Plasma Cell Dyscrasias

Medical Experts

Author

Abujasen

Kaileigh Bingham Abujasen, MD

Anatomic and Clinical Pathology Resident, University of Utah and ARUP Laboratories

Contributor

Delgado

Julio Delgado, MD, MS

Professor, Head of Clinical Operations for Cytogenetics, University of Utah School of Medicine

Vice Chair and Chief of the Division of Clinical Pathology, Executive Vice President, ARUP Laboratories

Contributor

Ng

David P. Ng, MD, FCAP

Associate Professor (Clinical), University of Utah

Medical Director, Hematopathology, Hematologic Flow Cytometry, Applied Artificial Intelligence and Bioinformatics, ARUP Laboratories

Plasma cell dyscrasias are a group of heterogeneous diseases of the hematologic system that involve the clonal proliferation of plasma cells, which often leads to the increased production of monoclonal proteins (M proteins) or paraproteins. The diseases range from asymptomatic premalignant conditions, such as monoclonal gammopathy of undetermined significance (MGUS), to more serious neoplastic conditions, including plasmacytoma, plasma cell myeloma/multiple myeloma, and various plasma cell neoplasms with associated paraneoplastic syndromes.

The most common malignant plasma cell dyscrasia is multiple myeloma. Multiple myeloma can evolve from the premalignant condition MGUS, which is characterized by low serum monoclonal protein, low bone marrow involvement, and the absence of end-organ damage that can be attributed to the disorder. The incidence of MGUS increases with age and is generally not associated with clinical symptoms. Once a certain threshold for serum or urinary M protein and/or bone marrow involvement is met, the disease is defined as smoldering (asymptomatic) multiple myeloma. When end-organ damage manifests or laboratory or imaging findings suggest the development of end-organ damage, the gammopathy has progressed to multiple myeloma. Newly diagnosed multiple myeloma is typically responsive to therapy, but relapse is common, which reflects the fact that multiple myeloma is a persistent disease that requires highly sensitive minimal residual disease (MRD) detection techniques.

Quick Answers for Clinicians

Which tests should be included in the initial workup for a suspected plasma cell dyscrasia?

Initial laboratory testing for a suspected plasma cell dyscrasia should include a CBC with differential, peripheral blood smear, comprehensive metabolic panel (CMP), and serum uric acid, lactate dehydrogenase (LDH), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and beta-2 (β2) microglobulin testing. To detect a monoclonal protein (M protein), a panel that includes serum protein electrophoresis (SPEP) and serum free light chain (SFLC) quantification should be used. Bone marrow aspirate and biopsy are also recommended to detect quantitative and/or qualitative abnormalities in bone marrow plasma cells. Molecular studies such as fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) may also provide useful diagnostic information. In certain scenarios, other testing might be required, such as a tissue biopsy, serum viscosity testing, amyloid tissue subtyping via mass spectrometry, and baseline clonotype identification.

Which tests are used to determine risk and prognosis in plasma cell dyscrasias?

The size and type of the monoclonal protein (M protein) and the free light chain (FLC) ratio predict the risk of progression from premalignant disorders, such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma, to multiple myeloma. Cytogenetic testing, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS) can identify markers of high-risk disease. Other markers of high-risk disease include an elevated serum beta-2 (β2) microglobulin, peripherally circulating plasma cells, extramedullary disease, and a high proliferation rate.

Which tests are used to detect minimal residual disease in multiple myeloma?

Minimal residual disease (MRD) assessment is important in prognostication and in assessing treatment response in multiple myeloma.^, 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 such as positron emission tomography (PET)/computed tomography (CT). 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 (0.001%) nucleated cells or higher. Next generation flow cytometry offers advantages over other testing methodologies, including greater accessibility and a faster turnaround time. Flow cytometry also does not require a previous specimen to detect MRD, whereas other methods require evaluation of a patient specimen at initial diagnosis using the same methodology to identify the molecular signature of the disease.

Classification

The World Health Organization (WHO) and the International Consensus Classification (ICC) have classification systems for the various plasma cell dyscrasias.^,

Indications for Testing

Laboratory evaluation for suspected plasma cell dyscrasias, including multiple myeloma, should be considered for individuals with any of the following presentations:

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 female individuals or male individuals younger than 65 years
Unexplained proteinuria or peripheral neuropathy
A premalignant condition (e.g., monoclonal gammopathy) detected incidentally in an asymptomatic patient
Solitary plasmacytoma visualized on imaging or with local symptoms
Suspected hyperviscosity syndrome

Laboratory Testing

Diagnosis

Serum Quantitative Immunoglobulins

Quantitative immunoglobulin (Ig) testing measures the primary immunoglobulins (IgG, IgA, and IgM), including both polyclonal (normal) and monoclonal (neoplastic) immunoglobulins. If an increase in an Ig class is identified, further testing by electrophoresis is required to determine if the elevation is caused by the presence of monoclonal Ig proteins.

Serum Protein Electrophoresis

Serum protein electrophoresis (SPEP) is used to identify and quantify an M protein and should be performed in conjunction with serum free light chain (SFLC) quantification for patients with suspected monoclonal gammopathies. SPEP is also used to determine the concentration or size of the M protein but cannot determine the Ig heavy and light chain class. Therefore, if an M protein is identified, serum immunofixation by electrophoresis (SIFE) must be performed to confirm and characterize the heavy and light chains.

Serum Immunofixation by Electrophoresis

SIFE is used for M protein confirmation and to 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 Ig light chains and can increase the sensitivity of diagnostic testing. Not all monoclonal gammopathies secrete excess free light chains (FLCs); therefore, SFLC testing alone is insufficient for diagnosis and should be performed along with SPEP. SFLC testing is also useful for prognosis and monitoring. It is important to note that some conditions, such as renal insufficiency and some autoimmune disorders, may cause abnormalities in SFLC measurements.

Urine Protein Electrophoresis and Urine Immunofixation

Urine protein electrophoresis (UPEP) and urine immunofixation electrophoresis (UIFE) are used in conjunction with SPEP and SIFE to detect M proteins in amyloid light chain (AL) amyloidosis. Similar to SIFE testing, 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 enables characterization of those proteins.

Monitoring

Monoclonal Gammopathy of Undetermined Significance

Monitoring recommendations in MGUS depend on the patient’s risk for progression, which is determined by the presence of >1.5 g/dL M protein, IgA or IgM isotypes, and/or a serum FLC ratio <0.26 or >1.65. Patients at low risk (those without risk factors) should be followed using SPEP in 6 months and every 2-3 years thereafter if stable; no bone marrow biopsy or imaging is needed unless biochemical testing suggests disease progression. For intermediate and high-risk MGUS, a bone marrow biopsy and aspirate with fluorescence in situ hybridization (FISH), along with lactate dehydrogenase (LDH), beta-2 (β2) microglobulin, and C-reactive protein testing, should be performed. A computed tomography (CT) scan of the abdomen may be indicated if the M protein is an IgM to exclude Waldenström macroglobulinemia. If these test results are all within normal limits, SPEP, a CBC with differential, and creatinine testing should be performed in 6 months, then annually for life.

Smoldering (Asymptomatic) Multiple Myeloma

A CBC with differential, along with creatinine, corrected calcium, and serum quantitative Ig testing, as well as SPEP, SIFE, and serum FLC testing, should be performed every 3-6 months. Additionally, a 24-hour urine test for total protein, UPEP, UIFE, and a bone marrow aspirate and biopsy with FISH, NGS, or multiparameter flow cytometry may be indicated.

Multiple Myeloma (Symptomatic)

Patients with multiple myeloma should be monitored for treatment response, symptoms associated with treatment, and disease progression. The NCCN recommends performing a CBC with differential and metabolic panel to assess patients for treatment toxicities. Serum quantitative Ig testing, SPEP, and SIFE are recommended to monitor changes in the various protein levels. Additionally, a 24-hour urine test for total protein, UPEP, and UIFE are recommended as clinically indicated. Bone marrow aspirate and biopsy with FISH should be repeated, as indicated, particularly at relapses. The SFLC ratio is important for assessing response to therapy, as is MRD testing. Flow cytometry-based testing can be used for the assessment of MRD but includes markers unaffected by front-line targeted drug therapies (e.g., daratumumab). Assessment of MRD as indicated for prognosis can be considered after shared decision-making with the patient.

For full response criteria for multiple myeloma, refer to the International Myeloma Working Group (IMWG) consensus criteria for response and MRD assessment.