What is the recommended treatment approach for patients with smoldering myeloma?

Management of Smoldering Multiple Myeloma

For patients with smoldering multiple myeloma, observation at 3-6 month intervals is the recommended standard of care, with clinical trial enrollment strongly encouraged, especially for high-risk patients. 1

Definition and Risk Stratification

Smoldering multiple myeloma (SMM) is an asymptomatic precursor to multiple myeloma characterized by:

• Absence of symptoms
• No related organ or tissue impairment
• No CRAB features (hypercalcemia, renal insufficiency, anemia, bone lesions)

Risk stratification is essential for management decisions:

Mayo 2018 20/2/20 Criteria 1

High-risk SMM is defined by having ≥2 of:

• Bone marrow plasma cells >20%
• M-protein >2 g/dL
• Free light chain ratio >20

Recommended Management Approach

Low-Risk SMM

• Observation at 3-6 month intervals (category 1 recommendation) 1
• Clinical trial enrollment when available

High-Risk SMM

• Clinical trial enrollment (preferred option) 1, 2
• Observation at 3-month intervals 1
• For selected high-risk patients:
  • Subcutaneous daratumumab monotherapy for 36 months (preferred if treatment is initiated) 2
  • Lenalidomide ± dexamethasone may be considered in carefully selected patients (category 2B recommendation) 1, 3, 4

Evidence for Early Intervention

Early intervention studies have shown promising results:

• The PETHEMA trial demonstrated that lenalidomide plus dexamethasone delayed progression to symptomatic disease (median time to progression not reached vs. 21 months in observation arm) and improved 3-year survival (94% vs. 80%) in high-risk SMM 3

• A larger multicenter phase III trial showed lenalidomide monotherapy improved progression-free survival compared to observation, particularly in high-risk patients 4

• Recent innovative approaches include KRd (carfilzomib, lenalidomide, dexamethasone) followed by transplant, which has shown promising results in high-risk SMM with 31% of patients maintaining undetectable minimal residual disease 4 years after transplant 5

Surveillance Recommendations

Regular monitoring is essential regardless of management approach:

• Laboratory tests every 3-6 months:

  • Complete blood count
  • Serum chemistry (creatinine, albumin, calcium, LDH, β2-microglobulin)
  • Serum quantitative immunoglobulins
  • Serum protein electrophoresis (SPEP) and immunofixation (SIFE)
  • Serum free light chain assay
  • 24-hour urine for total protein, UPEP, and UIFE

• Imaging:

  • Annual bone survey or as clinically indicated
  • Consider MRI, low-dose CT, or PET/CT annually or as clinically indicated
  • Use the same imaging modality for follow-up as used at diagnosis 1

• Bone marrow assessment:

  • As clinically indicated
  • Consider multiparameter flow cytometry to assess risk of progression 1

Important Considerations

• The definition of high-risk SMM continues to evolve, with some patients previously classified as high-risk SMM now considered to have active multiple myeloma requiring treatment 1

• The NCCN panel strongly believes there is a need to re-evaluate the definition of high-risk SMM 1

• Multiparameter flow cytometry can help individualize follow-up strategies by identifying patients at higher risk of progression 1

• Early intervention should be balanced against potential treatment-related toxicities, especially since some patients may have indolent disease for many years 6

• The risk of progression to symptomatic myeloma is lifelong, requiring ongoing surveillance regardless of initial risk classification 1