What is the management approach for a patient with a clonal plasma cell population showing lambda light chain predominance and estimated to be less than 5% of marrow cellularity?

Management of Clonal Plasma Cell Population <5% with Lambda Predominance

This patient has findings consistent with monoclonal gammopathy of undetermined significance (MGUS) or very low-burden smoldering multiple myeloma, and requires observation without treatment unless CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions) or other myeloma-defining events are present. 1

Diagnostic Classification

The bone marrow findings place this patient in a precursor plasma cell disorder category:

• Clonal plasma cells <5% with lambda light chain predominance by RNA in situ hybridization indicates a monoclonal population below the traditional 10% threshold for smoldering myeloma 1
• Background polyclonal plasma cells are present, which is more consistent with MGUS than active myeloma 1
• The presence of any detectable clonal plasma cells (even <5%) requires complete workup to exclude progression to symptomatic disease 1

Essential Immediate Workup

Laboratory Assessment Required

• Serum free light chain (FLC) assay to determine the kappa/lambda ratio and absolute involved light chain level 1

  • Abnormal FLC ratio (<0.26 for lambda-dominant) confirms light chain MGUS if other criteria met 1
  • Involved FLC ≥100 mg/L with ratio ≥100 is a myeloma-defining event requiring treatment 2

• Complete metabolic panel including calcium, creatinine, and albumin to assess for CRAB criteria 1, 2

  • Hypercalcemia ≥11.5 mg/dL indicates active myeloma 1
  • Creatinine >2 mg/dL or clearance <40 mL/min suggests renal involvement 1

• Complete blood count to evaluate for anemia (hemoglobin <10 g/dL or >2 g/dL below normal) 1, 2

• Serum protein electrophoresis (SPEP) with immunofixation to detect and quantify any M-protein 1, 3

• 24-hour urine collection with protein electrophoresis and immunofixation to detect Bence Jones proteinuria 1, 3

• Quantitative immunoglobulins (IgG, IgA, IgM) to assess for immunoparesis 1

Imaging Studies Required

• Whole-body low-dose CT or PET/CT to exclude lytic bone lesions, as their presence would upgrade to symptomatic myeloma requiring treatment 1, 2
• MRI of spine and pelvis if CT is negative but clinical suspicion remains, as >1 focal lesion ≥5mm is a myeloma-defining event 2

Risk Stratification Based on Results

If Classified as Light Chain MGUS (Low Risk)

All criteria must be met 1:

• Abnormal FLC ratio (<0.26 for lambda)
• No heavy chain on immunofixation
• Clonal BM plasma cells <10%
• No CRAB features
• Risk of progression: 1-2% per year 1

If Classified as Smoldering Myeloma (Higher Risk)

Criteria include 1:

• Clonal BM plasma cells ≥10% (not met in this case) OR
• Serum M-protein ≥3 g/dL
• No CRAB features or other myeloma-defining events
• Risk of progression: approximately 10% per year 1

Critical Myeloma-Defining Events That Mandate Treatment

If any of the following are present, immediate hematology referral and treatment initiation is required 2:

• CRAB criteria (calcium >11.5 mg/dL, creatinine >2 mg/dL, hemoglobin <10 g/dL, bone lesions) 1, 2
• BM clonal plasma cells ≥60% 2
• Involved/uninvolved FLC ratio ≥100 (provided involved FLC ≥100 mg/L) 2
• >1 focal lesion ≥5mm on MRI 2

Flow Cytometry Considerations

• Flow cytometry should be completed to assess for aberrant plasma cell phenotype (CD19-, CD56+, CD117+, CD20+, CD28+) which helps confirm clonality and may have prognostic implications 1
• The presence of >97% abnormal plasma cells (by phenotype) is typical of myeloma, while >3% normal plasma cells suggests MGUS 1
• At least 100 plasma cell events must be acquired for accurate enumeration and phenotyping 1
• Polyclonal antibodies are preferred over monoclonal antibodies for intracellular light chain detection to avoid false-negative results 4

Management Algorithm

If No Myeloma-Defining Events Present (Observation Strategy)

Initial monitoring schedule 1:

• Repeat SPEP, FLC assay, and CBC at 6 months 5
• If stable, continue monitoring annually 5
• Repeat bone marrow biopsy only if clinical or laboratory progression occurs 1

Monitoring for progression indicators 1:

• Rising M-protein or FLC levels
• Development of anemia, hypercalcemia, or renal dysfunction
• New bone pain or pathologic fractures
• Increasing BM plasma cell percentage on repeat biopsy

If Myeloma-Defining Events Present (Treatment Required)

First-line therapy for transplant-eligible patients 2:

• Bortezomib, lenalidomide, dexamethasone (VRd) for 3-4 cycles followed by autologous stem cell transplantation 2
• For high-risk disease (del17p, t(4;14), t(14;16), gain 1q, p53 mutation), consider daratumumab-VRd 2

First-line therapy for transplant-ineligible patients 2:

• VRd for 8-12 cycles followed by lenalidomide maintenance 2
• Alternative: Daratumumab, lenalidomide, dexamethasone (DRd) until progression 2

Critical Pitfalls to Avoid

• Do not assume benignity based solely on low plasma cell percentage (<5%), as flow cytometry may detect occult disease with prognostic significance 1
• Do not rely on immunohistochemistry alone for light chain assessment; RNA in situ hybridization and flow cytometry provide more sensitive clonality detection 1
• Recognize rare dual light chain expression can occur in plasma cell myeloma, which may confound interpretation and require comprehensive workup including double immunohistochemistry 6, 7, 8
• Always use the same FLC assay for serial measurements, as different assays have non-interchangeable reference ranges 5
• Avoid nephrotoxic agents (NSAIDs, IV contrast) that could precipitate light chain cast nephropathy if FLC levels are elevated 5, 3
• Do not delay imaging to exclude bone lesions, as their presence immediately changes management from observation to treatment 1, 2

Special Consideration for Lambda Light Chain Predominance

• Lambda light chain disorders may be associated with AL amyloidosis, particularly if unexplained proteinuria, cardiomyopathy (wall thickness >12mm), or neuropathy are present 5, 3
• Consider NT-proBNP (≥332 ng/L) and troponin T if cardiac symptoms exist 5
• Tissue biopsy with Congo red staining may be needed if amyloidosis is suspected 3