What is the recommended maintenance approach for a patient with smoldering myeloma?

Management of Smoldering Myeloma: Observation vs. Early Intervention

For patients with smoldering myeloma, observation with close monitoring at 3-6 month intervals remains the standard approach, with early treatment reserved specifically for high-risk patients who have >50% risk of progression within 2 years. 1, 2

Risk Stratification is Critical

The decision between observation and treatment hinges entirely on risk assessment:

• Standard/intermediate-risk patients should be observed without immediate treatment, as they may remain asymptomatic for years 1, 2
• High-risk patients should be considered for early intervention based on mounting evidence showing survival benefits 1

High-risk features include: 1

• Bone marrow plasma cells ≥10% AND monoclonal protein (IgG ≥3 g/dL, IgA ≥2 g/dL, or urinary Bence Jones protein >1 g/24 hours)
• ≥95% phenotypically aberrant plasma cells by flow cytometry
• Mayo 2018 20/2/20 criteria (bone marrow plasma cells ≥20%, M-protein ≥2 g/dL, serum free light chain ratio ≥20)

Observation Protocol for Standard-Risk Patients

For patients under observation, monitoring should occur every 3-6 months and include: 1

• CBC with differential and platelet count
• Serum chemistry (creatinine, albumin, corrected calcium)
• Serum quantitative immunoglobulins
• SPEP with SIFE as needed
• Serum free light chain assay
• 24-hour urine for total protein, UPEP, and UIFE
• Yearly imaging with whole-body MRI, low-dose CT, or whole-body FDG PET/CT for at least 5 years (bone surveys are inadequate) 1

Early Treatment for High-Risk Patients

When early intervention is pursued in high-risk smoldering myeloma, lenalidomide-based regimens have the strongest evidence for delaying progression and improving survival. 1

Evidence-Based Treatment Options:

Lenalidomide plus dexamethasone (Rd) has Level 1 evidence: 3, 4, 5

• The PETHEMA trial showed median time to progression was not reached with Rd versus 21-23 months with observation (HR 0.24)
• 3-year overall survival was 94% versus 80% (HR 0.31, P=0.03)
• After 12.5 years median follow-up, median TTP was 9.5 years with Rd versus 2.1 years with observation (HR 0.28, P<0.0001)
• Overall survival benefit persisted long-term (HR 0.57, P=0.032)

Triplet therapy with carfilzomib, lenalidomide, and dexamethasone (KRd) shows even more promising results in recent studies: 6, 7

• 70-month progression rate to active myeloma was only 6% (94% remained progression-free)
• 70.4% achieved MRD-negative complete response
• 31% maintained undetectable MRD 4 years after treatment
• 8-year probability of being free from progression was 91.2%

Treatment Regimen Details:

For Rd approach: 3, 5

• Induction: Lenalidomide 25 mg days 1-21 plus dexamethasone 20 mg days 1-4 and 12-15 of 28-day cycles for 9 cycles
• Maintenance: Lenalidomide 10 mg days 1-21 of 28-day cycles for up to 2 years

For KRd approach (for transplant-eligible high-risk patients): 6, 7

• Induction: 6-8 cycles of KRd
• Consider autologous stem cell transplantation
• Consolidation: 2 cycles KRd
• Maintenance: Lenalidomide for 2 years

Critical Caveats and Pitfalls

The NCCN Panel notes important limitations: 1

• Flow cytometry-based high-risk criteria are not uniformly available
• Some patients classified as "high-risk smoldering myeloma" in early trials may have actually had active myeloma by current criteria (SLiM-CRAB)
• Advanced imaging was not used in some defining trials

Toxicity considerations that must be discussed with patients: 1

• Grade 3-4 adverse events occur in 25-41% of patients on lenalidomide
• Two- to threefold increased risk of second primary malignancies (approximately 7% incidence)
• Neutropenia and infections are most common during treatment
• Thromboembolism risk requires prophylaxis

The presence of any SLiM-CRAB criteria predicts progression and should prompt immediate treatment as active myeloma rather than smoldering disease 6

When to Transition from Observation to Treatment

Patients should be re-evaluated for active myeloma treatment if they develop: 1

• CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions)
• SLiM criteria (≥60% bone marrow plasma cells, serum free light chain ratio ≥100, >1 focal lesion on MRI)
• Biochemical progression with concerning features

At that point, systemic therapy must be administered as clinically indicated for active myeloma, not as maintenance for smoldering disease. 1