How to Obtain an M Protein in Adults Suspected of Plasma Cell Disorders
To detect and characterize an M protein, you must perform serum protein electrophoresis (SPEP) combined with serum immunofixation electrophoresis (SIFE), quantitative immunoglobulin levels (IgG, IgA, IgM), serum free light chain (FLC) assay, plus 24-hour urine protein electrophoresis (UPEP) with urine immunofixation electrophoresis (UIFE). 1
Essential Serum Testing
The core serum workup includes:
- Serum protein electrophoresis (SPEP) to detect the presence of an M-protein as a discrete band or spike in the gamma globulin region 1
- Serum immunofixation electrophoresis (SIFE) to characterize the specific heavy chain (IgG, IgA, IgM) and light chain (kappa or lambda) type of the M-protein 1
- Quantitative immunoglobulin levels measuring IgG, IgA, and IgM to assess for immunoparesis and quantify the monoclonal protein 1
- Serum free light chain (FLC) assay with kappa/lambda ratio, which provides high sensitivity when combined with SPEP and SIFE for screening plasma cell disorders 1
The combination of SPEP, SIFE, and serum FLC assay yields the highest sensitivity for detecting M-proteins and is now standard practice. 1
Mandatory Urine Testing
You must collect a 24-hour urine sample for comprehensive M-protein detection, as approximately 20% of multiple myeloma patients have secretory urinary proteins (Bence Jones proteins). 1
- 24-hour urine protein electrophoresis (UPEP) performed on a concentrated sample to detect monoclonal free light chains 1, 2
- Urine immunofixation electrophoresis (UIFE) to confirm and characterize the light chain type, even when no visible peak appears on UPEP 2
- Total 24-hour urinary protein quantification to establish baseline tumor burden 2
Critical pitfall: Random urine samples are insufficient and cannot replace 24-hour urine collection, even when corrected for creatinine. 2, 3 Failing to collect a complete 24-hour sample leads to false-negative results. 2
Why Both Serum and Urine Testing Are Required
Approximately 3% of multiple myeloma patients have nonsecretory disease with neither serum nor urine M-proteins detectable by conventional methods. 1 However, most patients demonstrate M-protein in serum with or without urinary protein. 1 The serum FLC assay cannot replace 24-hour urine protein electrophoresis for monitoring patients with measurable urinary M-proteins. 1, 2
Immunofixation Is Non-Negotiable
Immunofixation must be performed on both serum and urine even if protein electrophoresis shows no measurable protein or visible peak, as it can detect M-proteins missed by electrophoresis alone. 2 This is essential for:
- Identifying the specific immunoglobulin heavy and light chain types 1, 2
- Documenting complete response to treatment (requires negative immunofixation in both serum and urine) 2
- Distinguishing monoclonal from polyclonal gammopathies 2
Serial Monitoring Considerations
Once you quantify the M-protein, you must use the same test method for all subsequent serial measurements to ensure accurate comparison and track disease progression or treatment response. 1, 2 Switching between different assays compromises the ability to accurately assess changes in M-protein levels over time.
Additional Diagnostic Context
While obtaining the M-protein is the primary laboratory objective, complete evaluation of suspected plasma cell disorders requires:
- Bone marrow aspiration and biopsy to quantify plasma cell infiltration (≥10% clonal plasma cells required for multiple myeloma diagnosis) 1, 3
- Full skeletal radiographic survey to detect lytic bone lesions 1, 3
- Complete blood count, calcium, creatinine, and beta-2 microglobulin to assess for CRAB criteria (hypercalcemia, renal failure, anemia, bone lesions) and staging 1, 3
The M-protein detection and characterization serves as the cornerstone for diagnosing plasma cell disorders, distinguishing between MGUS, smoldering myeloma, and active multiple myeloma, and monitoring treatment response. 1