What are the diagnostic and treatment steps for a patient suspected of having multiple myeloma?

Diagnostic and Treatment Approach for Multiple Myeloma

Diagnostic Workup

For a patient suspected of having multiple myeloma, begin with serum and 24-hour urine protein electrophoresis with immunofixation, serum free light chain assay, complete blood count, comprehensive metabolic panel including calcium and creatinine, and bone marrow aspiration with biopsy—followed by full skeletal imaging to detect lytic lesions. 1, 2

Essential Laboratory Tests

• Serum protein electrophoresis (SPEP) with immunofixation to detect and characterize the monoclonal protein (M-protein), measuring IgG, IgA, and IgM levels by nephelometry 3, 1
• 24-hour urine collection (not random sample) for protein electrophoresis and immunofixation to detect Bence Jones proteins—this is critical as random samples are insufficient and lead to false-negative results 1, 2
• Serum free light chain (FLC) assay with kappa/lambda ratio is essential, particularly when standard electrophoresis is negative or for monitoring non-secretory disease 1, 2, 4
• Complete blood count to assess for anemia (defined as hemoglobin <10 g/dL or ≥2 g/dL below normal) 1, 4
• Serum calcium to detect hypercalcemia (>11.5 mg/dL) 1, 4
• Serum creatinine and creatinine clearance to evaluate renal function (renal insufficiency defined as creatinine >2 mg/dL or clearance <40 mL/min) 1, 4
• Beta-2 microglobulin, serum albumin, and LDH for prognostic staging using the Revised International Staging System 3, 4

Bone Marrow Evaluation

• Bone marrow aspiration and biopsy are mandatory to quantify clonal plasma cells—diagnosis requires ≥10% clonal plasma cells 3, 1
• CD138 staining should be performed to accurately determine the plasma cell percentage 1
• Cytogenetic analysis and FISH studies are essential for risk stratification, specifically looking for del(17p), t(4;14), t(14;16), and del(13q), which confer poor prognosis 1, 2, 4

Imaging Studies

• Full skeletal X-ray survey is the standard initial imaging approach to detect lytic bone lesions 3, 2
• MRI of the spine and pelvis provides greater detail and is mandatory if spinal cord compression is suspected or if conventional X-rays are negative 3, 2
• PET/CT or whole-body CT may help distinguish between MGUS, smoldering myeloma, and active myeloma, and can detect extramedullary disease 3, 2

Diagnostic Criteria: CRAB Plus Plasma Cells

Multiple myeloma is diagnosed when there are ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma) PLUS evidence of end-organ damage defined by CRAB criteria: 1

• Calcium: serum calcium >11.5 mg/dL 1
• Renal insufficiency: creatinine >2 mg/dL or clearance <40 mL/min 1
• Anemia: hemoglobin <10 g/dL or ≥2 g/dL below normal 1
• Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures 1

Critical Distinctions to Avoid Misdiagnosis

• MGUS is characterized by serum monoclonal protein <3 g/dL, clonal bone marrow plasma cells <10%, and absence of CRAB criteria—these patients require monitoring only, not treatment 1, 5
• Smoldering multiple myeloma (SMM) has serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10%, but no CRAB criteria—these patients require closer monitoring (every 3 months initially) but no immediate treatment 1, 5
• Solitary plasmacytoma presents as a single biopsy-proven lesion without systemic disease and is treated with local radiation therapy (40-50 Gy), not systemic chemotherapy 6

Staging and Risk Assessment

• Durie-Salmon classification has been traditionally used but is being replaced by more modern systems 3
• Revised International Staging System (R-ISS) combines beta-2 microglobulin, albumin, LDH, and high-risk cytogenetics [t(4;14), del(17p), t(14;16)] to predict progression-free survival and overall survival 4
• Stage I patients (28% at diagnosis) have a median 5-year survival of 82%, while higher stages have progressively worse outcomes 4

Treatment Approach

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

For transplant-eligible patients, standard first-line therapy consists of induction with bortezomib (proteasome inhibitor), lenalidomide (immunomodulatory agent), and dexamethasone (VRd), followed by high-dose melphalan 200 mg/m² IV with autologous stem cell transplantation, then maintenance lenalidomide. 3, 4

• Induction therapy with VRd (bortezomib-lenalidomide-dexamethasone) is associated with median progression-free survival of 41 months 4
• High-dose melphalan 200 mg/m² IV is the preferred preparative regimen prior to autologous transplantation—this is superior to melphalan 140 mg/m² with total body irradiation 3
• Peripheral blood progenitor cells should be used as the stem cell source rather than bone marrow 3, 2
• Maintenance lenalidomide after transplantation significantly extends progression-free survival 4

Transplant-Ineligible Patients (Age >65-70, Significant Comorbidities)

For elderly or transplant-ineligible patients, the standard approach is daratumumab combined with lenalidomide and dexamethasone (DRd), which provides superior outcomes compared to lenalidomide-dexamethasone alone. 7

• Daratumumab-lenalidomide-dexamethasone (DRd) achieved median progression-free survival of 61.9 months versus 34.4 months with lenalidomide-dexamethasone alone (44% reduction in risk of progression or death) 7
• DRd demonstrated 32% reduction in risk of death compared to Rd alone, with overall response rate of 92.9% versus 81.3% 7
• Lenalidomide 25 mg daily on days 1-21 of 28-day cycles with dexamethasone 40 mg weekly (reduced to 20 mg for patients >75 years or BMI <18.5) 7
• Daratumumab 16 mg/kg IV is administered according to FDA-approved dosing schedule 7
• Alternatively, melphalan-prednisone-based regimens (MPT or VMP) can be used, repeated every 4-6 weeks until stable response, though these are less effective than DRd 3

Patients with Indolent/Smoldering Myeloma

• No immediate treatment is recommended for patients with smoldering myeloma 3
• These patients require monitoring every 3 months for the first year to establish disease evolution pattern, then adjusted based on risk 1

Supportive Care (Essential for All Patients)

• Bisphosphonates (such as zoledronic acid or pamidronate) should be administered long-term to reduce skeletal events in patients with bone disease 3, 8
• Thromboprophylaxis is required for most patients, particularly those on immunomodulatory agents 8
• Infection prophylaxis should be considered given the immunocompromised state 8
• Pain management and consideration of radiation therapy or orthopedic surgery for pathologic fractures or impending fractures 8, 9

Common Pitfalls to Avoid

• Failing to collect a complete 24-hour urine sample leads to false-negative results—random urine samples cannot replace this 2
• Not performing immunofixation even when electrophoresis shows no measurable protein—some myelomas are light chain only 2
• Missing extramedullary disease by relying solely on skeletal X-rays—use MRI or PET/CT when clinical suspicion is high 2
• Overlooking rising free light chain levels as an early sign of progression before other parameters change 2
• Treating smoldering myeloma immediately—these patients should be monitored, not treated, as immediate therapy does not improve outcomes 3
• Performing unnecessary bone marrow biopsies in low-risk MGUS patients with IgG M-protein ≤15 g/L and no end-organ damage 1

Monitoring During Treatment

• Every 3-6 months: complete blood count, comprehensive metabolic panel, quantitative immunoglobulins, SPEP with immunofixation, and serum free light chain assay 2
• Annual skeletal survey or as clinically indicated for new bone pain 2
• MRI, CT, or PET/CT as clinically indicated for suspected disease progression 2
• Response assessment using International Myeloma Working Group criteria (stringent complete response, complete response, very good partial response, partial response) 2