Smoldering Multiple Myeloma (SMM)

Article written and reviewed by Dr Luca Moretti

Smoldering Multiple Myeloma (SMM), or indolent multiple myeloma, is an asymptomatic, clinically silent but biologically unstable plasma cell neoplasm. SMM occupies an intermediate position between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic multiple myeloma, constituting a distinct entity with specific clinical, morphologic and prognostic characteristics.

The condition is defined by clonal plasma cell proliferation in the bone marrow above the threshold typical of MGUS but in the absence of CRAB criteria, including hypercalcemia, renal impairment, anemia and bone lesions, and of myeloma-defining events established by current international guidelines. Although asymptomatic, SMM carries a substantially increased risk of progression to active symptomatic multiple myeloma, especially during the first years after diagnosis.

Identification and management of SMM are crucial in modern hematologic oncology because it accounts for approximately 10-15% of all multiple myeloma diagnoses and because of the prognostic and therapeutic implications of its progression risk. The main clinical challenge is to distinguish patients at higher risk, who may benefit from early intervention, from those with more indolent forms and prolonged stability, for whom active monitoring remains the preferred strategy.

Etiology, pathogenesis and pathophysiology

The etiology of Smoldering Multiple Myeloma (SMM) lies in neoplastic transformation of a B cell differentiated toward the plasma cell phenotype and acquiring a clonal proliferative advantage. This primary event, which causes abnormal production of monoclonal immunoglobulins, the M-protein, results from acquired, nonhereditary genetic abnormalities in B-cell precursors within the bone marrow. Major abnormalities include chromosomal translocations involving the immunoglobulin heavy-chain locus, IgH at 14q32, and gene deletions or amplifications such as 13q deletion and 1q21 amplification, but no established environmental cause or single predisposing factor is recognized as necessary and sufficient for disease development.

Regarding risk factors, although no direct cause has been identified, the following have been described:

• Advanced age, with prevalence progressively increasing with age and peaking between the sixth and eighth decades of life;
• Male sex, with a slightly higher incidence;
• African American ancestry, with approximately twice the risk observed in White populations;
• Family history of monoclonal gammopathies or multiple myeloma;
• No specific validated environmental or immune risk factors have been defined for SMM.

These factors act as conditions of increased susceptibility and do not establish a direct causal relationship.

The pathogenetic mechanisms of SMM reflect a dynamic, multistep process that begins with monoclonal gammopathy of undetermined significance (MGUS) and may progress to symptomatic multiple myeloma. Biologic progression is marked by sequential accumulation of genetic, epigenetic and microenvironmental abnormalities that promote survival, proliferation and accumulation of clonal plasma cells in the bone marrow:

• Structural chromosomal abnormalities, including translocations involving genes such as CCND1, MMSET, c-MAF and FGFR3;
• Deletions/aneuploidies, including 17p deletion, 13q loss and hyperdiploidy;
• Driver mutations in oncogenes and cell-cycle regulatory genes, including KRAS, NRAS, BRAF and TP53;
• Bone marrow microenvironment remodeling, with production of cytokines, growth factors and proangiogenic signals supporting survival and expansion of the plasma cell clone.

These events are not yet sufficient to generate the organ damage typical of symptomatic multiple myeloma, but they create biologic instability associated with a high risk of progression.

From a pathophysiologic perspective, SMM is defined by clonal bone marrow plasma cells from 10% to less than 60% and/or a serum monoclonal component ≥3 g/dL and/or a urinary monoclonal component ≥500 mg/24 hours, without myeloma-defining events or attributable CRAB organ damage. Clonally expanded plasma cells produce monoclonal immunoglobulins that accumulate in the blood as the M-protein and, less often, in urine as Bence Jones proteinuria. At this stage, however, tumor burden, production of proinflammatory cytokines such as IL-6 and TNF-alpha, bone remodeling and tumor-induced immunosuppression are not yet sufficient to cause significant anemia, hypercalcemia, renal impairment or typical osteolytic lesions.

Progression to symptomatic multiple myeloma depends on increasing genomic instability, emergence of more aggressive subclones, amplification of cytokine networks and the ability to evade immune control. Over time, neoplastic plasma cells profoundly remodel the bone marrow microenvironment, progressively recruiting osteoclasts, inhibiting osteoblasts and activating immunosuppressive mechanisms that precede development of organ damage.

In summary, SMM pathogenesis reflects an unstable balance between clonal proliferation and absence of organ damage resulting from:

• Sequential genetic and genomic abnormalities in plasma cells;
• Clonal expansion and accumulation of monoclonal immunoglobulins without exceeding the critical threshold for tissue toxicity;
• Microenvironmental remodeling and partial activation of survival and immune-evasion pathways characteristic of active myeloma.

Clinical manifestations

Smoldering Multiple Myeloma (SMM) is defined by the absence of symptoms and clinical signs attributable to active myeloma, despite greater bone marrow plasma cell proliferation than in MGUS and an often elevated monoclonal component. Diagnosis is almost always incidental, typically during laboratory or instrumental investigations performed for other reasons.

On medical history, patients with SMM have no disorders attributable to myeloma-related organ involvement. Symptoms such as fatigue, bone pain, infections, paresthesias or urinary symptoms may nevertheless coexist for independent reasons and require assessment of attribution.

Physical examination should not reveal findings attributable to active myeloma; unrelated abnormalities may be present and should be evaluated separately.

The absence of clinical manifestations attributable to plasma cell proliferation distinguishes SMM from symptomatic myeloma and other plasma cell disorders. Differential diagnosis is based on rigorous exclusion of any sign attributable to organ damage or complications of plasma cell proliferation. Particular attention must be paid to actively searching for subclinical bone marrow, renal or skeletal damage through specific investigations because some complications may initially be asymptomatic but detectable by instrumental examinations.

Rarely, some patients may show nonspecific laboratory findings such as an increased serum monoclonal component, usually IgG, IgA or less frequently IgM, Bence Jones proteinuria or a modest increase in ESR or beta-2 microglobulin. These findings must not be accompanied by anemia, renal impairment or hypercalcemia attributable to plasma cell proliferation; abnormalities from other causes may coexist.

Ultimately, SMM is an asymptomatic plasma cell neoplasm detected through laboratory and instrumental investigations, and its differential diagnosis is based on rigorous exclusion of active multiple myeloma and other monoclonal gammopathies.

Investigations and diagnosis

The diagnostic pathway for Smoldering Multiple Myeloma requires a structured sequence of investigations from laboratory suspicion to systematic exclusion of organ damage. Identification of SMM is based on integration of hematologic, biochemical, morphologic and instrumental data together with rigorous application of international criteria.

Suspicion usually arises when serum hyperproteinemia, a high monoclonal component, typically ≥3 g/dL, or Bence Jones proteinuria is found in an asymptomatic patient. Occasionally, it may be discovered during evaluation of mild cytopenia, elevated ESR or increased beta-2 microglobulin without another explanation, always in the absence of specific symptoms.

First-line investigations include a complete blood count, renal profile, serum calcium, serum electrophoresis and immunofixation, measurement of serum free light chains with calculation of the kappa/lambda ratio, 24-hour urinary protein measurement or testing for Bence Jones proteinuria, beta-2 microglobulin and LDH. These parameters make it possible to quantify the monoclonal burden, assess organ function and estimate tumor mass.

Bone marrow biopsy is central to definitive diagnosis. A clonal plasma cell proportion of at least 10% and less than 60%, with the typical aberrant immunophenotype, CD38+, CD138+ and often CD56+, helps distinguish SMM from MGUS; exclusion of active myeloma also requires absence of myeloma-defining events. Cytogenetic and molecular analysis is important for identifying abnormalities associated with a higher risk of progression, including t(4;14), t(14;16), 17p deletion, hyperdiploidy and 1q21 amplification.

Skeletal imaging is crucial for excluding osteolytic lesions, pathologic fractures or extramedullary plasma cell masses. Conventional whole-body radiography has limited sensitivity in early stages. Recommended methods include low-dose whole-body CT, 18F-FDG PET/CT and whole-body or spine-and-pelvis MRI, selected according to the clinical question. CT and PET/CT primarily document osteolytic and extramedullary lesions, whereas MRI is more sensitive for marrow infiltration. More than one focal lesion measuring at least 5 mm on MRI is considered a myeloma-defining event and requires reclassification as active myeloma.

International diagnostic criteria, IMWG 2014 and subsequent updates, require the following for SMM:

• A serum monoclonal component ≥3 g/dL and/or urinary monoclonal component ≥500 mg/24 hours and/or clonal bone marrow plasma cells from 10% to less than 60%;
• Absence of CRAB criteria attributable to plasma cell proliferation and absence of myeloma-defining biomarkers: bone marrow plasma cells ≥60%; involved-to-uninvolved serum free light-chain ratio ≥100, provided the involved light chain is ≥100 mg/L; more than one focal lesion on MRI, each ≥5 mm;
• Exclusion of other plasma cell neoplasms, including plasma cell leukemia, AL amyloidosis and lymphomas with plasmacytic differentiation, through integrated clinical, laboratory and instrumental assessment.

Differential diagnosis requires careful assessment of MGUS, characterized by a monoclonal component below 3 g/dL and bone marrow plasma cells below 10%, and active multiple myeloma, which presents with at least one attributable CRAB criterion or a myeloma-defining biomarker. Mixed or atypical presentations should always be considered, particularly in older patients or those with comorbidities, in whom organ abnormalities may not be immediately attributable to myeloma.

Once the diagnosis has been established, management requires close follow-up, particularly during the first year, with periodic laboratory testing, urinary protein assessment, sFLC ratio measurement and targeted imaging if suspicious changes occur. The aim is to detect early signs of progression to the symptomatic phase and promptly initiate the appropriate treatment pathway.

Treatment and prognosis

Management of Smoldering Multiple Myeloma (SMM) is one of the most complex challenges among plasma cell dyscrasias and requires refined stratification of progression risk, individualized follow-up and continual assessment of whether early intervention is appropriate. Unlike symptomatic myeloma, SMM does not automatically require immediate treatment at diagnosis and often calls for vigilant observation guided by the best predictive criteria and advanced diagnostic tools.

Clinical observation and surveillance remain the standard approach for most patients with low- and intermediate-risk SMM. The primary aim is to detect progression to active disease promptly while avoiding both premature treatment, which would expose patients to toxicity without real benefit, and therapeutic delay in rapidly evolving disease. Follow-up generally includes assessments every 3-6 months during the first year with:

• Complete blood count, serum calcium, creatinine, ESR, beta-2 microglobulin and LDH
• Serum electrophoresis and immunofixation, immunoglobulin measurement and Bence Jones proteinuria
• Serum free light chains and kappa/lambda ratio
• Periodic imaging, with whole-body or regional MRI according to availability and individual risk

Monitoring should be intensified in patients with high-risk features, fluctuating laboratory values, an M-protein increase of more than 25% from baseline with an absolute increase of at least 0.5 g/dL, rapidly increasing bone marrow plasma cells or changes in bone marrow imaging patterns.

The risk of progression is not uniform and is highest during the first years. The Mayo 20/2/20 model and other systems integrate M-protein level, bone marrow plasma-cell percentage, FLC ratio and additional characteristics. In the highest-risk categories, the two-year risk of progression may exceed 50%. More than one focal MRI lesion measuring at least 5 mm is already a myeloma-defining event rather than merely a prognostic variable of SMM.

For many years, observation was the standard for all patients. Randomized trials have evaluated early intervention in high-risk profiles, and subcutaneous daratumumab is now an approved option for patients meeting specific criteria. Lenalidomide with or without dexamethasone and other regimens are not universal standards and should be considered according to regulatory approvals and clinical protocols.

Treatment is risk based: structured observation for profiles that are not high risk; subcutaneous daratumumab for eligible patients according to the approved indication; other regimens within clinical trials. Development of a myeloma-defining event or attributable CRAB organ damage establishes active myeloma and requires initiation of the appropriate myeloma therapy.

• Eligibility for approved treatment of high-risk SMM;
• Participation in a clinical trial of early intervention;
• Reclassification as active myeloma when a myeloma-defining event occurs.

In other cases, close monitoring remains preferable, with prompt conversion to standard therapy only when myeloma-defining criteria emerge.

Overall survival and time to progression are highly variable and depend on the risk profile. The most relevant prognostic factors include bone marrow plasma-cell percentage, M-protein level, FLC ratio, cytogenetics, immunoparesis and the longitudinal behavior of clonal markers.

Multidisciplinary management – Patients should receive information about progression risk and psychological support when needed; genetic counselling is not routinely indicated in the absence of a specific suspicion of inherited predisposition.

Complications

In Smoldering Multiple Myeloma, by definition, the clinical complications typical of active disease are absent. Nevertheless, understanding potential progression and risk situations is essential both for follow-up and for early identification of transformation.

Complications of occult progression: even in the absence of symptoms, subclinical abnormalities may precede transition to active myeloma. These include a progressive reduction in hemoglobin, subclinical anemia, increased serum creatinine or increasing Bence Jones proteinuria. Development of any of the following requires diagnostic reassessment:

• New or worsening anemia attributable to plasma cell proliferation, with hemoglobin <10 g/dL or more than 2 g/dL below the lower limit of normal
• Increased serum calcium attributable to plasma cell proliferation, >11 mg/dL or more than 1 mg/dL above the upper limit of normal
• Renal impairment attributable to plasma cell proliferation, with serum creatinine >2 mg/dL or creatinine clearance <40 mL/min
• Imaging evidence of one or more osteolytic lesions; a pathologic fracture without an osteolytic lesion attributable to myeloma is not by itself a myeloma-defining event

Any one of these events, when attributable to plasma cell proliferation, marks transition from smoldering disease to symptomatic myeloma and requires prompt initiation of specific therapy.

Surveillance-related complications: prolonged uncertainty and the need for close follow-up may have a substantial psychological impact, including anticipatory anxiety, adjustment disorders and reduced quality of life. Effective clinician-patient communication and specialist psychological support are recommended, particularly for younger patients and those in vulnerable family circumstances.

Iatrogenic and early-treatment complications: in patients receiving early treatment, adverse events depend on the regimen used. With subcutaneous daratumumab, administration-related reactions, infections and cytopenias are particularly relevant; venous thromboembolism is associated especially with regimens containing immunomodulatory agents and corticosteroids. Neurotoxicity is not a typical adverse effect of daratumumab. The decision to begin therapy must always balance individual risks and benefits and, for nonapproved regimens, should be made within controlled clinical trials.

Other complications: although uncommon, high-risk cytogenetic abnormalities may be associated with more rapid progression to active multiple myeloma. These patients require even closer monitoring and multidisciplinary assessment at highly specialized centers.

Management of complications in SMM is therefore based on clinical and laboratory vigilance, prompt diagnosis of progression and multidisciplinary care addressing the psychological, social and medical needs of the patient, with the aim of optimizing prognosis and quality of life throughout the natural history of the disease.

References
1. Rajkumar SV et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncology. 15, 12, 2014, e538-e548.
2. Mateos MV et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma. Blood Cancer Journal. 10, 10, 2020, 102.
3. Mateos MV et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. New England Journal of Medicine. 369, 5, 2013, 438-447.
4. Dimopoulos MA et al. Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma. New England Journal of Medicine. 392, 18, 2025, 1777-1788.
5. Kyle RA et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. New England Journal of Medicine. 356, 25, 2007, 2582-2590.
6. Lakshman A et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer Journal. 8, 6, 2018, 59.
7. Lonial S et al. Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma. Journal of Clinical Oncology. 38, 11, 2020, 1126-1137.
8. Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood. 125, 20, 2015, 3069-3075.
9. Rajkumar SV et al. Smoldering multiple myeloma current treatment algorithms. Blood Cancer Journal. 12, 2022, 129.
10. Landgren O, Kyle RA, Rajkumar SV. From myeloma precursor disease to multiple myeloma: new diagnostic concepts and opportunities for early intervention. Clinical Cancer Research. 17, 6, 2011, 1243-1252.