What is the appropriate investigation and treatment approach for a patient with suspected multiple myeloma?

Multiple Myeloma Investigation and Treatment

Diagnostic Workup

For suspected multiple myeloma, obtain serum protein electrophoresis with immunofixation, quantitative immunoglobulins, serum free light chain assay, 24-hour urine protein electrophoresis with immunofixation, complete blood count, comprehensive metabolic panel including calcium and creatinine, β2-microglobulin, bone marrow aspiration and biopsy with cytogenetics/FISH, and full skeletal radiographic survey. 1, 2

Essential Laboratory Tests

• Serum studies: Perform serum protein electrophoresis (SPEP) combined with serum immunofixation electrophoresis (SIFE) to detect and characterize the M-protein, measuring IgG, IgA, and IgM levels to assess for immunoparesis 1, 3, 2

• Serum free light chain assay: Obtain kappa/lambda ratio, as this combination with SPEP and SIFE provides the highest sensitivity for M-protein detection 1, 3, 2

• Mandatory urine testing: Collect 24-hour urine for protein electrophoresis (UPEP) and immunofixation (UIFE)—random urine samples are insufficient, as approximately 20% of patients have Bence Jones proteins detectable only in urine 1, 3, 2

• Baseline blood work: Complete blood count to assess for anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal), serum calcium (>11.5 mg/dL indicates hypercalcemia), creatinine (>2 mg/dL or clearance <40 mL/min indicates renal failure), albumin, LDH, and β2-microglobulin for staging 1, 2, 4

Bone Marrow Evaluation

• Bone marrow aspiration and biopsy: Required to quantify plasma cell infiltration (≥10% clonal plasma cells needed for diagnosis) and perform cytogenetic/FISH studies to identify high-risk features including del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation 1, 2

Imaging Studies

• Full skeletal X-ray survey: Remains the standard for detecting lytic bone lesions, including spine, pelvis, skull, humeri, and femurs 1, 2

• MRI of spine and pelvis: Provides superior detail and is mandatory if spinal cord compression is suspected or if skeletal survey is negative but bone pain is present 1, 2

• CT or PET/CT: Use as clinically indicated for evaluating symptomatic sites and detecting extramedullary disease 1

Diagnostic Criteria

Multiple myeloma requires ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma) PLUS at least one myeloma-defining event: 2

• CRAB criteria: Hypercalcemia (calcium >11.5 mg/dL), renal failure (creatinine >2 mg/dL or clearance <40 mL/min), anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal), or bone lesions (lytic lesions, severe osteopenia, pathologic fractures) 1, 2

• Biomarker criteria: ≥60% bone marrow plasma cells, involved/uninvolved serum free light chain ratio ≥100, or >1 focal lesion ≥5mm on MRI 2

Risk Stratification

• International Staging System (ISS): Stage I (β2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL), Stage II (neither Stage I nor III), Stage III (β2-microglobulin ≥5.5 mg/L) 2

• Cytogenetic risk: High-risk features fundamentally alter treatment approach and include del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation 2

Treatment Approach

Transplant-Eligible Patients (Age ≤65, Good Performance Status, No Renal Failure)

Administer induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd) for 3-4 cycles, followed by autologous stem cell transplantation with high-dose melphalan 200 mg/m² IV, then lenalidomide maintenance. 2

• Induction regimen: VRd consists of bortezomib (proteasome inhibitor), lenalidomide (immunomodulatory agent), and dexamethasone, which achieves median progression-free survival of 41 months compared to historical 8.5 months without therapy 4

• Stem cell collection: Use peripheral blood progenitor cells rather than bone marrow 1

• Conditioning regimen: High-dose melphalan 200 mg/m² IV is preferred over melphalan 140 mg/m² plus total body irradiation 1

Transplant-Ineligible Patients (Elderly, Poor Performance Status, Comorbidities)

Treat with daratumumab, lenalidomide, and dexamethasone (DRd) until disease progression, which provides superior outcomes compared to lenalidomide-dexamethasone alone. 2, 5

• DRd regimen efficacy: The MAIA trial demonstrated median progression-free survival of 61.9 months with DRd versus 34.4 months with lenalidomide-dexamethasone alone (44% reduction in risk of disease progression or death), with 32% reduction in risk of death 5

• Dosing: Daratumumab 16 mg/kg IV with lenalidomide 25 mg daily on days 1-21 of 28-day cycles plus dexamethasone 40 mg weekly (20 mg weekly if >75 years or BMI <18.5) 5

• Response rates: Overall response rate of 92.9% with DRd versus 81.3% with lenalidomide-dexamethasone, with complete response or better in 47.6% versus 24.9% 5

• Alternative for elderly: VRd for 8-12 cycles followed by lenalidomide maintenance is also acceptable 2

Supportive Care (All Patients)

• Bisphosphonates: Administer long-term oral or intravenous bisphosphonates to reduce skeletal events in patients with stage III or relapsed disease 1

• Thromboprophylaxis: Provide prophylaxis against venous thromboembolism, particularly with immunomodulatory agents 6

• Infection prophylaxis: Implement antimicrobial prophylaxis as indicated by treatment regimen 6

Asymptomatic (Smoldering) Myeloma

Do not initiate immediate treatment for smoldering myeloma; instead, observe with laboratory monitoring every 3-6 months and annual skeletal survey. 1, 7

Follow-Up Monitoring

• Laboratory tests every 3-6 months: CBC, comprehensive metabolic panel including creatinine, albumin, calcium, LDH, β2-microglobulin, quantitative immunoglobulins, SPEP with SIFE, and serum free light chain assay 7

• Imaging: Annual skeletal survey or as clinically indicated; MRI/CT/PET-CT for suspected progression or extramedullary disease 7

• Bone marrow assessment: Perform when disease progression is suspected 7

Critical Pitfalls to Avoid

• Never use random urine samples for protein electrophoresis—only 24-hour collections are adequate for monitoring Bence Jones proteins 7, 2

• Do not miss spinal cord compression—obtain urgent MRI when clinically suspected, as this is an oncologic emergency 1, 2

• Do not overlook cytogenetic testing—high-risk features fundamentally alter treatment approach and prognosis 2

• Do not fail to obtain both serum and urine studies—approximately 3% of patients have nonsecretory disease, and 20% have urinary-only M-proteins 3

• Do not miss extramedullary disease progression—utilize appropriate imaging beyond skeletal survey when clinically indicated 7