What are the next steps for an adult patient with an abnormal Serum Protein Electrophoresis (SPEP) result, possibly indicating multiple myeloma or lymphoma, and presenting with symptoms such as anemia, bone pain, or recurrent infections?

Next Steps for Abnormal SPEP with Suspected Multiple Myeloma or Lymphoma

When an adult patient presents with an abnormal SPEP showing a monoclonal spike alongside symptoms such as anemia, bone pain, or recurrent infections, you must immediately proceed with comprehensive laboratory workup including serum immunofixation electrophoresis (SIFE), serum free light chain (FLC) assay with kappa/lambda ratio, quantitative immunoglobulins (IgG, IgA, IgM), 24-hour urine collection for urine protein electrophoresis (UPEP) and urine immunofixation electrophoresis (UIFE), complete blood count, serum calcium, creatinine, beta-2 microglobulin, and albumin, followed by bone marrow aspirate and biopsy with cytogenetics and FISH, and skeletal survey. 1, 2

Immediate Laboratory Workup

Essential Confirmatory Tests

• Serum immunofixation electrophoresis (SIFE) must be performed to identify the exact immunoglobulin type (IgG, IgA, IgM) and light chain (kappa or lambda) of the M-protein detected on SPEP. 1, 2, 3 This is critical because SIFE is more sensitive than SPEP alone and can detect small monoclonal proteins that SPEP may miss. 2

• Serum free light chain (FLC) assay with kappa/lambda ratio is mandatory because approximately 15-20% of myeloma cases produce only light chains without complete antibodies, which may not create a visible spike on standard SPEP. 1, 2 The combination of SPEP plus serum FLC analysis achieves 100% sensitivity for detecting plasma cell disorders. 2

• Quantitative immunoglobulin levels (IgG, IgA, IgM) are required to assess the specific monoclonal immunoglobulin concentration and detect immune paresis (suppression of uninvolved immunoglobulin classes), which is an important prognostic feature in multiple myeloma. 1, 2, 3

Urine Studies

• 24-hour urine collection for total protein, urine protein electrophoresis (UPEP), and urine immunofixation electrophoresis (UIFE) must be obtained because 20% of multiple myeloma patients have secretory urinary proteins, and some patients may have light chain-only disease detectable primarily in urine. 1, 2

Baseline Laboratory Assessment

• Complete blood count to evaluate for anemia (hemoglobin <100 g/L is present in approximately 30% of myeloma patients at diagnosis). 1

• Serum calcium and creatinine to assess for hypercalcemia and renal dysfunction, which are defining features of end-organ damage in multiple myeloma. 1

• Beta-2 microglobulin and serum albumin are essential prognostic markers incorporated into the International Staging System (ISS) for multiple myeloma, with elevated beta-2 microglobulin (>5.5 mg/L) associated with advanced disease and poorer survival. 1, 4 Note that renal dysfunction can artificially elevate beta-2 microglobulin independent of tumor burden. 4

Bone Marrow Evaluation

• Unilateral bone marrow aspirate and biopsy is required to measure plasma cell percentage and confirm the diagnosis. 1 A bone marrow is always required if the patient has unexplained anemia, renal insufficiency, hypercalcemia, or bone lesions. 1

• Cytogenetics using conventional karyotyping and fluorescence in situ hybridization (FISH) should be performed on plasma cells from bone marrow to detect chromosomal abnormalities including del(13), t(4;14), t(11;14), del(17), and t(14;16), which have prognostic significance. 1

• Bone marrow immunohistochemistry and flow cytometry can help confirm monoclonal plasma cells and define the disease more accurately. 1

Imaging Studies

• Skeletal survey (plain radiographs of skull, spine, pelvis, ribs, and long bones) is mandatory to detect lytic bone lesions characteristic of multiple myeloma. 1

• MRI, CT, or PET/CT scan may be useful under certain circumstances, particularly when skeletal survey is negative but clinical suspicion remains high, or to evaluate specific areas of concern. 1 Active myeloma is positive on PET scan. 1

• For IgM monoclonal protein, a CT scan of the abdomen should be performed because asymptomatic retroperitoneal lymph nodes may be present, suggesting Waldenstrom's macroglobulinemia or lymphoma. 1

Risk Stratification Based on Initial Results

If M-protein <15 g/L, IgG type, normal FLC ratio (Low-Risk MGUS)

• If clinical evaluation, CBC, creatinine, and calcium are normal without bone lesions, this suggests low-risk MGUS with only 5% risk of progression at 20 years. 1

• Repeat SPEP in 3-6 months to exclude multiple myeloma or Waldenstrom's macroglobulinemia, then if stable, follow every 2-3 years. 1

• Bone marrow examination is not routinely indicated in this scenario unless symptoms develop. 1

If M-protein ≥15 g/L, IgA or IgM type, or abnormal FLC ratio (Intermediate/High-Risk MGUS)

• Bone marrow aspirate and biopsy should be performed at baseline to rule out underlying plasma cell malignancy. 1

• Risk of progression at 20 years is 21-58% depending on number of risk factors present. 1

• Follow with SPEP and CBC in 6 months, then annually for life. 1

If M-protein ≥30 g/L or bone marrow plasma cells ≥10% without end-organ damage (Smoldering Multiple Myeloma)

• This represents smoldering (asymptomatic) multiple myeloma with 10% per year risk of progression for the first 5 years. 1

• Close monitoring is required but treatment is not indicated unless part of a clinical trial. 1

If End-Organ Damage Present (Active Multiple Myeloma)

• Presence of hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB criteria) with M-protein and/or ≥10% clonal plasma cells confirms active (symptomatic) multiple myeloma requiring immediate treatment. 1

Critical Diagnostic Pitfalls

• SPEP alone has only 71% sensitivity for plasma cell neoplasms in patients with lytic bone lesions, meaning 29% of cases will be missed if relying solely on SPEP. 5 This is why the comprehensive workup including SIFE, FLC, and UPEP is mandatory. 2

• Approximately 3% of patients have non-secretory myeloma with no detectable M-protein on either SPEP or UPEP, requiring serum FLC assay for diagnosis and monitoring. 1, 2

• Light chain escape can occur where disease evolves to produce only light chains during treatment, which may not be adequately captured by standard SPEP, necessitating ongoing FLC monitoring. 2

• Biclonal gammopathy can rarely occur, appearing as two M-bands on SPEP, but immunofixation electrophoresis is required to differentiate true biclonality from a single clone producing two bands. 6

Urgent Hematology/Oncology Referral

• Any detected monoclonal protein on SPEP should prompt referral to a hematologist/oncologist. 2

• Urgent referral (within 1-2 weeks) is recommended for patients with significant M-protein spike, accompanying symptoms (anemia, bone pain, recurrent infections), anemia, renal dysfunction, or hypercalcemia. 2