a. Definition. Plasma cell dyscrasias are a monoclonal proliferation of plasma cells that produce a clonal immunoglobulin protein (i.e., monoclonal gammopathies or paraproteinemias). They are derived from malignant B lymphocytes. Common plasma cell dyscrasias include multiple myeloma and Waldenström’s macroglobulinemia.
b. Clinical manifestations of plasma cell dyscrasias
i. The clinical manifestations of all plasma cell dyscrasias result from:
1. Proliferation of the neoplastic cells and invasion of various organs
2. Secretion of cell products (either immunoglobulins or their subunits)
3. Host response to the tumor
ii. Patients with plasma cell dyscrasias often have an M (monoclonal) protein (clonal immunoglobulin) in their serum.
1. The M component represents the immunoglobulin (or solitary light or heavy chain) that is being secreted and can be quantitated by performing an immunofixation on a serum protein electrophoresis. Qualitative assessment can also be made with this assay (classification of the heavy and light chains). Quantification of the light chain can also be performed using a serum free light chain assay.
2. M components are not specific to plasma cell dyscrasias. They are also seen in leukemia, lymphoma, sarcoidosis, cryoglobulinemia, rheumatoid arthritis and other connective tissue disorders, monoclonal gammopathy of uncertain significance (MGUS), and other diseases.
B. Multiple Myeloma
a. Epidemiology. Myeloma accounts for 1% of all malignant disease and more than 10% of hematologic malignancies in the United States.
i. It is a disease primarily of older people; the median age at diagnosis is 65–70 years.
ii. The incidence in African Americans is twice that of caucasian populations.
b. Clinical manifestations of multiple myeloma. The most common presenting symptoms are related to anemia, bone pain, and infection. The important clinical manifestations of multiple myeloma can be remembered using the mnemonic, “PLASMA.”
MNEMONIC: Important Clinical Manifestations of Multiple Myeloma (“PLASMA”)
Lytic bone lesions and hypercalcemia
Anemia and Abnormal bleeding
Sepsis and infections
i. Proteinuria/renal insufficiency is multifactorial in etiology, with causes including light-chain proteinuria, hypercalcemia, hyperuricemia, amyloidosis, and pyelonephritis.
ii. Lytic bone lesions and hypercalcemia. Bone pain occurs in 70% of patients, usually involving the back and ribs. Because the lesions are lytic, plain radiographs are better than bone scans.
iii. Anemia and abnormal bleeding. Seventy percent of patients have anemia (usually normocytic) at the time of diagnosis. Rouleaux formation is frequently seen because of the paraprotein. Paraproteinemias may cause qualitative platelet dysfunction, leading to abnormal bleeding, but patients with myeloma also frequently have thrombocytopenia.
iv. Sepsis and infection. Because of the excess production of abnormal immunoglobulins, myeloma patients usually have decreased levels of normal immunoglobulins leading to increased susceptibility to infection. Seventy-five percent of patients with multiple myeloma will experience a serious infection at some time.
v. Marrow involvement. Plasma cells infiltrate the bone marrow causing anemia, thrombocytopenia, and potentially bone marrow failure.
vi. Secondary amyloidosis develops in a minority of patients and occurs when light chains deposit in normal tissue. This may lead to carpal tunnel syndrome, congestive heart failure (CHF), renal or liver disease.
c. Laboratory findings
i. Proteinuria may be evident on urinalysis, but the dipstick is often negative because it tests for albumin, not globulin.
ii. Anemia is usually normocytic and normochromic, and rouleaux formation may be noted on the peripheral smear.
iii. Narrow anion gap. Because globulin is cationic, the increased unmeasured cations decrease the anion gap.
iv. Low serum bicarbonate. A type 2 renal tubular acidosis may result from proximal tubular damage as a result of filtered light chains.
v. Elevated creatinine signifying renal damage may be present.
vi. Pseudohyponatremia may result from increased paraprotein, which can cause laboratory errors.
vii. Hypercalcemia may occur from increased osteoclast activity leading to lytic bone lesions.
viii. Elevated erythrocyte sedimentation rate (ESR). The ESR is frequently elevated, but this is a nonspecific finding.
d. Approach to the patient
i. Protein electrophoresis on serum and urine is usually ordered based on suspicious symptoms, signs, or laboratory test results.
1. Procedure. Albumin and α-, β-, and γ-globulin are separated in a gel medium based on their size. In myeloma, an increased quantity of monoclonal paraprotein causes an abnormal “spike” in a specific area (usually in the γ region). This spike may not be seen unless immunofixation is performed on the separated gel.
2. Results. When used together, serum and urine protein electrophoresis will miss approximately 1% of myeloma patients (as some myelomas do not secrete any proteins). However, of patients who have a variant of myeloma (solitary bone plasmacytoma or extramedullary plasmacytoma), fewer than 30% will have a positive protein electrophoresis.
a. Serum protein electrophoresis will confirm the diagnosis of myeloma in 80–90% of patients. Approximately two-thirds of patients with positive serum protein electrophoresis results will also test positive on urine protein electrophoresis.
b. Urine protein electrophoresis. In approximately 15% of patients, only the light chain is secreted. The light chain can be detected using urine protein electrophoresis with immunofixation or a spot urine Bence Jones protein assessment.
c. Serum free light chain. Free light-chain proteins can also be quantified from the serum using an immunodiagnostic turbidity assay.
ii. Immunoelectrophoresis is performed to determine whether the abnormal spike is polyclonal or monoclonal.
1. A polyclonal spike is seen in reactive conditions (e.g., infection, malignancy, collagen vascular disease).
2. A monoclonal (M component) spike often signifies a plasma cell dyscrasia but may also be found in other conditions (e.g., chronic lymphocytic leukemia, lymphoma, sarcoidosis). Therefore, this test should not be used to screen patients who do not have symptoms because the clinical context is critical to correct interpretation.
3. Diagnostic criteria for multiple myeloma (Table 72.1):
a. Multiple criteria exist for establishing the diagnosis of multiple myeloma (versus smoldering myeloma or MGUS).
b. The International Myeloma Working Group criteria have largely replaced the World Health Organization (WHO) criteria in the diagnosis.
Table 72.1 Diagnosis of Multiple Myeloma
International Myeloma Working Group1
World Health Organization Criteria2
A. Presence of a serum or urinary monoclonal protein
B. Presence of clonal plasma cells in the bone marrow or a plasmacytoma
C. Presence of end-organ damage considered related to the plasma cell dyscrasia, including one of the following:
a. Lytic bone lesions
b. Increased calcium (>11.5 mg/dL)
c. Anemia (hemoglobin <10 g/dL)
d. Renal failure (creatinine >2 mg/dL)
e. Others, including symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (>2 episodes in 12 months)
B. Bone marrow plasmacytosis (>30% plasma cells)
C. Monoclonal immunoglobulin spike on serum electrophoresis:
a. IgG >3.5 g/dL or IgA >2 g/dL
b. Urine kappa or lambda light-chain excretion >1 g/day over 24 hours
A. Bone marrow plasmacytosis (10–30% plasma cells)
B. Monoclonal immunoglobulin spike present but of lesser magnitude than given above
C. Lytic bone lesions
D. IgM <50 mg/dL, IgA <100 mg/dL, or IgG <600 mg/dL
1 Must have each of three factors present for the diagnosis of symptomatic myeloma. Adapted from International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br Haematol 2003;121(5):749–57.
2 Myeloma may be diagnosed with any two major criteria, or one major criterion plus one minor criterion, or three minor criteria. Adapted from Jaffe ES, Harris NL, Stein H, et al. Tumors of haematopoietic and lymphoid tissues: pathology and genetics. World Health Organisation Classification of Tumours. Lyon: IARC Press; 2001; and van Marion AMW, Lokhorst HM, van den Tweel JG. Pathology of multiple myeloma. Curr Diagn Pathol 2003;9(5):281–337.
An immunoglobulin G (IgG) spike >3.5 g/dL or an IgA spike >2 g/dL almost always represents myeloma (and will be seen as a monoclonal spike when tested by immunoelectrophoresis alone).
iii. Differential diagnosis. The main disorder to distinguish from myeloma is MGUS. Characteristics of MGUS usually include:
1. M component usually ≤3 g/dL
2. Marrow plasmacytosis <10%
3. Absence of anemia, renal disease, hypercalcemia, and bone lesions
For patients diagnosed with MGUS, approximately 1% per year will progress to multiple myeloma.
e. Prognosis is influenced by multiple factors.
i. The serum β2-microglobulin level is an important prognostic indicator and should be checked at diagnosis.
ii. As with many hematopoietic malignancies, cytogenetic changes are prognostically significant for both the anticipated response to chemotherapy and overall survival. Translocations involving chromosomes 4 and 14 [t(4;14)], chromosomes 14 and 16 [t(14;16)], and deletion of the short arm of chromosome 17 (del17p) are associated with a poor prognosis.
iii. Circulating plasma cells (CD38+/CD45– cells) are also associated with a poorer prognosis.
iv. A commonly used prognostic model is the International Staging System (Table 72.2).
Table 72.2 International Staging System for Multiple Myeloma
β2-Microglobulin <3.5 mg/L and serum albumin ≥3.5 g/dL
Neither stage 1 nor stage 3
β2-Microglobulin ≥5.5 mg/L
Source: Derived from Greipp PR, San Miguel J, Durie BG. International staging system for multiple myeloma. J Clin Oncol 2005;23(15):3412–20.
f. Treatment. The only known curative option for multiple myeloma is an allogeneic bone marrow transplantation. However, newer chemotherapies have drastically improved the overall survival in most patients.
i. Chemotherapy traditionally involved the use of an alkylating agent (i.e., melphalan) and prednisone, or combination cytotoxic chemotherapy (vincristine, doxorubicin, and dexamethasone). Melphalan and prednisone are a mainstay of treatment for patients who are not considered candidates for bone marrow transplantation.
ii. Targeted chemotherapies have dramatically increased the response rate and overall survival. Targeted therapies are now being evaluated in combinations together with traditional chemotherapeutics.
1. The immunomodulatory drugs—thalidomide and lenalidomide—are active agents against myeloma.
2. The proteasomal inhibitor, bortezomib, also shows significant efficacy in myeloma.
iii. Autologous bone marrow transplantation is frequently used as a consolidation treatment after initial chemotherapy. Allogeneic bone marrow transplantation is frequently used in relapsed disease after failing an autologous transplantation.
iv. Radiation is also used for individual painful bone lesions or plasmacytomas.
v. Bisphosphonates are administered monthly to reduce skeletal complications.
vi. Pneumococcal vaccination should be given to help prevent infectious complications.
C. Waldenström’s Macroglobulinemia. Macroglobulinemia describes an elevated production of an IgM antibody. In Waldenström’s macroglobulinemia, a clonal B cell proliferates and secretes a clonal IgM protein.
a. Clinical manifestations of Waldenström’s macroglobulinemia. The secreted IgM protein accounts for most of the symptomatic manifestations. The clinical manifestations are similar to those of myeloma; however, there are some important differences.
i. Hyperviscosity is much more common in Waldenström’s macroglobulinemia than multiple myeloma. Symptoms may include headache, altered mental status, visual disturbances, stroke, and mucosal bleeding.
ii. Hepatomegaly, adenopathy, and splenomegaly are commonly seen in Waldenström’s macroglobulinemia, but not in myeloma.
iii. Hypercalcemia, bony lesions, and renal insufficiency are less common in Waldenström’s macroglobulinemia.
iv. A simple way to remember the features that may distinguish Waldenström’s macroglobulinemia from multiple myeloma is to use the mnemonic, “Uncle Waldo loves HAMS.”
MNEMONIC: Characteristics of Waldenström’s Macroglobulinemia (“Uncle Waldo loves HAMS”)
i. Waldenström’s macroglobinemia is an indolent disease with a median survival time of more than 8 years but is largely incurable. Therefore, treatment is directed toward minimizing symptoms and complications from the macroglobulinemia. Symptom-free patients may be observed.
ii. Alkylating agents (e.g., chlorambucil) are typically considered for patients who are not candidates for bone marrow transplantation.
iv. Rituximab (a monoclonal antibody to the cell surface B cell antigen CD20) demonstrates significant activity in Waldenström’s.
v. Plasmapheresis may also be needed frequently to treat symptoms of hyperviscosity.
Suggested Further Readings
Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med 2017;376:1311–20.Find this resource:
Dimopoulos MA, Kastritis E, Terpos E. Recent data supporting novel management strategies for patients with multiple myeloma. JAMA Oncol 2016;2:1261–2.Find this resource:
Sigurdardottir E, Turesson I, Lund S, et al. The role of diagnosis and clinical follow-up of monoclonal gammopathy of undetermined significance on survival in multiple myeloma. JAMA Oncol 2015;1:168–74.Find this resource:
Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med 2015;372:1430–40.Find this resource: