PLASMA CELL DISORDERS

PLASMA CELL DISORDERS

Plasma cell disorders are neoplastic or potentially neoplastic diseases associated with the clonal proliferation of immunoglobulin-secreting plasma cells. They are characterized by the secretion of electrophoretically and immunologically homogeneous (monoclonal) proteins that represent intact or incomplete immunoglobulin molecules. Monoclonal proteins are commonly referred to as M proteins, myeloma proteins, or paraproteins.

PLASMA CELL PROLIFERATIVE DISORDERS

  1. Premalignant monoclonal gammopathies
    1. Monoclonal gammopathy of undetermined significance (MGUS)
    2. MGUS in association with chronic lymphocytic leukaemia and non-Hodgkin lymphoma
    3. Biclonal and triclonal gammopathies of undetermined significance
    4. Idiopathic Bence Jones proteinuria and light chain MGUS
    5. Smouldering multiple myeloma
  1. Malignant monoclonal gammopathies
  • Multiple myeloma and related malignant neoplasms (IgG, IgA, IgD, IgE, and free light chains)
      1. Symptomatic multiple myeloma
      2. Plasma cell leukaemia
      3. Osteosclerotic myeloma (including POEMS syndrome)
      4. Solitary plasmacytoma of bone
      5. Solitary extramedullary plasmacytoma
    • Waldenström macroglobulinemia (IgM)
  1. Heavy chain diseases (HCDs)
    • γ-HCD
    • α-HCD
    • µ-HCD
  2. Cryoglobulinemia (types I, II, and III)
  1. Immunoglobulin light chain amyloidosis

Ig = immunoglobulin; POEMS = polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes.

Syndromes associated with plasma cell disorders and monoclonal proteins include premalignant disorders (monoclonal gammopathy of undetermined significance, smouldering multiple myeloma), malignant neoplasms (multiple myeloma, Waldenström macroglobulinemia), and disorders primarily related to the unique properties of the secreted monoclonal protein (cryoglobulinemia, immunoglobulin light chain [AL] amyloidosis, light chain deposition disease).

Intact immunoglobulins consist of two heavy (H) polypeptide chains of the same class and subclass and two light (L) polypeptide chains of the same type. The heavy polypeptide chains are designated by Greek letters: γ in immunoglobulin G (IgG), α in immunoglobulin A (IgA), µ in immunoglobulin M (IgM), δ in immunoglobulin D (IgD), and ε in immunoglobulin E (IgE). The light chain types are kappa (κ) and lambda (λ). Both heavy chains and light chains have constant and variable regions with respect to the amino acid sequence. The class specificity of each immunoglobulin is defined by a series of antigenic determinants on the constant regions of the heavy chains (γ, α, µ, δ, and ε) and the two major classes of light chains (κ and λ). The amino acid sequence in the variable regions of the immunoglobulin molecule corresponds to the active antigen-combining site of the antibody.

In the majority of clonal plasma cell disorders, intact immunoglobulin molecules are secreted as monoclonal (M) proteins. In addition, there can also be abnormal secretion of excess monoclonal free light chains that are released without being bound to immunoglobulin heavy chains. In some patients, heavy chain expression is completely lost, and only monoclonal free light chains (commonly referred to as Bence Jones proteins) are secreted. Even less frequently, only heavy chains are secreted, resulting in heavy chain diseases (HCDs). Rare patients with multiple myeloma secrete no identifiable immunoglobulin (nonsecretory myeloma).

Protein electrophoresis of the serum and urine detects M protein as a narrow peak (like a church spire) on the densitometer tracing or as a dense, discrete band on agarose gel. Electrophoresis also permits quantitation of M proteins. Monoclonal light chains (Bence Jones proteinemia) are rarely seen on serum electrophoresis but are easily detected on urine electrophoresis. Urine electrophoresis requires a 24-hour urine collection.

Immunofixation of the serum and urine is performed when a peak or band is first seen on protein electrophoresis to identify the heavy and light chain types of the M protein. Immunofixation is also a more sensitive test than protein electrophoresis, and it should always be performed in conjunction with electrophoresis when multiple myeloma or related disorders are first suspected to detect small, unmeasurable M proteins that may be missed on electrophoresis. This is particularly important in oligosecretory myeloma, primary amyloidosis, and solitary plasmacytoma and after successful treatment of multiple myeloma or macroglobulinemia. In these instances, a small M protein can be concealed in the normal β or γ areas of the electrophoresis gel and may be overlooked.

Monoclonal proteins must be distinguished from an excess of polyclonal immunoglobulins (one or more heavy chain types and both κ and λ light chains, usually limited to the γ region), which produce a broad-based peak or broad band. This finding is associated with chronic infectious or inflammatory states, including chronic liver disease.

The serum free light chain assay measures the level of free κ and λ immunoglobulin light chains (i.e., light chains that are not bound to intact immunoglobulin). An abnormal κ/λ free light chain ratio (normal range, 0.26 to 1.65) indicates an excess of one light chain type versus the other and is interpreted as representing a monoclonal elevation of the corresponding light chain type. The serum free light chain assay is more sensitive than electrophoresis or immunofixation in detecting free monoclonal light chains and is useful in the diagnostic evaluation of plasma cell disorders and in risk stratification.

Definition

Monoclonal gammopathy of undetermined significance (MGUS; formerly called benign monoclonal gammopathy) is a premalignant clonal plasma cell disorder characterized by the presence of a serum M protein in persons who lack evidence of multiple myeloma, macroglobulinemia, amyloidosis, or other related diseases. MGUS is defined by a serum M protein concentration lower than 3 g/dL; less than 10% clonal plasma cells in the bone marrow; and absence of lytic bone lesions, anaemia, hypercalcemia, and renal insufficiency that can be attributed to a plasma cell disorder. The main clinical significance of MGUS is its lifelong risk of transformation to myeloma or related malignant disease at a fixed but unrelenting rate of 1% per year.

Epidemiology

More than 50% of patients in whom a serum M protein is detected have MGUS. The prevalence of MGUS in the general population increases with age, from approximately 1% in persons 50 to 60 years old to more than 5% in those older than 70 years. The age-adjusted prevalence is higher in men than in women and is twice as high in blacks compared with whites. There is an increased prevalence of MGUS as well as of multiple myeloma among blood relatives of individuals with monoclonal gammopathies.

Pathobiology

MGUS represents a limited, nonmalignant expansion of monoclonal plasma cells. The aetiology of MGUS is unknown, but age, male gender, family history, immunosuppression, and exposure to certain pesticides are known risk factors. It is hypothesized that infection, inflammation, or other antigenic stimuli, acting in concert with the development of cytogenetic abnormalities in the plasma cells, are the initiating pathogenetic events in most patients. Approximately 40% of MGUS is associated with plasma cell translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32 (IgH-translocated MGUS), 40% with trisomies involving odd-numbered chromosomes (hyperdiploid MGUS), 15% with both trisomies and IgH translocations, and the remaining with other cytogenetic abnormalities. The primary IgH translocations seen in MGUS commonly involve one of five recurrent partner chromosome loci: 11q13 ( CCND1 [cyclin D1 gene]), 4p16.3 ( FGFR3 and MMSET ), 6p21 ( CCND3 [cyclin D3 gene]), 16q23 (c- maf ), and 20q11 ( mafB ).

Clinical Manifestations

MGUS is asymptomatic and is usually diagnosed incidentally on laboratory testing. Patients with MGUS progress to multiple myeloma or related malignant disease at a rate of approximately 1% per year. The interval from the time of recognition of the M protein to the diagnosis of serious disease ranges from 1 to 32 years (median, 10.6 years), and the relative risk versus a control population is 25.0 for progression to multiple myeloma, 8.4 for primary amyloidosis, 46.0 for Waldenström macroglobulinemia, 2.4 for the development of other forms of non-Hodgkin lymphoma, and 8.5 for plasmacytoma.

Diagnosis

MGUS is differentiated from multiple myeloma and smouldering multiple myeloma by the size of the M protein; the bone marrow plasma cell percentage; and the presence or absence of anaemia, renal failure, hypercalcemia, or lytic bone lesions. Because anaemia and renal insufficiency are relatively common in the elderly population with MGUS, the causes of these conditions should be carefully investigated with adequate laboratory studies. For example, in a patient with anaemia, tests to exclude iron, vitamin B12 , or folate deficiency must be performed. In certain instances, such as unexplained renal failure, a renal biopsy may be needed. Only patients with strong evidence of end-organ damage thought to be directly related to a plasma cell disorder can be considered to have myeloma or a related malignant disease.

CRITERIA FOR THE DIAGNOSIS OF PLASMA CELL DISORDERS

DISORDER DISEASE DEFINITION
Monoclonal gammopathy of undetermined significance (MGUS) All 3 criteria must be met:

·         1. Serum monoclonal protein (IgG, IgA, or IgM) <3 g/dL

·         2. Clonal bone marrow plasma cells <10%

·         3. Absence of end-organ damage, such as hypercalcemia, renal insufficiency, anaemia, and bone lesions, that can be attributed to the plasma cell proliferative disorder (or, in the case of IgM MGUS, no evidence of anaemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly that can be attributed to the underlying lymphoproliferative disorder)

Light chain MGUS All 6 criteria must be met:

·         1. Abnormal FLC ratio (<0.26 or >1.65)

·         2. Increased level of the appropriate involved light chain (increased κ FLC in patients with ratio >1.65 and increased λ FLC in patients with ratio <0.26)

·         3. No immunoglobulin heavy chain expression on immunofixation

·         4. Absence of end-organ damage that can be attributed to the plasma cell proliferative disorder

·         5. Clonal bone marrow plasma cells <10%

·         6. Urinary monoclonal protein <500 mg/24h

Smouldering multiple myeloma (also referred to as asymptomatic multiple myeloma) Both criteria must be met:

·         1. Serum monoclonal protein (IgG or IgA) ≥3 g/dL (or urinary monoclonal protein ≥500 mg/24 hours) and/or clonal bone marrow plasma cells 10-60%

·         2. Absence of myeloma defining events or amyloidosis

Multiple myeloma Both criteria must be met:

·         1. Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma

·         2. Any one or more of the following myeloma defining events:

o    • Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

§  • Hypercalcemia: serum calcium >1 mg/dL (>0.25 mmol/L) higher than the upper limit of normal or >11 mg/dL (>2.75 mmol/L)

§  • Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >2 mg/dL (>177 µmol/L)

§  • Anaemia: haemoglobin value of >2 g/dL below the lower limit of normal, or a haemoglobin value <10 g/dL

§  • Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT

o    • Any one or more of the following biomarkers of malignancy:

§  • Clonal bone marrow plasma cell percentage ≥60%

§  • Involved: uninvolved serum free light chain ratio ≥100 (involved free light chain level must be ≥100 mg/L)

§  • >1 focal lesions on MRI studies (at least 1mm in size)

Waldenström macroglobulinemia Both criteria must be met:

·         1. IgM monoclonal gammopathy (regardless of the size of the M protein)

·         2. >10% bone marrow lymphoplasmacytic infiltration (usually intertrabecular) by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation and a typical immunophenotype (surface IgM , CD5 +/– , CD10 – , CD19 , CD20 , CD23 ) that satisfactorily excludes other lymphoproliferative disorders, including chronic lymphocytic leukaemia and mantle cell lymphoma

Smouldering Waldenström macroglobulinemia (also referred to as indolent or asymptomatic Waldenström macroglobulinemia) Both criteria must be met:

·         1. Serum IgM monoclonal protein ≥3 g/dL and/or bone marrow lymphoplasmacytic infiltration ≥10%

·         2. No evidence of end-organ damage, such as anaemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly, that can be attributed to a lymphoplasma cell proliferative disorder

Solitary plasmacytoma All 4 criteria must be met:

·         1. Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells

·         2. Normal bone marrow with no evidence of clonal plasma cells

·         3. Normal skeletal survey and either MRI of spine and pelvis or PET computed tomography (except for the primary solitary lesion)

·         4. Absence of end-organ damage, such as hypercalcemia, renal insufficiency, anaemia, or bone lesions, that can be attributed to a plasma cell proliferative disorder

POEMS syndrome All 4 criteria must be met:

·         1. Presence of a monoclonal plasma cell disorder (almost always λ type)

·         2. Peripheral neuropathy

·         3. Any one of the following 3 major features: sclerotic bone lesions, Castleman disease, elevated levels of vascular endothelial growth factor

·         4. Any one of the following 7 minor features: organomegaly, edema, endocrinopathy (excluding diabetes mellitus or hypothyroidism), typical skin changes, papilledema, thrombocytosis, polycythaemia

The features should have a temporal relationship to one another, with no other attributable cause

CT = computed tomography; FLC = free light chain; MRI = magnetic resonance imaging; PET = positron emission tomography.

Although a reduction in the levels of the immunoglobulin classes other than M protein (i.e., the normal polyclonal or background immunoglobulins) is more frequently seen in multiple myeloma or Waldenström macroglobulinemia, such reductions also occur in almost 40% of patients with MGUS.

MGUS is associated with numerous diseases. However, because 3% of the general population older than 50 years has MGUS, it is often difficult to determine whether these reported associations are causal or coincidental. Some associations have been verified on the basis of epidemiologic studies; these include peripheral neuropathy, proliferative glomerulonephritis, deep venous thrombosis, osteoporosis, and lymphoproliferative disorders. A secondary form of MGUS also occurs with immunosuppression after organ transplantation and autologous or allogeneic stem cell transplantation. M proteins also occur in the sera of some patients with chronic lymphocytic leukaemia but have no recognizable effect on the clinical course.

Approximately 5% of patients with sensorimotor peripheral neuropathy of unknown cause have an associated monoclonal gammopathy (monoclonal gammopathy–associated neuropathy). In half of such patients, the M protein binds to myelin-associated glycoprotein. These patients have a slowly progressive sensory neuropathy more than motor neuropathy, beginning in the distal ends of the extremities and extending proximally. The clinical and electrodiagnostic manifestations of MGUS neuropathy resemble those of a chronic inflammatory demyelinating polyneuropathy. A causal relationship is usually assumed in younger patients and those without other conditions known to cause neuropathy in whom the neuropathy is severe and progressive. Therapeutic approaches include plasmapheresis and, occasionally, chemotherapy (similar to myeloma for IgG or IgA monoclonal proteins, and rituximab or rituximab-based regimens for IgM monoclonal proteins).

Monoclonal gammopathy is also thought to be the underlying cause of approximately 50% of idiopathic proliferative glomerulonephritis, including membranoproliferative glomerulonephritis and C3 glomerulopathy. Certain skin disorders are also known to be associated with MGUS. Lichen myxedematosus (papular mucinosis, scleromyxedema) is associated with an IgG γ protein. Pyoderma gangrenosum and necrobiotic xanthogranuloma are other associated skin disorders.

No treatment is necessary for MGUS. Low-risk patients can be evaluated when symptoms suggestive of myeloma or related disorders occur. In all other patients with MGUS, the M protein level in serum and urine should be measured serially, together with periodic reevaluation of clinical and other laboratory findings, to determine whether multiple myeloma or another related disorder is present. In general, electrophoresis, complete blood count, and creatinine and calcium levels should be repeated at 6 months and, if stable, yearly thereafter.

RISK OF PROGRESSION OF MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE TO MYELOMA OR RELATED DISORDERS

RISK GROUP RELATIVE RISK CUMULATIVE ABSOLUTE RISK OF PROGRESSION AT 20 YEARS (%) * CUMULATIVE ABSOLUTE RISK OF PROGRESSION AT 20 YEARS ACCOUNTING FOR DEATH AS A COMPETING RISK (%)†
Low risk: serum M protein <1.5 g/dL, IgG subtype, normal free light chain ratio (0.26-1.65) 1 5 2
Low-intermediate risk: any 1 factor abnormal 5.4 21 10
High-intermediate risk: any 2 factors abnormal 10.1 37 18
High risk: all 3 factors abnormal 20.8 58 27

Ig = immunoglobulin.

* Estimates in this column represent the risk of progression assuming that patients do not die of other causes during this period.
† Estimates in this column represent the risk of progression calculated by use of a model that accounts for the fact that patients can die of unrelated causes during this time.

Differentiating a patient with MGUS in whom the disorder will remain stable for life from one in whom multiple myeloma, macroglobulinemia, or a related disorder will eventually develop is difficult when the M protein is first recognized. The size and type of the M protein at diagnosis of MGUS and an abnormal serum free light chain ratio are prognostic factors for progression. A study of 728 Swedish cases of MGUS observed for up to 30 years showed a cumulative risk of 15.4% for development of lymphoid disorder and a cumulative risk of 10.6% for progression to multiple myeloma (approximately 0.5% annual risk). Three factors were significantly associated with progression: (1) abnormal free light chain ratio (<0.26 or >1.65); (2) M-protein level of 1.5 g/dL and higher; and (3) reduction of one or two non-involved immunoglobulin isotype levels (immunoparesis). The first two of these confirm the factors considered by the Mayo Clinic group.

Biclonal gammopathies occur in at least 5% of patients with clonal plasma cell disorders. A biclonal gammopathy of undetermined significance (analogous to MGUS) accounts for about two thirds of such patients. The remainder have multiple myeloma, macroglobulinemia, or other lymphoproliferative diseases. Rarely, triclonal gammopathies may occur.

The diagnosis of typical MGUS requires expression of an intact heavy chain type. In some patients, a premalignant clonal plasma cell disorder characterized by the presence of monoclonal immunoglobulin light chains without expression of heavy chains can occur (light chain MGUS). By definition, these patients should not have evidence of end-organ damage attributable to the light chain, and the clonal bone marrow plasma cell percentage should be less than 10%. No therapy is indicated unless progression to malignancy occurs.

Definition

Multiple myeloma is a malignant neoplasm of plasma cells characterized by bone marrow infiltration and extensive skeletal destruction resulting in anaemia, bone pain, and fractures. Multiple myeloma (commonly referred to as myeloma) is defined by the presence of 10% or more clonal plasma cells on bone marrow examination or biopsy-proven plasmacytoma; and evidence of one or more myeloma defining events. Patients with multiple myeloma must be differentiated from those with MGUS and smouldering multiple myeloma.

Epidemiology

Multiple myeloma accounts for 1% of all malignant disease and slightly more than 10% of hematologic malignant neoplasms in the United States. The annual incidence of multiple myeloma is 4 per 100,000. Its incidence in blacks is almost twice that in whites. Multiple myeloma is slightly more common in men than in women. The median age of patients at the time of diagnosis is about 65 years; only 2% of patients are younger than 40 years.

Pathobiology

The cause of multiple myeloma is unclear. Exposure to radiation, benzene, and other organic solvents, herbicides, and insecticides may play a role. Multiple myeloma has been reported in familial clusters of two or more first-degree relatives and in identical twins.

Almost all cases of myeloma evolve from a premalignant MGUS phase, although the MGUS is clinically recognized before the diagnosis of myeloma in only a small minority of patients. The progression of MGUS to myeloma suggests a simple, random, two-hit genetic model of malignant transformation in which the risk of progression is fixed (approximately 1% per year) regardless of the duration of MGUS. Unfortunately, the precise mechanisms of progression are unknown, although several potentially pathogenetic abnormalities have been described in the clonal plasma cells. These include RAS and p53 mutations, p16 methylation, MYC abnormalities, and secondary translocations. Changes in the bone marrow microenvironment may also play a role in the pathogenesis, including induction of angiogenesis and abnormal paracrine loops involving cytokines such as interleukin (IL)–6, which serves as a major growth factor for plasma cells.

The lytic bone lesions, osteopenia, hypercalcemia, and pathologic fractures in patients with myeloma are a result of abnormal osteoclast activity induced by the neoplastic plasma cells as well as inhibition of osteoblast differentiation. Osteoclasts are activated by stimulation of the transmembrane receptor RANK (receptor activator of nuclear factor κB), which belongs to the tumour necrosis factor receptor superfamily. The ligand for this receptor (RANKL) also has a decoy receptor, osteoprotegerin (OPG). In myeloma, there is an increase in RANKL expression by osteoblasts (and possibly plasma cells), accompanied by a reduction in the level of OPG. The resultant increase in the RANKL/OPG ratio causes osteoclast activation and increased bone resorption and turnover. Other factors that may play a role in osteoclast activation include increased levels of macrophage inflammatory protein 1α, stromal cell–derived factor α, IL-3, IL-1β, and IL-6. In addition to these changes that promote osteoclast activation, there is simultaneous suppression of osteoblasts mediated by increased levels of IL-3, IL-7, and dickkopf 1 (DKK1). This combination leads to the pure osteolytic bone disease that is the hallmark of multiple myeloma.

Cytogenetic Abnormalities

As discussed earlier, primary translocations involving the IgH loci (chromosome 14q32) are seen in up to 40% of patients with multiple myeloma (IgH-translocated or nonhyperdiploid myeloma). Approximately 40% of patients do not have IgH translocations but have evidence of trisomies (hyperdiploid myeloma), 15% have both IgH translocations and trisomies, and 5% have other abnormalities. Although primary IgH translocations and trisomies originate at the MGUS stage, response to therapy and prognosis of myeloma are affected by the specific underlying abnormality. Besides these cytogenetic abnormalities, other secondary cytogenetic abnormalities occur as late events during the course of symptomatic myeloma; these include activating mutations of N- and K- RAS, inactivating mutations of p53, and dysregulation of c- MYCs. Complete or partial deletions of chromosome 13 are well described in myeloma and have prognostic value, but they also occur at the MGUS stage.

STAGING AND PROGNOSTIC FACTORS IN MULTIPLE MYELOMA

STAGE/RISK FACTOR MEDIAN SURVIVAL
INTERNATIONAL STAGING SYSTEM
Stage I (serum β -microglobulin <3.5 mg/L and serum albumin ≥3.5 g/dL) 62 months
Stage II (neither stage I nor stage III) 44 months
Stage III (serum β -microglobulin ≥5.5 mg/L) 29 months
RISK STRATIFICATION *
High-risk myeloma (any one of the following in the absence of trisomies):
Translocations t(14;16), t(14;20)
Deletion 17p
24-36 months
Intermediate-risk myeloma
Translocation t4;14
Similar to standard-risk myeloma with bortezomib-based induction, transplantation, and maintenance
Standard-risk myeloma
Translocations t(11;14), t(6;14)
Trisomies
84-120 months
OTHER ADVERSE PROGNOSTIC FACTORS
Elevated lactate dehydrogenase level
Poor performance status
Increased circulating plasma cells
Plasmablastic morphology
Increased plasma cell labelling index ≥1%

* Typically detected in clonal plasma cells by fluorescence in situ hybridization of plasma cells.

Bone pain, particularly in the back or chest and less often in the extremities, is present at the time of diagnosis in more than two thirds of patients. The patient’s height may be reduced by several inches because of vertebral collapse. Weakness and fatigue are common and are often associated with anaemia. Fever is rare and, when present, is generally from an infection; in some patients, the infection itself is the initial feature. Other symptoms may result from renal insufficiency, hypercalcemia, nephrotic syndrome, radiculopathy, or amyloidosis.

MAJOR CLINICAL MANIFESTATIONS OF MULTIPLE MYELOMA

CLINICAL FINDINGS APPROXIMATE PERCENTAGE OF PATIENTS WITH ABNORMALITY AT DIAGNOSIS
Skeletal involvement: pain, reduced height, lytic bone lesions, pathologic fractures 80
Anaemia (haemoglobin ≤12 g/dL): caused mainly by decreased erythropoiesis; produces weakness and fatigue 75
Renal insufficiency (serum creatinine ≥2 mg/dL): caused mainly by “myeloma kidney” from light chains or hypercalcemia, rarely from amyloidosis 20
Hypercalcemia (≥11 mg/dL) 15
Light chain amyloidosis 10
Evidence of monoclonal protein by immunofixation and serum free light chain assay 97
Evidence of clonal plasma cells ≥10% in bone marrow 96

Pallor is the most frequent physical finding. The liver is palpable in about 5% of patients and the spleen in 1%. Tenderness may be noted at sites of bone involvement. Radiculopathy may be caused by spinal compression fractures. On occasion, extramedullary plasmacytomas are palpable.

A normocytic, normochromic anaemia is present initially in approximately 75% of patients, but it eventually occurs in nearly every patient with multiple myeloma. Serum protein electrophoresis shows an M protein in 80% of patients. With serum immunofixation, an M protein can be detected in 93% of patients. When these serum studies are combined with urine electrophoresis plus immunofixation, an M protein can be detected in 97% of patients with myeloma. The serum free light chain assay is more convenient and can be used in place of urine studies in the diagnostic evaluation. The type of M protein is IgG in 52%, IgA in 21%, light chain only (Bence Jones proteinemia) in 16%, IgD in 2%, and biclonal gammopathy in 2%; the light chain type is κ in 65% of cases and λ in 35%. In 3% of patients, no secreted M protein can be identified; these patients are considered to have nonsecretory myeloma.

In the bone marrow, clonal plasma cells account for more than 10% of all nucleated cells in 96% of patients. In 4% of patients, bone marrow examination shows less than 10% plasma cells, even though the patient otherwise meets the criteria for myeloma; because bone marrow involvement in myeloma may be focal rather than diffuse, repeated bone marrow examinations or biopsy of a discrete bone or extramedullary lesion may be required. In most cases, the plasma cells in myeloma are cytoplasmic Ig , CD38 , CD45 − , CD138 , CD56 , and CD19 ; only a minority express CD10 and HLA-DR, and 20% express CD20. The clonality of the plasma cells is established by the κ/λ ratio, which is abnormal in myeloma (either >4 : 1, indicating a clonal κ population, or <1 : 2, indicating a clonal λ population). This is helpful for differentiation of monoclonal plasma cell proliferation in multiple myeloma from reactive plasmacytosis related to connective tissue disease, metastatic carcinoma, liver disease, and infection.

Conventional radiographs reveal abnormalities consisting of punched-out lytic lesions, osteoporosis, or fractures in nearly 80% of patients. The vertebrae, skull, thoracic cage, pelvis, and proximal ends of the humerus and femur are the most frequent sites of involvement. Technetium Tc99m bone scanning is inferior to conventional radiography and should not be used. Positron emission tomography and magnetic resonance imaging are increasingly used to evaluate patients in whom there is doubt about the magnitude of the disease burden, in those who have skeletal pain but no abnormality on radiographs, and for monitoring of the response to therapy.

Renal

At diagnosis, the serum creatinine value is increased initially in almost half of patients and is more than 2 mg/dL in 20%.

The two major causes of renal insufficiency are light chain cast nephropathy (myeloma kidney ) and hypercalcemia. Light chain cast nephropathy is characterized by the presence of large, waxy, laminated casts in the distal and collecting tubules. The casts are composed mainly of precipitated monoclonal light chains. The extent of cast formation correlates directly with the amount of free urinary light chain and with the severity of renal insufficiency. Dehydration may precipitate acute renal failure.

Hypercalcemia, which is present in 15 to 20% of patients initially, is a major and treatable cause of renal insufficiency. It results from destruction of bone. Hyperuricemia may contribute to renal failure. Besides light chain cast nephropathy and hypercalcemia, there are other mechanisms by which renal dysfunction can occur in myeloma. For example, light chain amyloidosis occurs in nearly 10% of patients and may produce nephrotic syndrome, renal insufficiency, or both. Acquired Fanconi syndrome, characterized by proximal tubular dysfunction, results in glycosuria, phosphaturia, and aminoaciduria. Deposition of monoclonal light chains in the renal glomerulus (light chain deposition disease) may also produce renal insufficiency and nephrotic syndrome.

Neurologic

Radiculopathy, the single most frequent neurologic complication, usually occurs in the thoracic or lumbosacral area and results from compression of the nerve by the vertebral lesion or by the collapsed bone itself. Compression of the spinal cord occurs in up to 10% of patients. Peripheral neuropathy is uncommon in multiple myeloma and, when present, is generally caused by amyloidosis. Rarely, myeloma cells diffusely infiltrate the meninges. Intracranial plasmacytomas almost always represent extensions of myelomatous lesions of the skull.

Other Systemic Involvement

Hepatomegaly from plasma cell infiltration is uncommon. Plasmacytomas of the ribs are common and arise either as expanding bone lesions or as soft tissue masses. The incidence of infections is increased in patients with multiple myeloma. Historically, Streptococcus pneumoniae and Staphylococcus aureus have been the most frequent pathogens, but gram-negative organisms now account for more than half of all infections. The propensity for infection results from impairment of the antibody response, deficiency of normal immunoglobulins, and neutropenia. Bleeding from coating of the platelets by M protein may occur. Myeloma patients have an increased risk of deep venous thrombosis, particularly in relation to its therapy.

Patients with MGUS or smouldering multiple myeloma should not be treated until evidence of multiple myeloma develops.

In the approximately 50% of patients with newly diagnosed multiple myeloma who are considered candidates for autologous stem cell transplantation on the basis of good performance status, no or limited comorbid conditions, and younger physiologic age (<65 to 70 years), autologous peripheral blood stem cell transplantation with high-dose chemotherapy improves overall survival in comparison to conventional chemotherapy. Currently, it is not possible to eradicate myeloma cells completely with conditioning regimens, and reinfused autologous stem cells are usually contaminated by myeloma cells or their precursors. As a result, autologous transplantation is not curative, but it prolongs event-free and overall survival.

Initial therapy for stem cell transplant candidates typically consists of a non–melphalan-containing induction regimen for approximately 4 months followed by the stem cell collection. Most modern induction regimens have not been compared against each other in randomized trials, and the choice of regimen is dependent on availability and costs. Common induction regimens include lenalidomide plus low-dose dexamethasone (Rd); bortezomib, thalidomide, plus dexamethasone (VTD); bortezomib, lenalidomide, plus dexamethasone (VRD); and bortezomib, cyclophosphamide, plus dexamethasone (VCD). VTD is associated with superior response rates and progression-free survival compared with thalidomide-dexamethasone (TD). In a randomized trial, lenalidomide plus low-dose dexamethasone (40 mg once a week) was associated with superior overall survival compared with lenalidomide and high-dose dexamethasone (40 mg on days 1 to 4, 9 to 12, and 17 to 20). As a result, high-dose pulse dexamethasone is no longer recommended in the context of initial therapy. Toxicities of lenalidomide include deep venous thrombosis, and all patients must be treated with prophylactic aspirin or an anticoagulant.

TREATMENT REGIMENS IN NEWLY DIAGNOSED MULTIPLE MYELOMA

REGIMEN SUGGESTED STARTING DOSES * OVERALL RESPONSE RATE (%)
REGIMENS FOR TRANSPLANT-ELIGIBLE AND TRANSPLANT-INELIGIBLE PATIENTS
Lenalidomide-dexamethasone
(Rd)
Lenalidomide, 25 mg orally, on days 1-21 every 28 days
Dexamethasone, 40 mg orally, on days 1, 8, 15, 22 every 28 days
Repeated every 4 weeks
70
Bortezomib-thalidomide-dexamethasone * (VTD) Bortezomib, 1.3 mg/m IV, on days 1, 8, 15, 22
Thalidomide, 100-200 mg orally, on days 1-21
Dexamethasone, 20 mg on day of/after bortezomib (or 40 mg on days 1, 8, 15, 22)
Repeated every 4 weeks
95
Bortezomib-cyclophosphamide-dexamethasone * (VCD) Cyclophosphamide, 300 mg/m orally, on days 1, 8, 15 and 22
Bortezomib, 1.3 mg/m IV, on days 1, 8, 15, 22
Dexamethasone, 40 mg orally, on days 1, 8, 15, 22
Repeated every 4 weeks
90
Bortezomib-lenalidomide-dexamethasone * (VRD) Bortezomib, 1.3 mg/m IV, on days 1, 8, 15
Lenalidomide, 25 mg orally, on days 1-14
Dexamethasone, 20 mg on day of and day after bortezomib (or 40 mg on days 1, 8, 15, 22)
Repeated every 3 weeks
100
REGIMENS FOR TRANSPLANT-INELIGIBLE PATIENTS
Melphalan-prednisone-thalidomide
(MPT)
Melphalan, 0.25 mg/kg orally, on days 1-4 (use 0.20 mg/kg/day orally on days 1-4 in patients older than 75 years)
Prednisone, 2 mg/kg orally, on days 1-4
Thalidomide, 100-200 mg orally, on days 1-28 (use 100-mg dose in patients >75 years)
Repeated every 6 weeks
70
Bortezomib-melphalan-prednisone * (VMP) Bortezomib, 1.3 mg/m IV, on days 1, 8, 15, 22
Melphalan, 9 mg/m orally, on days 1-4
Prednisone, 60 mg/m orally, on days 1-4
Repeated every 35 days
70

* Doses of dexamethasone and bortezomib reduced from initial trial reports to once-weekly schedules.

After induction therapy, peripheral blood stem cells adequate for one or two stem cell transplants are collected with the use of granulocyte colony-stimulating factor, with or without plerixafor or cyclophosphamide to aid in mobilization. Autologous stem cell transplantation is performed with melphalan 200 mg/m as the conditioning regimen, followed by infusion of the peripheral blood stem cells. Patients who do not achieve a complete or very good partial response with the first autologous transplant can be considered for a second autologous transplant.

An alternative approach in patients with newly diagnosed disease is to cryopreserve stem cells for future use after initial therapy. Patients then continue initial therapy, such as lenalidomide plus low-dose dexamethasone, until progression or achievement of a plateau phase, with stem cell transplantation reserved for the first relapse. Data from randomized trials comparing early versus delayed transplantation indicate no significant difference in survival between the two strategies. The choice is based on the patient’s preferences and other clinical conditions, but early transplantation is often preferred because its mortality is low (<1%), and it avoids the inconvenience, cost, and potential side effects of prolonged chemotherapy.

After stem cell transplantation, a short course of bortezomib administered as consolidation has been shown to improve response rates and progression-free survival.  Similarly, studies suggest that long-term outcome may be improved by the administration of prolonged maintenance therapy after autologous stem cell transplantation. In randomized trials, lenalidomide maintenance (10 mg/day for the first 3 months, increased to 15 mg if tolerated) significantly prolongs progression-free survival but has the potential for more toxicity and second cancers.  There are emerging data that bortezomib maintenance administered every 2 weeks may also provide a similar benefit. At present, the routine use of consolidation and maintenance in all patients after transplantation remains controversial because of lack of clear overall survival benefit and concerns about toxicity, cost, and impact on quality of life. Consolidation and maintenance should be considered, however, in intermediate- and high-risk myeloma (bortezomib maintenance preferred) and in patients not achieving a very good partial response or better with transplantation (lenalidomide maintenance preferred).

Most patients with multiple myeloma cannot undergo allogeneic bone marrow transplantation because of their age, lack of an HLA-matched sibling donor, or inadequate renal, pulmonary, or cardiac function. There are no clear data showing the benefit of either conventional myeloablative allogeneic transplantation or nonmyeloablative (mini) allogeneic transplantation compared with autologous stem cell transplantation, and results of randomized trials are conflicting. The treatment-related mortality is approximately 20%. Allogeneic transplantation for myeloma is best performed in the context of clinical trials or as second-line salvage therapy in selected high-risk patients who are willing to accept the high treatment-related mortality rate associated with the procedure.

Approximately 50% of newly diagnosed patients are not considered candidates for stem cell transplantation because of advanced age, poor performance status, or associated comorbidities. For decades, the oral administration of melphalan and prednisone was the standard of care. Randomized trials have shown that the addition of thalidomide or bortezomib to the standard regimen of melphalan plus prednisone improves event-free and overall survival compared with melphalan plus prednisone alone in patients with newly diagnosed myeloma who are not candidates for transplantation. On the basis of these data, melphalan and prednisone plus either thalidomide (MPT) or bortezomib (VMP) are two treatments for this population of patients. More recently, non–melphalan-containing regimens such as Rd, VRD, and VCD used in patients who are candidates for stem cell transplantation are being increasingly preferred over melphalan-based regimens in this group of patients as well. In a large randomized trial, Rd administered until progression was associated with superior progression-free and overall survival compared with MPT. By contrast, the addition of lenalidomide to melphalan and prednisone does not improve overall survival and is not recommended.

Regimens such as VCD, VRD, MPT, and VMP are typically given for approximately 12-18 months. Rd can be given until progression or for approximately 18 months, based on tolerability.

Almost all patients with multiple myeloma eventually relapse. Single-agent dexamethasone, alkylating agents, thalidomide, lenalidomide, and bortezomib, administered alone or in combination, are options for the treatment of relapsed refractory myeloma. Methylprednisolone, 2 g three times a week intravenously for a minimum of 4 weeks, then reduced to once or twice a week if there is a response, is helpful for patients with pancytopenia and may be associated with fewer side effects than with dexamethasone.

Thalidomide (50 to 200 mg/day orally) produces an objective response, with a median duration of about 1 year, in about a third of patients with refractory myeloma. Side effects are sedation, constipation, peripheral neuropathy, rash, bradycardia, and thrombotic events. The addition of dexamethasone to thalidomide increases the response rate to approximately 50%, and combinations of thalidomide, dexamethasone, and alkylating agents produce response rates exceeding 70% in patients with relapsed refractory disease.

Lenalidomide, an analogue of thalidomide, is better tolerated and produces objective benefits in approximately 40% of patients with relapsed refractory myeloma as a single agent; in combination with dexamethasone, 60% of patients benefit. Lenalidomide plus dexamethasone significantly prolongs time to progression and overall survival compared with dexamethasone alone. The starting dose of lenalidomide is 25 mg orally on days 1 to 21, every 28 days. Lenalidomide has significantly fewer nonhematologic toxicities than thalidomide does; myelosuppression is the most common adverse event.

Bortezomib, an inhibitor of the ubiquitin-proteasome pathway, acts through multiple mechanisms to arrest tumour growth, tumour spread, and angiogenesis. It produces objective responses in about a third of patients with refractory myeloma and is superior to single-agent dexamethasone. Bortezomib is usually combined with dexamethasone and other active agents (e.g., lenalidomide, thalidomide, or cyclophosphamide) to increase response rates. The usual dose is 1.3 mg/m administered subcutaneously on days 1, 8, 15, and 22 every 28 days. The once-weekly subcutaneous dosing is associated with significantly lower neuropathy than the twice-weekly intravenous schedule. The most common adverse events are gastrointestinal side effects, fatigue, and neuropathy.

Options for the treatment of patients with myeloma refractory to lenalidomide and bortezomib include pomalidomide (an analogue of lenalidomide) and carfilzomib (a novel keto-epoxide tetrapeptide proteasome inhibitor). Pomalidomide and carfilzomib have a response rate of approximately 25% in this population of patients and can be combined with other active agents to improve response rates. In a randomized trial, the addition of carfilzomib to lenalidomide and dexamethasone significantly improved progression-free survival.

Patients with relapsed refractory myeloma should also be considered for clinical trials. Promising investigational agents with single-agent activity include MLN 9708 (an oral proteasome inhibitor), marizomib (proteasome inhibitor), ARRY-520 (kinesin spindle protein inhibitor), monoclonal antibodies to CD38, and cyclin-dependent kinase inhibitors. Additional agents with potential activity in combination with standard anti-myeloma agents include panobinostat (histone deacetylase inhibitor) and elotuzumab (an anti–CS-1 antibody).

Palliative radiation in a dose of 20 to 30 Gy should be limited to patients who have multiple myeloma with disabling pain and a well-defined focal process that has not responded to chemotherapy and to patients with spinal cord compression from a plasmacytoma. Analgesics in combination with chemotherapy can usually control the pain.

Hypercalcemia

Hypercalcemia, present in 15 to 20% of patients at diagnosis, should be suspected in those with anorexia, nausea, vomiting, polyuria, polydipsia, constipation, weakness, confusion, or stupor. If hypercalcemia is untreated, renal insufficiency may develop. Hydration, preferably with isotonic saline plus prednisone (25 mg four times/day), usually relieves the hypercalcemia. Bisphosphonates, such as zoledronic acid or pamidronate, are recommended and will correct hypercalcemia in almost all patients.

Renal Insufficiency

The most common cause of acute renal failure is light chain cast nephropathy in patients who have excess excretion of monoclonal protein in urine (myeloma kidney). Aggressive treatment of acute renal failure due to light chain cast nephropathy is critical for long-term overall survival. If the patient is not oliguric, intravenous fluids and furosemide are needed to maintain a high urine flow rate (100 mL/hour). If the underlying cause is thought to be light chain cast nephropathy on the basis of clinical findings (e.g., serum free light chains >150 mg/dL) or renal biopsy, plasmapheresis is recommended daily for 5 days to reduce the levels of circulating light chains. Haemodialysis is necessary for symptomatic azotaemia. The mainstay of therapy is aggressive treatment of myeloma with a regimen such as bortezomib, thalidomide, and dexamethasone (VTD) or bortezomib, cyclophosphamide, and dexamethasone (VCD). Allopurinol is necessary if hyperuricemia is present.

Infection

Prompt, appropriate therapy for bacterial infections is necessary. Prophylactic antibiotics, such as trimethoprim-sulfamethoxazole, should be considered in patients taking high-dose corticosteroids. Acyclovir should be given as prophylaxis against herpes zoster in patients receiving bortezomib. Intravenously administered gamma globulin is reserved for patients with hypogammaglobulinemia and recurrent severe infections. Pneumococcal and influenza immunizations should be given to all patients.

Skeletal Lesions

Patients should be encouraged to be as active as possible but to avoid trauma. Pamidronate (90 mg infused intravenously during a 4-hour period every 4 weeks) or zoledronic acid (4 mg intravenously during at least 15 minutes every 4 weeks) reduces the incidence of bone pain, pathologic fractures, and spinal cord compression; such prophylaxis is now routinely recommended for all patients with myeloma bone disease and may improve overall survival. After 1 to 2 years, the dosing can be reduced to once every 3 months in patients who are stable to minimize the risk of osteonecrosis of the jaw, which is a complication of long-term bisphosphonate therapy.

Spinal cord compression from an extramedullary plasmacytoma should be suspected in patients who have severe back pain, weakness or paresthesias of the lower extremities, or bladder or bowel dysfunction. Initial treatment is with dexamethasone-based therapy or radiation therapy. If the neurologic deficit increases, surgical decompression is necessary.

Miscellaneous Complications

Symptomatic hyperviscosity is less common than in Waldenström macroglobulinemia. Anaemia that persists despite adequate treatment of underlying myeloma often responds to erythropoietin.

Multiple myeloma is considered incurable at present, but survival has improved significantly in recent years. The median survival is approximately 5 years, but it varies widely according to clinical stage and risk stratification factors. In some patients, an acute or aggressive terminal phase is characterized by rapid tumour growth, pancytopenia, soft tissue subcutaneous masses, decreased M protein levels, and fever; survival in this subset is generally only a few months.

Future efforts must be directed toward identifying new active agents and developing effective combinations of active drugs. Studies are under way to improve the conditioning regimen used in autologous stem cell transplantation and to better integrate novel therapies with stem cell transplantation.

Smouldering (asymptomatic) multiple myeloma is defined by the presence of an M protein level higher than 3 g/dL in serum or 10 to 60% clonal plasma cells in bone marrow in the absence of myeloma defining events and amyloidosis. Patients with smouldering multiple myeloma are biologically similar to those with MGUS but carry a much higher risk for progression to myeloma or related malignant disease: 10% per year for the first 5 years, 5% per year for the next 5 years, and 1 to 2% per year thereafter. As a result, patients must be observed more closely (every 3 to 4 months), but they should not be treated unless progression to symptomatic multiple myeloma occurs. A small randomized trial found improved survival with the use of Rd as preventive therapy in patients with high-risk smouldering multiple myeloma, but additional data are needed before this approach can be recommended as routine practice. However, patients with ultrahigh-risk features (such as serum free light chain ratio ≥100 or presence of one or more focal lesions on magnetic resonance imaging) are candidates for therapy similar to that for symptomatic myeloma because they are at imminent risk of progression.

Patients with plasma cell leukaemia have more than 20% plasma cells in the peripheral blood and an absolute plasma cell count of 2000/µL or higher. Plasma cell leukaemia is classified as primary when it is diagnosed in the leukemic phase (60%) or as secondary when there is leukemic transformation of a previously recognized multiple myeloma (40%). Patients with primary plasma cell leukaemia are younger and have a greater incidence of hepatosplenomegaly and lymphadenopathy, higher platelet count, fewer bone lesions, smaller serum M protein component, and longer survival (median, 6.8 vs. 1.3 months) than do patients with secondary plasma cell leukaemia. Treatment of plasma cell leukaemia is unsatisfactory. An aggressive initial treatment regimen such as bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide (VDT-PACE) for two cycles, followed by autologous stem cell transplantation and subsequent maintenance therapy with a bortezomib-based regimen, is a reasonable strategy if the patient’s clinical condition permits such an approach. Secondary plasma cell leukaemia rarely responds in a durable manner to chemotherapy because the patients have already received chemotherapy and are resistant.

Patients with nonsecretory myeloma have no M protein in either serum or urine and account for only 3% of cases of myeloma. For the diagnosis to be made, the clonal nature of bone marrow plasma cells should be established by immunoperoxidase, immunofluorescence, or flow cytometric methods. Treatment and survival are similar to those of patients with typical myeloma. The serum free light chain assay is abnormal in more than 60% of patients and can be used to monitor the response to therapy.

This syndrome is characterized by polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS). The major clinical features are a chronic inflammatory-demyelinating polyneuropathy with predominantly motor disability and sclerotic skeletal lesions. The bone marrow usually contains less than 5% plasma cells, and hypercalcemia and renal insufficiency rarely occur. Almost all patients have a λ-type M protein. The diagnosis is confirmed by identification of monoclonal plasma cells obtained at biopsy of an osteosclerotic lesion.

If the lesions are in a limited area, radiation therapy substantially improves the neuropathy in more than 50% of patients. If the patient has widespread osteosclerotic lesions, treatment is with autologous stem cell transplantation or other systemic therapy similar to that used for myeloma.

The diagnosis of solitary bone plasmacytoma is based on histologic evidence of a solitary tumour consisting of monoclonal plasma cells identical to those in multiple myeloma. In addition, complete skeletal radiographs and magnetic resonance imaging of the spine and pelvis must show no other lesions of myeloma, and the bone marrow aspirate must contain no evidence of clonal plasma cells. An M protein may be present in serum or urine at diagnosis, but persistence of the M protein after radiation therapy is associated with an increased risk for progression to multiple myeloma. Treatment consists of radiation in the range of 40 to 50 Gy. Almost 50% of patients who have a solitary plasmacytoma are alive at 10 years, and disease-free survival rates at 10 years range from 15 to 25%. Progression to myeloma, when it occurs, usually takes place within 3 years, but patients must be monitored indefinitely. There is no convincing evidence that adjuvant chemotherapy decreases the rate of conversion to multiple myeloma.

Extramedullary plasmacytomas outside the bone marrow are most commonly found in the upper respiratory tract (80% of cases), especially in the nasal cavity and sinuses, nasopharynx, and larynx. Extramedullary plasmacytomas may also occur in the gastrointestinal tract, central nervous system, urinary bladder, thyroid, breast, testes, parotid gland, or lymph nodes. Extramedullary plasmacytomas may be solitary, or they may occur in the context of existing myeloma. The diagnosis of solitary extramedullary plasmacytoma is based on detection of a plasma cell tumour in an extramedullary site, absence of clonal plasma cells on bone marrow examination, and absence of other bone or extramedullary lesions on radiographic studies. Treatment of solitary extramedullary plasmacytoma consists of either complete surgical resection or tumoricidal irradiation. The plasmacytoma may recur locally, metastasize to regional nodes, or, rarely, develop into multiple myeloma.

Definition

Waldenström macroglobulinemia is the result of the uncontrolled proliferation of lymphocytes and plasma cells in which an IgM M protein is produced. 12 The cause is unknown; familial clusters have been reported. The median age of patients at the time of diagnosis is about 65 years, and approximately 60% are male. The diagnostic criteria are IgM monoclonal gammopathy (regardless of the size of the M protein), 10% or greater bone marrow infiltration (usually intertrabecular) by clonal lymphocytes that exhibit plasmacytoid or plasma cell differentiation, and a typical immunophenotype (e.g., surface IgM , CD5 +/− , CD10 − , CD19 , CD20 , CD23 ) that would satisfactorily exclude other lymphoproliferative disorders, including chronic lymphocytic leukaemia and mantle cell lymphoma. A recurrent mutation of the MYD88 gene (MYD88 L265P) has recently been shown to be present in most patients with Waldenström macroglobulinemia and is thought to be relatively specific for this disease.

Clinical Manifestations

Weakness, fatigue, and bleeding (especially oozing from the oronasal area) are common initial symptoms. Blurred or impaired vision, dyspnoea, weight loss, neurologic symptoms, recurrent infections, and heart failure may occur. In contrast to multiple myeloma, lytic bone lesions, renal insufficiency, and amyloidosis are rare. Physical findings include pallor, hepatosplenomegaly, and lymphadenopathy. Retinal haemorrhages, exudates, and venous congestion with vascular segmentation (“sausage” formation) may occur. Sensorimotor peripheral neuropathy is common. Pulmonary involvement is manifested by diffuse pulmonary infiltrates and isolated masses.

Laboratory Evaluation

Almost all patients have moderate to severe normocytic, normochromic anaemia. The serum electrophoretic pattern is characterized by a tall, narrow peak or dense band that is of the IgM type on immunofixation. Quantitative IgM levels are high. A monoclonal light chain is detected in the urine of 80% of patients, but the amount of urinary protein is generally modest.

The bone marrow aspirate is often hypocellular, but the biopsy specimen is hypercellular and extensively infiltrated with lymphoid cells and plasma cells. The number of mast cells is frequently increased. Rouleau formation is prominent, and the sedimentation rate is markedly increased. About 10% of cases may have an associated type I cryoglobulinemia.

Diagnosis

Diagnosis requires the combination of typical symptoms and physical findings, the presence of an IgM M protein, and 10% or greater lymphoplasmacytic infiltration of the bone marrow. The lymphoplasmacytic cells express CD19, CD20, and CD22, whereas expression of CD5 and CD10 occurs in a minority. Asymptomatic patients with 10% or greater lymphoplasmacytic infiltration of the bone marrow are considered to have smouldering Waldenström macroglobulinemia. Multiple myeloma, chronic lymphocytic leukaemia, and MGUS of the IgM type must be excluded.

Patients meeting the diagnostic criteria for Waldenström macroglobulinemia but who have less than 3 g/dL IgM protein at diagnosis have sometimes been classified as having lymphoplasmacytic lymphoma with an IgM M protein. However, except for hyperviscosity, the clinical picture, therapy, and prognosis for these patients do not differ from those of patients with an IgM level of 3 g/dL or higher; thus, these patients are also considered to have Waldenström macroglobulinemia by the current definition.

Patients should not be treated unless they have anaemia, constitutional symptoms (such as weakness, fatigue, night sweats, or weight loss), hyperviscosity, or significant hepatosplenomegaly or lymphadenopathy. Rituximab, a chimeric anti-CD20 monoclonal antibody, produces a response in at least 50% of untreated patients. The most common regimen used as front-line therapy is the combination of rituximab with cyclophosphamide and dexamethasone (RCD). This combination is highly active and also preserves the ability to mobilize stem cells for transplantation, if necessary. Alternatives include bendamustine plus rituximab (BR); rituximab, bortezomib plus dexamethasone; and cladribine with or without rituximab.

In general, for minimally symptomatic patients, rituximab as a single agent is an excellent choice for initial therapy. For patients with more advanced symptoms, including severe anaemia or hyperviscosity, combination approaches such as RCD or BR are preferred.

For relapse, the agents used as initial therapy can be given alone or in combination. Autologous stem cell transplantation can be considered for eligible patients with relapsed disease.

Spuriously low haemoglobin and haematocrit levels may occur because of the increased plasma volume from the large amount of intravascular M protein. Consequently, transfusions should not be given solely on the basis of the haemoglobin or haematocrit value. Symptomatic hyperviscosity should be treated by plasmapheresis. The median survival of patients with macroglobulinemia is 5 years.

Hyperviscosity syndrome occurs in patients with Waldenström macroglobulinemia who have high levels of serum IgM M protein (>5 g/dL) and occasionally in those with myeloma, especially of the IgA type. Hyperviscosity is disproportionately more common relative to the same serum concentration of IgM and IgA M proteins compared with IgG M proteins because of the inherent tendency of IgM and IgA molecules to polymerize. Typically, IgM forms pentamers, whereas IgA forms dimers or sometimes trimers, resulting in high-molecular-weight complexes. Chronic nasal bleeding and oozing from the gums are the most frequent symptoms of hyperviscosity, but postsurgical or gastrointestinal bleeding may also occur. Retinal haemorrhages are common, and venous congestion with sausage-like segmentation and papilledema may be seen. The patient occasionally complains of blurring or loss of vision. Dizziness, headache, vertigo, nystagmus, decreased hearing, ataxia, paresthesias, diplopia, somnolence, and coma may occur. Hyperviscosity can precipitate or exacerbate heart failure. Most patients have symptoms when the relative viscosity is greater than 4 cP, but the relationship between serum viscosity and clinical manifestations is not precise. There have been no randomized trials on management of hyperviscosity syndrome. Patients with symptomatic hyperviscosity should be treated with plasmapheresis and with chemotherapy to treat the underlying malignant disease. Plasma exchange of 3 to 4 L with albumin should be performed daily until the patient is asymptomatic. Plasma exchange is rapidly effective (two or three exchanges) in the case of IgM M proteins, which are primarily distributed in the intravascular space; with IgG M proteins, in contrast, multiple attempts may be needed because a significant amount of IgG can exist in the extravascular space.

ange this text. Lorem ipsum dolor sit amet, consectetur adipiscing elit. Ut elit tellus, luctus nec ullamcorper mattis, pulvinar dapibus leo.

The HCDs are characterized by the presence of an M protein consisting of a portion of the immunoglobulin heavy chain in serum, urine, or both. These heavy chains are devoid of light chains and represent a lymphoplasma cell proliferative process. There are three major types: γ-HCD, α-HCD, and µ-HCD.

γ-HCD

Patients with γ-HCD often initially have a lymphoma-like illness, but the clinical findings are diverse and range from an aggressive lymphoproliferative process to an asymptomatic state. Hepatosplenomegaly and lymphadenopathy occur in about 60% of patients. Anaemia is found in approximately 80% initially and in nearly all eventually. The electrophoretic pattern often shows a broad-based band more suggestive of a polyclonal increase than an M protein. The diagnosis depends on the identification of an isolated monoclonal γ heavy chain on serum immunofixation, without evidence of either monoclonal κ or λ light chain expression.

Treatment is indicated only for symptomatic patients and consists of chemotherapy with melphalan plus prednisone or regimens used to treat non-Hodgkin lymphoma, such as cyclophosphamide, vincristine, and prednisone. The prognosis of γ-HCD is variable and ranges from a rapidly progressive downhill course of a few weeks’ duration to the asymptomatic presence of a stable monoclonal heavy chain in serum or urine.

α-HCD

α-HCD is the most common form of HCD and occurs in patients from the Mediterranean region or the Middle East, generally in the second or third decade of life. About 60% are men. The gastrointestinal tract is most commonly involved, and severe malabsorption with diarrhoea, steatorrhea, and weight loss is noted. Plasma cell infiltration of the jejunal mucosa is the most frequent pathologic feature. Immunoproliferative small intestinal disease is restricted to patients with small intestinal lesions who have the pathologic features of α-HCD but do not synthesize α heavy chains.

The serum protein electrophoretic pattern is normal in half the cases; in the remainder, an unimpressive broad band may appear in the α2 or β region. The diagnosis depends on identification of an isolated monoclonal α heavy chain on serum immunofixation, without evidence of either monoclonal κ or λ light chain expression. The amount of α heavy chain in urine is small.

In the absence of therapy, α-HCD is typically progressive and fatal. The usual treatment consists of antibiotics, such as tetracyclines, and the eradication of any concurrent parasitic infection. Patients who do not respond adequately to antibiotics are given chemotherapy similar to that used to treat non-Hodgkin lymphoma, for example, the cyclophosphamide, hydroxy­daunomycin, vincristine (Oncovin), and prednisone (CHOP) regimen.

 µ-HCD

This disease is characterized by the demonstration of an isolated monoclonal µ chain fragment on serum immunofixation, without evidence of either monoclonal κ or λ light chain expression.

The serum protein electrophoretic pattern is usually normal, except for hypogammaglobulinemia. Bence Jones proteinuria has been found in two thirds of cases. Lymphocytes, plasma cells, and lymphoplasmacytoid cells are increased in the bone marrow. Vacuolization of the plasma cells is common and should suggest the possibility of HCD. The course of µ-HCD is variable, and survival ranges from a few months to many years. Treatment is with corticosteroids and alkylating agents.

Cryoglobulins are plasma proteins that precipitate when cooled and dissolve when heated. They are designated idiopathic or essential when they are not associated with any recognizable disease. Cryoglobulins are classified into three types: type I (monoclonal), type II (mixed monoclonal plus polyclonal), and type III (polyclonal).

Type I Cryoglobulinemia

Type I (monoclonal) cryoglobulinemia is most commonly of the IgM or IgG class, but IgA and Bence Jones cryoglobulins have been reported. Most patients, even with large amounts of type I cryoglobulin, are completely asymptomatic from this source. Others with monoclonal cryoglobulins in the range of 1 to 2 g/dL may have evidence of vasculitis with pain, purpura, Raynaud phenomenon, cyanosis, and even ulceration and sloughing of skin and subcutaneous tissue on exposure to cold because their cryoglobulins precipitate at relatively high temperatures. Type I cryoglobulins are associated with macroglobulinemia, multiple myeloma, or MGUS. Therapy for patients with symptomatic type I cryoglobulinemia and significant symptoms is similar to that for Waldenström macroglobulinemia for the IgM type and multiple myeloma for the non-IgM type.

Type II Cryoglobulinemia

Type II (mixed) cryoglobulinemia typically consists of an immune complex of IgM M protein and polyclonal IgG, although monoclonal IgG or monoclonal IgA may also be seen with polyclonal IgM. Serum protein elec­trophoresis generally shows a normal pattern or a diffuse, polyclonal hypergammaglobulinemic pattern. The quantity of mixed cryoglobulin is usually less than 0.2 g/dL. Despite the monoclonal component, most patients do not have a clonal plasma cell disorder; rather, they have serologic evidence of infection with hepatitis C virus. At present, hepatitis C is thought to be the cause of most cases of type II cryoglobulinemia.

Most clinical manifestations are related to the development of vasculitis and include palpable purpura, livedo reticularis, polyarthralgias, and neuropathy. Involvement of the joints is symmetrical, but joint deformities rarely develop. Raynaud phenomenon, necrosis of the skin, and neurologic involvement may be present. In almost 80% of renal biopsy specimens, glomerular damage can be identified. Nephrotic syndrome may result, but severe renal insufficiency is uncommon.

Early administration of corticosteroids is the most frequent therapy. Treatment should also target underlying hepatitis C infection with interferon alfa-2 or ribavirin. Agents to treat the monoclonal component, such as cyclophosphamide, chlorambucil, azathioprine, or rituximab, are used if there is no response. Plasmapheresis (with a warmed circuit) is helpful in the acute management of symptoms by removal of circulating immune complexes.

Type III Cryoglobulinemia

Type III (polyclonal) cryoglobulinemia does not have a monoclonal component and is not associated with a clonal plasma cell proliferative disorder. Type III cryoglobulins are found in many patients with chronic infections or inflammatory diseases and are usually of no clinical significance unless they are associated with hepatitis C infection.

TestimonialsWhat They Are Saying

KNOWLEDGE BASE
About Genomic Medicine UK

Genomic Medicine UK is the home of comprehensive genomic testing in London. Our consultant medical doctors work tirelessly to provide the highest standards of medical laboratory testing for personalised medical treatments, genomic risk assessments for common diseases and genomic risk assessment for cancers at an affordable cost for everybody. We use state-of-the-art modern technologies of next-generation sequencing and DNA chip microarray to provide all of our patients and partner doctors with a reliable, evidence-based, thorough and valuable medical service.

Leave a Reply

Your email address will not be published. Required fields are marked *

X