Plasma cell dyscrasias are diseases of the hematologic system; the most common plasma cell dyscrasia is multiple myeloma. Multiple myeloma can evolve from a premalignant monoclonal gammopathy. Monoclonal gammopathy of undetermined significance (MGUS) is present in 3-4% of adults older than 50 years and is characterized by low levels of monoclonal protein, low bone marrow involvement, and the absence of end-organ damage. Once a certain monoclonal protein threshold is reached, the disease is defined as smoldering multiple myeloma (SMM), and once end-organ damage appears, the gammopathy has progressed to multiple myeloma. Newly diagnosed multiple myeloma is typically responsive to therapy, but relapse is common, reflecting the fact that multiple myeloma is a persistent disease that requires highly sensitive minimal residual disease (MRD) detection techniques.
Plasma cell dyscrasia evaluation begins with an investigation of the presence and type of monoclonal proteins (also known as M proteins). Serum free light chain (SFLC) quantification aids in diagnosing multiple myeloma and determining prognosis. Bone marrow evaluation is essential for diagnosis. Further testing can include multiparameter flow cytometry and plasma cell fluorescence in situ hybridization (FISH) to further determine prognosis and cytogenetic studies to identify high-risk variants. Posttherapy assessment increasingly involves MRD evaluation to determine the depth of response.
Quick Answers for Clinicians
The International Myeloma Working Group (IMWG) and National Comprehensive Cancer Network (NCCN) recommend a panel that includes serum protein electrophoresis (SPEP), serum immunofixation by electrophoresis (SIFE), and serum free light chain (SFLC) quantification. Urine protein electrophoresis (UPEP) and urine immunofixation electrophoresis (UIFE) provide additional diagnostic information. Bone marrow aspiration and biopsy are also recommended to detect quantitative and/or qualitative abnormalities of bone marrow plasma cells.
Abnormal serum free light chain (SFLC) ratios, absolute increases in the involved free light chain (FLC) concentrations, and specified involved-to-uninvolved FLC ratios predict risk of progression from premalignant disorders, such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), to multiple myeloma. Cytogenetic and fluorescence in situ hybridization (FISH) testing can identify markers of high-risk disease.
Extensive data indicate that minimal residual disease (MRD) assessment is an important prognostic marker in multiple myeloma, particularly to predict the outcomes of patients who achieve a complete response (CR) independent of therapy. MRD testing may also be helpful to identify high-risk patients and assist clinicians in developing optimal treatment plans. Thus, MRD status assessment is increasingly being incorporated into posttreatment assessment.
MRD can be evaluated within the bone marrow using next generation sequencing (NGS) or next generation flow cytometry and outside of the bone marrow using imaging techniques. The International Myeloma Working Group (IMWG) consensus defines MRD negativity as the absence of phenotypically aberrant clonal plasma cells using flow and sequencing technology with a minimum sensitivity of 1 in 105 nucleated cells or higher. Although NGS was able to reach this sensitivity level, conventional flow techniques could not. However, newer, next generation high-sensitivity flow cytometry assays, including the Multiple Myeloma Minimum Residual Disease by Flow Cytometry assay available at ARUP Laboratories, provide a dramatic improvement over previous conventional flow MRD approaches, achieving a sensitivity of 1 in 105 cells (0.001%). Next generation flow cytometry offers additional advantages over other testing methodologies, including wider accessibility and a faster turnaround time. Flow cytometry also does not require an a priori specimen to detect MRD, whereas other methods require evaluation of the patient at initial diagnosis with the same methodology to identify the molecular signature of the disease.
Indications for Testing
- Unexplained anemia, elevated serum protein, bone pain with lytic lesions on plain films, recurrent infections, renal failure, hypercalcemia, fatigue, or other systemic symptoms that indicate malignancy
- Age-inappropriate bone fractures with no known risk factors in premenopausal females or males younger than 65 years
- Unexplained proteinuria or peripheral neuropathy
- Premalignant condition (eg, monoclonal gammopathy) detected incidentally in asymptomatic patient
- Solitary plasmacytoma visualized on imaging or with local symptoms
- Suspected hyperviscosity syndrome
The International Myeloma Working Group (IMWG) and National Comprehensive Cancer Network (NCCN) recommend diagnosing monoclonal gammopathies with a testing combination of serum protein electrophoresis (SPEP), serum immunofixation by electrophoresis (SIFE), and SFLC quantification. Urine studies might be required for diagnosis of light chain amyloidosis. Bone marrow evaluation also provides information about the quantitative and/or qualitative abnormalities of bone marrow plasma cells.
Initial Workup of Suspected Plasma Cell Dyscrasias
Serum Quantitative Immunoglobulins
Quantitative immunoglobulin testing measures the primary immunoglobulins (IgG, IgA, and IgM), including both polyclonal (normal) and monoclonal (myeloma related) immunoglobulins. If an increase in an immunoglobulin class is identified, further testing by electrophoresis is required to determine if the elevation is caused by the presence of monoclonal immunoglobulin proteins.
Serum Protein Electrophoresis
SPEP is used to identify and quantify an M protein. SPEP is also used to determine the concentration or size of the M protein, but cannot determine the immunoglobulin heavy and light chain class. Therefore, if an M protein is identified, SIFE must be performed to confirm and characterize the heavy and light chains.
Serum Immunofixation by Electrophoresis
SIFE is used in conjunction with SPEP to confirm the M protein and characterize the heavy and light chains. SIFE is a more sensitive technique than SPEP for the identification of small M proteins found in patients with amyloidosis, early or treated myeloma, light chain myeloma, and plasmacytoma.
Serum Free Light Chains
SFLC testing measures the concentration of free kappa and lambda immunoglobulin light chains and can increase the sensitivity of diagnostic testing. Not all monoclonal gammopathies secrete excess free light chains (FLCs), so SFLC testing alone is insufficient for diagnosis and should be paired with SPEP and SIFE. SFLC testing is also useful for prognosis and monitoring, and may negate the need for 24-hour urine collections. It is important to note that some conditions, such as renal insufficiency and some autoimmune conditions, may cause abnormalities in SFLC measurements.
Urine Protein Electrophoresis and Urine Immunofixation
Once a serum M protein is identified, urine protein electrophoresis (UPEP) may be ordered to detect an M protein in the urine (Bence Jones protein). Similar to SIFE testing, urine immunofixation electrophoresis (UIFE) provides complementary information for its analogous test, UPEP, including characterization of the light chain M protein. UIFE is more sensitive than UPEP for detection of Bence Jones proteins and allows for characterization of those proteins. UPEP and UIFE are also useful tests to detect nephrotic syndrome and to detect M proteins in amyloidosis.
- CBC, differential, platelet count
- Peripheral blood smear
- Serum blood urea nitrogen (BUN)/creatinine, electrolytes, albumin, calcium
- Serum uric acid
- Serum lactate dehydrogenase (LDH) and beta-2 (β2) microglobulin
- Unilateral bone marrow aspirate and biopsy (including bone marrow immunohistochemistry and/or bone marrow multiparameter flow cytometry)
- Plasma cell FISH panel on bone marrow
- Serum viscosity (in the event of elevated M-protein levels and suspected hyperviscosity syndrome)
|Possible Dyscrasia||Immunoglobulin||M-Protein Concentration||FLC Ratio||Other Criteria|
|IgM MGUS||IgM||<3 g/dL (serum)||n/a||
No organ/tissue damage
Clonal BM plasma cells <10%
|Non-IgM MGUS||IgG or IgA||<3 g/dL (serum)||n/a||
No organ/tissue damage
Clonal BM plasma cells <10%
|Light chain MGUS||Free kappa or lambda light chain||<500 mg/24 hrs (urine)||
Abnormal ratio (<0.26 or >1.65)
Increase in involved light chain concentration
No immunoglobulin heavy chain expression
No end-organ damage
Clonal BM plasma cells <10%
|SMM (asymptomatic)||IgG or IgA||≥3 g/dL (serum) or >500 mg/24 hrs (urine)||n/a||
Clonal BM plasma cells 10-59%
No myeloma-defining eventa or CRAB featuresb
|Multiple myeloma (symptomatic)||IgG, IgA, IgD, IgE||≥3 g/dL (serum)||Involved:uninvolved ratio ≥100||
Clonal BM plasma cells ≥10%
≥1 myeloma-defining eventa or CRAB featuresb
aMyeloma-defining events: clonal BM plasma cells ≥60%; serum involved:uninvolved FLC ratio of ≥100; >1 focal lesion on MRI ≥5 mm
bCRAB features: elevated calcium (>11 mg/dL), renal insufficiency (serum creatinine >2 mg/dL or creatinine clearance <40 mL/min), anemia (Hb <10 g/dL or 2 g/dL < normal), bone disease (≥1 lytic lesions on skeletal radiography, CT, or PET-CT)
BM, bone marrow; CT, computed tomography; Hb, hemoglobin; MRI, magnetic resonance imaging; n/a, not applicable; PET, positron emission tomography
After diagnosis, SPEP should be repeated in 3-6 months to exclude multiple myeloma or Waldenström macroglobulinemia. If serum monoclonal protein is <1.5 g/dL, and IgG type and FLC ratio are normal, the risk of progression to myeloma or related malignancy is considered to be low. Patients should be followed with SPEP in 6 months and every 2-3 years thereafter if stable; no bone marrow biopsy or skeletal survey is needed, unless biochemical testing suggests progression of disease. For intermediate and high-risk MGUS, SPEP should be performed in 6 months, then annually for life. MRD testing is not indicated in patients with untreated plasma cell neoplasms.
Smoldering Multiple Myeloma (Asymptomatic)
CBC, differential, platelet count, creatinine, corrected calcium, serum immunoglobulins, SPEP, SIFE, and serum FLC should be performed every 3-6 months. Additionally, a 24-hour urine, UPEP, and UIFE are recommended at baseline and as clinically indicated or if there is a significant change in FLC levels. Bone marrow aspirate and biopsy with FISH, single nucleotide polymorphism (SNP) array, next generation sequencing (NGS), or multiparameter flow cytometry may be used as clinically indicated. Abnormal ratios and absolute amounts of the involved FLCs may predict progression of disease. In smoldering myeloma, a cutoff of involved:uninvolved FLCs >100 is used as a marker of progression to active disease to identify patients for treatment before end-organ damage occurs. MRD testing is not indicated in patients with untreated plasma cell neoplasms.
Multiple Myeloma (Symptomatic)
- Change in serum or urine M protein
- Change in the difference between involved and uninvolved SFLCs
- Increase in bone marrow plasma cell percentage ≥10%
- Increase in circulating plasma cells ≥50% (if this is the only measure of disease)
- New lesion or change in lesion size
NCCN recommends assessing CBC plus differential, platelet count, blood glucose and electrolytes, and metabolic panel for treatment toxicities. Serum quantitative immunoglobulins, SPEP, and SIFE are needed only if protein electrophoresis is negative during follow-up. Additionally, a 24-hour urine test, UPEP, and UIFE are recommended at baseline and as clinically indicated or if there is a significant change in FLC levels. Bone marrow aspirate and biopsy with multiparameter flow cytometry, as clinically indicated, are also recommended at initial evaluation and follow-up.
Finally, assessment of MRD in the posttherapy setting, as indicated for prognosis, can be considered after shared decision-making with the patient. For full response criteria for multiple myeloma, refer to the IMWG’s consensus criteria for response and MRD assessment.
Refer to institutional protocols for further specific testing directives.
ARUP Laboratory Tests
Quantitative Capillary Electrophoresis/Qualitative Immunofixation Electrophoresis/Quantitative Immunoturbidimetry/Quantitative Spectrophotometry
Components: SPEP, quantitative immunoglobulins (IgA, IgG, IgM)
Reflex: If patterns from SPEP are monoclonal or suspicious, then SIFE is performed
Qualitative Immunofixation Electrophoresis/Quantitative Capillary Electrophoresis/Quantitative Immunoturbidimetry/Quantitative Spectrophotometry
Components: SPEP, quantitative immunoglobulins (IgA, IgG, IgM), SIFE, SFLCs
Components: IgA, IgG, IgM
Qualitative Immunofixation Electrophoresis/Quantitative Immunoturbidimetry
Components: urine kappa and lambda free light chains, SIFE
Qualitative Immunofixation Electrophoresis
Fluorescence in situ Hybridization
Evaluate for hyperviscosity syndrome
Caers J, Garderet L, Kortüm KM, et al. European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when. Haematologica. 2018;103(11):1772-1784.
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548.
Dispenzieri A, Kyle R, Merlini G, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009;23(2):215-224.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Multiple myeloma. Version 1.2020 [Last update: Sep 2019; Accessed: Oct 2019]
Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78(1): 21-33.
Willrich MAV, Katzmann JA. Laboratory testing requirements for diagnosis and follow-up of multiple myeloma and related plasma cell dyscrasias. Clin Chem Lab Med. 2016;54(6):907-919.
Paiva B, van Dongen JJ, Orfao A. New criteria for response assessment: role of minimal residual disease in multiple myeloma. Blood. 2015;125(20):3059-3068.
Flores-Montero J, Sanoja-Flores L, Paiva B, et al. Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia. 2017;31(10):2094-2103.
Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e346.
Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010;24(6):1121-1127.
Dejoie T, Corre J, Caillon H, et al. Serum free light chains, not urine specimens, should be used to evaluate response in light-chain multiple myeloma. Blood. 2016;128(25):2941-2948.
Dimopoulos M, Kyle R, Fermand JP, et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood. 2011;117(18):4701-4705.
Genzen JR, Murray DL, Abel G, et al. Screening and diagnosis of monoclonal gammopathies: an international survey of laboratory practice. Arch Pathol Lab Med. 2018;142(4):507-515.
Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-2869.
Pratt G, Morris TC. Review of the NICE guidelines for multiple myeloma. Int J Lab Hematol. 2017;39(1):3-13.