What is the management approach for patients with smoldering multiple myeloma?

Management of Smoldering Multiple Myeloma

For patients with smoldering multiple myeloma (SMM), the standard of care remains observation at 3-6 month intervals, with early intervention using lenalidomide ± dexamethasone or subcutaneous daratumumab considered for high-risk patients. 1

Risk Stratification

Risk stratification is essential for determining management approach:

High-Risk SMM Definition:

• Presence of ≥2 of the following:
  • Bone marrow plasma cells >20%
  • M-protein >2 g/dL
  • Free light chain ratio >20 1

Risk Assessment Tools:

• Multiparameter flow cytometry to assess plasma cell phenotype
• Cytogenetic abnormalities
• Imaging findings
• Progression of M-protein levels over time 2, 1

Management Algorithm

Standard-Risk SMM:

1. Observation (Category 1 recommendation) 2, 1
   • No therapy initiation
   • Close monitoring every 3-6 months

High-Risk SMM:

1. Clinical trial enrollment (preferred option) 1
2. Early intervention options:
   • Lenalidomide ± dexamethasone (Category 2B recommendation) 2, 1
   • Subcutaneous daratumumab monotherapy for 36 months 1

Evidence Supporting Early Intervention

• The PETHEMA trial showed that lenalidomide plus dexamethasone in high-risk SMM significantly:

  • Delayed progression to symptomatic disease (HR 0.24; 95% CI, 0.14-0.41) 2
  • Improved overall survival at 3 years (94% vs 80%; HR 0.31) 2, 3
  • Demonstrated sustained benefit after 12.5 years of follow-up (median TTP 9.5 vs 2.1 years) 4

• The E3A06 trial showed lenalidomide monotherapy significantly delayed progression to symptomatic disease compared to observation (HR 0.28; 95% CI, 0.12-0.62) 5

Monitoring Protocol

Laboratory Tests (every 3-6 months):

• Complete blood count with differential
• Serum chemistry (creatinine, albumin, calcium)
• Serum quantitative immunoglobulins
• Serum protein electrophoresis (SPEP) with immunofixation (SIFE)
• Serum free light chain assay
• LDH and beta-2 microglobulin as indicated 2, 1

Urine Tests (every 3-6 months):

• 24-hour urine for total protein
• Urine protein electrophoresis (UPEP)
• Urine immunofixation (UIFE) 2

Imaging (annually or as clinically indicated):

• Whole-body MRI, low-dose CT, or PET/CT
• Use same imaging modality as initial workup
• Conventional bone surveys are inadequate 2, 1

Bone Marrow Assessment:

• As clinically indicated
• Include multiparameter flow cytometry 1

Important Considerations and Pitfalls

• Lifelong surveillance is essential regardless of initial risk classification, as progression risk persists indefinitely 1

• Avoid misclassification: Some patients previously classified as high-risk SMM may actually have active multiple myeloma requiring treatment 1

• Treatment toxicity awareness: Grade 3-4 adverse events occurred in 28% of patients on lenalidomide in the E3A06 trial 5, with neutropenia and infections being the most common serious adverse events 6

• Herpes zoster prophylaxis should be considered during treatment, especially with daratumumab 1

• Subcutaneous administration of daratumumab is preferred over IV for patient convenience and reduced infusion reactions 1

• Recognize progression: If progression to symptomatic multiple myeloma occurs, prompt re-evaluation and initiation of appropriate systemic therapy is required 2

By following this structured approach to SMM management, clinicians can appropriately balance the risks of disease progression against treatment-related toxicities, with the goal of preventing morbidity and mortality associated with progression to symptomatic multiple myeloma.