composite scale (points assigned for free light chain ratio, M-protein level, BMPC%, and presence of high-risk FISH abnormalities). This study will continue for up to 24 months or until loss of clinical benefit, and all patients undergo PBSC collection after 4 cycles of therapy. Among patients with available FISH results, 64% had high-risk cytogenetic features including +1q and t (4;14). The primary endpoint is CR rate. At a median follow-up of 6 months, in the TEC arm ORR was 100% with CR in 42% compared to ORR of 66% with no CR in the control arm. In conclusion, TEC demonstrated tolerability and deep responses in high-risk SMM (35).

Several limitations were noted, including the lack of an observation cohort which makes it hard to gauge the true efficacy and safety of the intervention, potentially leading to overestimation of the benefit of treatment. When the average characteristics of Immuno-PRISM patients were evaluated using the PANGEA risk model, high-risk patients had only an 11% chance of progression at 2 years, suggesting an 89% likelihood of not requiring treatment during that period and raising concerns about potential overtreatment in this population. Additionally, the small sample size of 19 patients, limited follow-up, and possible toxicities from treatment with TEC, particularly in asymptomatic patients, may warrant caution. Finally, 24 cycles of treatment in this trial may be excessive, as the average time to MRD negativity was around 4 cycles.

Other bispecific antibody approaches are being explored in combination regimens. One ongoing study is comparing TEC plus daratumumab with talquetamab (bispecific antibody targeting G-protein coupled receptor family C group 5 member D/GPRC5D) plus daratumumab in high-risk SMM. This ongoing trial aims to determine if treating high-risk SMM with TEC or talquetamab in combination with daratumumab can delay the progression of high-risk SMM to active MM (NCT06100237).

3.4 Chimeric antigen receptor- T cell therapy

CAR-T therapy has been proven to be efficacious and safe in relapsed and refractory MM (RRMM). It is currently being investigated in SMM. A single arm, phase 2 study of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, in high-risk SMM reported safety and efficacy in the safety run-in cohort at a short 6-month follow-up. CR and MRD rates were both 100%. It is of note that patients did not receive induction therapy in this trial. Long-term follow up is required to determine whether these responses will be sustained and the effect on survival (62).

Collectively, these studies underscore the rapidly evolving landscape of early intervention in high-risk SMM with bispecific antibodies and CAR-T cell therapies showing remarkable potential to induce CR and MRD negativity and delay progression to MM. However, their long-term benefit, safety, and cost-effectiveness remain to be fully established.

4 Discussion

There has been a huge drive towards intervening early in patients with smoldering myeloma in an attempt to prevent its conversion to active myeloma and thereby stall the end-organ damage and reduce the likelihood of dying from it. Most studies have shown improved response rates and reduced rate of progression to MM with treatment compared to observation/active monitoring which makes it an appealing strategy (43–45). However, early therapeutic intervention presents its own set of challenges and remains a double-edged sword. While early treatment may benefit those at increased risk, it also increases the risk of overtreatment in patients who may potentially never progress to active disease, given the significant heterogeneity of SMM. This could result in unnecessary exposure to therapies with lack of curative potential, attendant treatment toxicities, both short-term and long-term, resulting in impaired overall health as well as the emergence of resistant clones.

Various criteria exist to stratify risk among patients with SMM; however, significant inconsistencies remain that limit its applicability across different clinical settings and geographic regions. Also, trials often use differing definitions of high-risk SMM, which can lead to misclassification. Some patients may be labeled as having SMM when they meet diagnostic criteria for MM, especially in the absence of advanced imaging. Progression rates among patients identified as high-risk vary widely, revealing the limitations of current models in predicting individual disease evolution. While most scoring systems provide a snapshot of risk at diagnosis, they fall short in accounting for the dynamic nature of the disease (14, 42). This can result in either premature initiation of treatment or missed opportunities for timely intervention. Additionally, the long-term effects of many agents are under investigation and remain unknown. This uncertainty underscores the need for caution.

The decision to initiate treatment in asymptomatic individuals is fraught with significant challenges. Exposing patients to immunomodulatory therapies without certainty of improved long-term outcomes risk not only physical toxicity but also emotional and psychological harm leading to impaired QOL. Labeling a patient as needing treatment may fundamentally alter their self-perception, reinforcing an identity of being ‘sick’ and potentially increasing the risk of anxiety and depression not only for the patient, but also for their caregivers. It is therefore essential that patients are involved in the decision-making process considering their priorities and expectations from treatment. They should be provided with transparent and balanced information regarding both the potential benefits and risks of early intervention, along with any limitations of current evidence. Financial toxicity further complicates the picture in resource-limited settings. Most novel therapies are expensive, require long-term administration, and can lead to lost productivity from missed workdays. While early treatment may be cost-effective in high-risk groups, applying the same approach to lower-risk patients is difficult to justify.

Identification of suitable candidates for treatment of SMM remains the subject of ongoing debate. The success of treatment of SMM, therefore, relies heavily on the accurate diagnosis and identification of the risk of conversion to MM along with personalized treatments tailored to individual patients. General health condition and medical comorbidities should be paid attention to when selecting candidates for treatment, given the potential for toxicity that would determine the overall risk-benefit analysis.

We recommend enrolling eligible patients with SMM in clinical trials, whenever possible, that would enable us to gain insights into the best strategies to manage this precursor condition for MM. Standard of care for SMM has been active monitoring until recently. However, given the significant benefit in delaying the progression to active myeloma or death in recent studies (44, 56), we recommend treatment with single agent daratumumab in eligible patients with high-risk SMM. The study that gained FDA approval for daratumumab in SMM showed a favorable safety profile, no adverse impact on the QOL with a small improvement in overall survival which makes it an appealing strategy to treat the high-risk population. Lenalidomide is another option for the treatment of high-risk SMM; however, the high incidence of adverse events, both hematological and non-hematological, treatment discontinuation rate due to toxicities and increased risk of SPM make it a less attractive option (53). Patient selection is very important in the treatment of asymptomatic patients with these therapies so any potential benefit of reduced conversion to MM and end organ damage is not offset by the toxicities. For potentially transplant-eligible patients, we recommend harvesting and storage of peripheral blood stem cells before completion of six cycles of treatment to avoid prolonged exposure to lenalidomide and/or daratumumab that could hinder the collection.

We recommend continuing active surveillance for patients with low-risk SMM given the lack of benefit with preemptive therapy in this population. Monitoring should include complete blood count with differential, measurement of creatinine, calcium, quantitative immunoglobulins, M protein and free light chains in the serum, and urine studies as indicated. Imaging is recommended annually or as indicated, preferably with the same modality used at diagnosis. Patients can be followed every 3–4 months for the first five years from the time of diagnosis and then reduce the frequency to every 6 months.

Extended follow-up of studies involving multi-drug regimens, bispecific antibodies and cellular therapies is needed to study their long-term efficacy and toxicity before they can be adopted into clinical practice.

5 Future directions

Future efforts in managing SMM should prioritize a more individualized approach. Risk stratification tools must evolve to reflect the dynamic nature of disease progression, as current models often fail to reflect how a patient’s condition may change over time. Additionally, there is a need for global consistency in defining and diagnosing high-risk SMM before enrolling patients into clinical trials. Standardizing these criteria will help better differentiate patients who are truly at risk of progressing to active MM from those who can be safely monitored without unnecessary treatment.

Future research should also prioritize shared decision-making, ensuring that patients are informed and actively involved in choosing the approach that aligns with their personal values and preferences.

Author contributions

AG: Data curation, Methodology, Writing – original draft, Writing – review & editing. SD: Conceptualization, Supervision, Writing – review & editing.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Conflict of interest

The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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