Smoldering Myeloma Treatment: Best Approaches and Strategies

Smoldering multiple myeloma (SMM) is an asymptomatic precursor to active multiple myeloma, making it challenging to determine when and how to intervene. While some patients never progress, others face a high risk, highlighting the importance of early identification and tailored management.

Advancements in risk assessment have improved treatment decisions. Understanding the best approaches—from pharmacological interventions to lifestyle modifications—can optimize outcomes while avoiding unnecessary treatments.

Criteria That Distinguish Smoldering And Active Disease

Smoldering multiple myeloma (SMM) is defined by monoclonal plasma cells in the bone marrow at levels between 10% and 60%, along with a serum monoclonal protein (M-protein) concentration of at least 3 g/dL or urinary monoclonal protein excretion, but without symptoms of active disease. The absence of myeloma-defining events—such as end-organ damage—distinguishes SMM from active multiple myeloma (MM), making precise diagnostics essential.

The transition to active disease is marked by CRAB criteria: hypercalcemia, renal insufficiency, anemia, and bone lesions. The International Myeloma Working Group (IMWG) has also identified additional biomarkers predicting imminent progression, including a bone marrow plasma cell percentage of 60% or higher, a serum free light chain ratio exceeding 100, and more than one focal lesion on MRI.

Advanced imaging techniques refine these distinctions. Whole-body low-dose computed tomography (LDCT) and positron emission tomography-computed tomography (PET-CT) detect early bone involvement not visible on conventional X-rays. MRI, particularly diffusion-weighted imaging, identifies focal lesions that indicate a higher risk of progression, allowing for earlier intervention.

Risk Stratification Tools

Assessing the likelihood of SMM progressing to active disease is key to patient management. Risk stratification tools categorize patients into low, intermediate, or high-risk groups, ensuring treatment aligns with disease advancement probability.

The Mayo Clinic model categorizes patients based on three factors: bone marrow plasma cell percentage, M-protein levels, and serum free light chain ratio. Low-risk patients typically have a 10-year progression risk of 25%, while high-risk individuals—those with a serum free light chain ratio above 100, M-protein levels over 3 g/dL, and a bone marrow plasma cell percentage near 60%—face a 75% or greater likelihood of developing symptomatic myeloma within five years.

The IMWG’s 2/20/20 model further refines risk assessment, incorporating a bone marrow plasma cell percentage of 20% or higher, an M-protein concentration of at least 2 g/dL, and a serum free light chain ratio above 20. Those meeting all three criteria are considered high-risk, with a median time to progression of about two years.

Advanced imaging enhances risk assessment. Whole-body MRI and PET-CT can detect early disease activity. A study in Blood found that patients with more than one focal lesion on MRI had a 70% chance of developing active MM within two years.

Genomic profiling adds another layer of precision. Cytogenetic abnormalities, such as t(4;14), t(14;16), and deletions of chromosome 17p, indicate a more aggressive disease course. Next-generation sequencing and fluorescence in situ hybridization (FISH) help identify these high-risk markers, guiding closer monitoring or earlier intervention.

Pharmacological Approaches

Deciding when to initiate pharmacological treatment in SMM requires balancing the benefits of early intervention against the risks of unnecessary toxicity. Historically, observation was the standard approach, but emerging evidence suggests targeted therapy in high-risk individuals can delay progression.

Lenalidomide, an immunomodulatory drug, has shown promise. A phase 3 trial in The New England Journal of Medicine demonstrated that lenalidomide monotherapy significantly extended progression-free survival compared to observation, with a median time to progression of 60 months versus 21 months. Its manageable toxicity profile, primarily mild-to-moderate hematologic and gastrointestinal side effects, led to its inclusion in clinical guidelines for high-risk patients.

Combination therapies enhance efficacy. Adding dexamethasone to lenalidomide further suppresses malignant plasma cell proliferation. A trial by the Spanish Myeloma Group found this combination improved progression-free survival and response rates, though corticosteroids introduce risks such as metabolic disturbances and bone density reduction.

Proteasome inhibitors like carfilzomib and ixazomib disrupt protein degradation in malignant plasma cells, inducing apoptosis. Early studies suggest combining these inhibitors with lenalidomide and dexamethasone yields deeper responses, though concerns about cardiotoxicity and peripheral neuropathy necessitate further safety data.

Transplant Strategies

Autologous stem cell transplantation (ASCT) is a mainstay of active MM treatment, but its role in SMM remains under investigation. While high-risk SMM patients face a significant probability of progression, determining whether early transplantation improves survival is complex.

Clinical trials have explored early ASCT in high-risk SMM. A study in Haematologica found that patients undergoing early transplantation following lenalidomide and dexamethasone induction achieved high rates of minimal residual disease (MRD) negativity, a factor associated with prolonged progression-free survival. However, the long-term impact on overall survival remains uncertain, as some patients may never progress, avoiding the risks of intensive therapy. ASCT may be viable for select patients with aggressive disease markers but is not universally recommended.

Bone Health Management

SMM patients face an increased risk of skeletal complications due to the presence of monoclonal plasma cells in the bone marrow. While overt lytic lesions are absent, subtle bone remodeling changes can predispose individuals to fractures and reduced bone mineral density.

Bisphosphonates, such as zoledronic acid and pamidronate, reduce bone resorption by inhibiting osteoclast activity. Although their routine use in SMM is debated, some studies suggest they may delay skeletal-related events in high-risk patients. A 2022 meta-analysis in The Oncologist found that zoledronic acid improved bone density and reduced vertebral fractures. However, the risk of osteonecrosis of the jaw necessitates careful screening and preventive dental care. Denosumab, a monoclonal antibody targeting RANK ligand, offers an alternative for patients with renal impairment.

Weight-bearing exercise and adequate calcium and vitamin D intake are essential for bone health. Resistance training stimulates osteoblastic activity, while sufficient vitamin D supports calcium absorption and bone remodeling. Routine screening for vitamin D deficiency is recommended, as low levels are prevalent in myeloma patients and may exacerbate skeletal fragility.

Nutritional And Lifestyle Support

Optimizing nutrition and lifestyle choices can support overall well-being and potentially delay disease progression. While no specific diet prevents progression, certain dietary patterns and lifestyle modifications may influence systemic inflammation and immune function.

A plant-forward diet rich in antioxidants, polyphenols, and omega-3 fatty acids may help reduce oxidative stress and inflammation. The Mediterranean diet, emphasizing fruits, vegetables, whole grains, nuts, and olive oil, has been associated with lower inflammatory markers such as C-reactive protein and interleukin-6, which are implicated in myeloma progression. Maintaining adequate protein intake is also crucial for preserving muscle mass, with lean protein sources such as fish, legumes, and poultry providing necessary amino acids without excessive saturated fat.

Physical activity and stress management contribute to health maintenance. Regular exercise improves immune surveillance and reduces systemic inflammation. A study in Cancer Epidemiology, Biomarkers & Prevention found that moderate-intensity exercise at least three times per week lowered pro-inflammatory cytokines. Mindfulness practices such as meditation and yoga reduce cortisol levels and improve quality of life, potentially benefiting SMM patients.