James R. Berenson and Dennis A. Casciato
Immunoglobulins are produced by B lymphocytes and plasma cells. Properties of normal serum immunoglobulins are shown in Table 22.1. A clone of cells producing immunoglobulins may proliferate to sufficient mass that a monoclonal protein (M-protein or paraprotein) is detectable as a peak or “spike” on serum protein electrophoresis (PEP). The “M” in M-protein can stand for monoclonal, myeloma, macroglobulinemia, or the M-like appearance of the serum PEP graph. These disorders are included in the World Health Organization’s classification of neoplastic diseases of lymphoid tissues (Appendix C6). Their immunohistochemistry phenotypes are shown in Appendix C5.
Table 22.1 Normal Human Serum Immunoglobulins
Ig, immunoglobulin; IV, proportion of Ig distributed intravascularly; MW, molecular weight; T1/2, half-life
aFour subclasses comprise IgG. About 70% of IgG is IgG1, 17% is IgG2, 8% is IgG3, and 5% is IgG4. The data shown apply to all subtypes except IgG3. IgG3 differs from the other subclasses in that 65% is distributed IV, its serum half-life is 7 days, and it is not affected by high serum concentrations; it most avidly binds complement (other subclasses do so weakly, if at all), and it is most likely to produce hyperviscosity.
I. EPIDEMIOLOGY AND ETIOLOGY
A. Classification of diseases associated with monoclonal paraproteinemia
1. Plasma cell neoplasms
a. Multiple myeloma (MM)
b. Amyloidosis
c. Heavy chain disease
d. Papular mucinosis
2. Other neoplastic diseases
a. Waldenstrom macroglobulinemia (WM)
b. Malignant B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL)
c. Neoplasms of cell types not known to synthesize immunoglobulins (solid tumors, monocytic leukemia, myelodysplastic syndromes)
3. Nonneoplastic disorders
a. Monoclonal gammopathy of undetermined significance (MGUS)
b. Autoimmune diseases (e.g., systemic lupus erythematosus)
c. Hepatobiliary disease
d. Chronic inflammatory diseases
e. Immunodeficiency syndromes
f. Miscellaneous diseases (e.g., Gaucher disease)
g. Pseudoparaproteinemia (see Section IX.C)
B. Incidence. MGUS, MM, and WM are the most common disorders associated with M-proteins. The average age at the time of diagnosis is 65 years, and the incidence increases with age.
1. MGUS (formerly benign monoclonal gammopathy). The approximate incidence of MGUS is 0.2% for patients 25 to 49 years of age, 2% for those 50 to 79 years of age, and 10% for those 80 to 90 years of age.
2. MM develops in 3/100,000 population and constitutes 1% of new cancer cases in the United States. The average age is 65 years and many patients are >70 years of age. Men are affected slightly more often than women. MM is the most common lymphohematopoietic malignancy in blacks.
3. WM has an incidence that is about 5% to 10% of that of MM. Two-thirds of cases occur in men.
4. Lymphomas. Excluding MGUS, MM, and WM, about half of the patients with monoclonal gammopathies have lymphocytic lymphoma or CLL. The M-protein is nearly always either IgM or IgG and usually causes no symptoms. Patients with other types of lymphoma do not have an increased incidence of monoclonal proteins.
C. Etiology. No specific etiologic agent for the plasma cell dyscrasias has been found. Predisposing factors in humans appear to be the following:
1. Radiation exposure increases the risk of MM. Survivors of the atomic bomb in Japan have been shown to have a higher risk of developing monoclonal gammopathies.
2. Chronic antigen stimulation. Many M-proteins have been shown to be antibodies directed against specific antigens, such as microbial antigens, red blood cell antigens, neural antigens, lipoproteins, rheumatoid factors, and coagulation factors. Chronic antigenic stimulation (e.g., chronic osteomyelitis or cholecystitis) may predispose to the development of MM or MGUS. Patients with autoimmune disease may be at high risk for MM. A recent case-controlled study suggests that female patients who have had silicone gel breast implants also may be at high risk for MM.
3. Environmental exposure. Exposure to pesticides and benzene in the workplace and the use of hair dye are associated with an increased incidence of MM. Farmworkers have been shown to be at high risk for MM in several epidemiologic studies.
4. Human herpesvirus 8 (HHV-8) has been found in the nonmalignant bone marrow dendritic cells of patients with myeloma. It remains to be determined if HHV-8 contributes to the growth of the malignant plasma cells in these patients.
5. Family history of a monoclonal gammopathy is a risk factor for the development of a plasma cell dyscrasia.
D. Cytogenetics
1. MM. Multiple, complex karyotypic changes are observed in the malignant plasma cells of most patients. Fluorescent in situ hybridization (FISH) analysis has shown that most patients with MM have malignant cells with translocations involving chromosome 14 at the site of the immunoglobulin heavy chain gene locus and a limited number of nonimmunoglobulin partner chromosomes. Unlike the site of translocation in other B-cell malignancies that involves the joining region JH, the location of the breakpoint in myeloma usually occurs in the switch regions that are involved in heavy chain class switching from Cμ to another heavy chain class.
Hyperdiploidy is observed in approximately 40% of cases of MM and associated with an improved survival. In contrast, patients with hypodiploidy have a worse outcome as this is commonly associated with chromosomal translocations associated with poor survival.
a. The most common sites of the nonimmunoglobulin breakpoints include chromosomes 11 at the site of cyclin D, chromosome 16 at the site of the c-MAF proto-oncogene, and chromosome 4 at the site of the fibroblastic growth factor receptor 3. Loss of material on the long arm of chromosome 13 occurs in nearly 20% of patients. Loss of 17p is observed in approximately 10% of patients. In addition, addition of material at 1q21 commonly occurs in MM.
Prior to bortezomib- and lenalidomide-based therapies (see below), specific translocations such as 4;14 were associated with poor outcomes, whereas patients with 11;14 translocations had improved outcomes. However, following the introduction of these agents in combination therapies, only chromosome 17p loss is associated with poor survival.
b. Mutations of ras genes occur in about 20% of myelomas and are associated with a poor prognosis. Similarly, mutations of p53 are found in 15% to 20% of cases and are associated with more advanced and clinically aggressive disease. Abnormalities in the c-MYC proto-oncogene may occur much more commonly than was previously suggested.
These studies have led to a new classification of myeloma based on these results. Recent studies suggest that clinical features such as the presence of bone disease are associated with specific gene-expression profiles. In addition, single-nucleotide polymorphism and comparative genomic hybridization studies have identified patients with different outcomes in MM.
c. Gene-expression profiling has identified specific subgroups of patients with MM. These studies have suggested a markedly different outcome depending on the expression of specific genes. These profiles also may predict responsiveness to specific therapies.
d. Telomerase activity and telomere length, indicators of the aging of specific cells, are directly related to the type of myeloma as well as to the outcome among patients. Patients with higher telomerase activity and shorter telomere length tend to have a poor prognosis.
2. MGUS. Studies have shown that patients with MGUS have similar karyotypic abnormalities to patients with MM.
3. WM. Complex karyotypes are also commonly observed in WM. Occasional patients have translocations involving the immunoglobulin heavy chain locus on chromosome 14 and either c-MYC on chromosome 8 or BCL-2 on chromosome 18.
II. PATHOLOGY AND NATURAL HISTORY
A. Bone marrow pathology is usually distinctive in MM and WM. Plasma cells that constitute ≥10% of the nucleated marrow cells (excluding erythroblasts) are characteristic but not diagnostic of MM.
1. MGUS. By definition, patients have <10% light chain–restricted plasma cells.
2. MM. Plasma cells usually constitute 10% to 100% of the marrow cells; they have abundant basophilic cytoplasm and eccentric nuclei with para-nuclear clear zones. Immaturity of the plasma cells is evident with the presence of prominent nucleoli (“myeloma cells”). Bone marrow biopsy showing monotonous infiltration with plasma cells is the only diagnostic criterion for MM accepted by many authorities. The presence of large, homogeneous infiltrates or nodules of plasma cells is highly suggestive of MM. Early in its course, however, marrow involvement is patchy, and normal marrow particles may be obtained.
3. WM may closely resemble CLL. Bone marrow in WM contains 10% to 90% plasmacytoid lymphocytes or small mature lymphocytes; mast cells are often prominent.
4. Reactive plasmacytosis. Peripheral blood plasmacytosis occurs in many viral illnesses (including human immunodeficiency virus [HIV] infection), serum sickness, and plasma cell leukemia (which is rare). Bone marrow plasmacytosis, when not caused by myeloma, is characterized by a diffuse distribution (not infiltrative) and alignment of mature plasma cells along blood vessels or near marrow reticulum cells. Since reactive plasmacytosis is not a malignant clonal disorder, the plasma cells do not show kappa or lambda light chain restriction. Reactive bone marrow plasmacytosis is commonly seen in many disorders, including the following:
a. Viral infections
b. Serum sickness
c. Collagen vascular disease
d. Granulomatous disease
e. Liver cirrhosis
f. Neoplastic disease
g. Marrow hypoplasia
B. Natural history of MGUS. MGUS occurs in nearly 5% of individuals over the age of 70. Although these individuals are symptom-free at diagnosis, nearly 25% of cases progress to a malignant disorder (usually MM) by 25 years of follow-up.
Importantly, the risk for malignancy remains constant over time (approximately 1%/year). The risk of developing MM from MGUS is directly related to the size of the monoclonal peak. The presence of a high ratio of abnormal to normal plasma cells as characterized by immunofluorescence has been shown to predict a higher risk of developing MM. Some studies suggest that patients with MGUS are at higher risk of developing accelerated bone loss and fractures, especially of the vertebral bodies. In addition, these patients appear to be at higher risk of developing thromboembolic events.
1. Karyotypic abnormalities in these patients are similar to those seen with MM.
2. The presence of depressed normal immunoglobulin levels occurs in many patients with MGUS, but is not associated with a higher risk for infection and does not predict a higher risk for malignancy.
3. Peripheral neuropathy is not uncommon and may be associated with a monoclonal antibody with reactivity to a myelin-associated glycoprotein (see Section IX.B).
C. Natural history of WM. WM originates from clones of lymphocytes or plasma cells that synthesize μ chains. The natural history of WM resembles lymphocytic lymphoma much more than MM. Many patients do not require therapy for more than a decade of follow-up. Separating WM from MGUS, CLL, or lymphocytic lymphoma with IgM spikes may be more arbitrary than real.
Lymphadenopathy, splenomegaly, and hyperviscosity are hallmarks of WM; skeletal lesions and impaired renal function are unusual. Concomitant macroglobulinemia and osteolytic lesions usually signify malignant lymphoma or solid tumor rather than primary WM. Glomerular lesions are frequent in WM, but renal failure is uncommon. Low levels of light chains in the urine occur in about 25% of patients.
D. Natural history of MM. Three to twenty years of clonal growth may pass before MM becomes clinically evident. The disease may be localized (5% of cases), indolent (10%), or disseminated and progressive (85%). Nearly all cases of MM originate as MGUS. Manifestations of disease progression arise from bone marrow and skeletal involvement, plasma protein abnormalities, and the development of renal disease.
1. Hematopoiesis is often impaired. At the time of diagnosis, 60% of patients have anemia; 15%, leukopenia; and 15%, thrombocytopenia. Nucleated red blood cells and immature granulocytes may be present in the peripheral blood (leukoerythroblastic reaction).
2. Plasmacytomas (plasma cell tumors) may develop anywhere in the skeleton or, rarely, in extraskeletal sites, such as the nasopharynx or paranasal sinuses. Localized plasmacytomas produce a monoclonal spike in the serum or urine protein electrophoresis in only half of the cases. The median survival is >8 years. Most plasmacytomas that appear to be solitary become generalized in about 3 years, particularly those involving the skeleton. Extraskeletal plasmacytomas have a better prognosis than those of skeletal origin and less frequently progress to multiple myeloma.
3. Skeletal disease in MM
a. Osteolytic lesions. Multiple osteolytic lesions are present in about 70% of patients at diagnosis, single osteolytic lesions or diffuse osteoporosis in 15%, and normal skeletal radiographs in 15%. Lesions are most commonly seen in the skull, vertebrae, ribs, pelvis, and proximal long bones. The use of MRI indicates that skeletal abnormalities exist in nearly all patients with myeloma.
Previously, it was thought that the demineralization and lytic lesions occur as a result of osteoclastic-activating factors and osteoblastic-inhibitory factors produced by neoplastic plasma cells and activated by inflammatory cytokines. The loss of bone in these patients, however, now appears to be a complex interplay involving the tumor cells, stromal cells in the bone marrow, and both the osteoblasts and osteoclasts. The factors responsible involve other important molecules, including macrophage colony-stimulating factor, vascular endothelial growth factor, specific matrix metalloproteinases, macrophage inflammatory protein-1α (MIP1-α), dickkopf1 (DKK-1), secreted frizzled protein-3, and the receptor for activation of nuclear factor-κB (NF-κB). The latter receptor is designated as “RANK” and is coupled with RANK ligand (RANKL) to comprise the RANKL-RANK signaling pathway.
(1) RANK–RANKL proteins play a key role in the development of myeloma bone disease. Increased levels of RANKL have been found in myeloma bone marrow and are associated with enhanced bone loss.
(2) Osteoprotegerin (OPG), the natural soluble decoy inhibitor of RANKL–RANK signaling, is decreased in MM bone marrow and blood. Blockade of RANKL prevents skeletal lesions in animal models of MM. The ratio of circulating RANKL/OPG predicts bone disease in MM patients.
(3) The chemokine macrophage inflammatory protein (MIP1-α) also appears to play a key role in myeloma bone disease. MIP1-α is elevated in myeloma bone marrow; it is associated with increased bone loss and may stimulate myeloma cell growth.
(4) DKK1, an inhibitor of osteoblast development and function, also has an important role in myeloma bone disease. Levels of DKK1 are elevated in the blood and bone marrow from patients with myeloma compared with normal subjects. The inhibition of osteoblast function ultimately leads to a loss of bone formation and enhanced bone loss.
b. Osteoblastic lesions occur in <2% of patients, often in association with neuropathy and the POEMS syndrome. Because of their rarity, the diagnosis of MM should be doubted in the presence of osteoblastic lesions.
c. POEMS syndrome is a multisystem disorder usually associated with osteosclerotic myeloma. It is characterized by the combination of polyneuropathy (chronic inflammatory demyelinating neuropathy), organomegaly, endocrinopathy, M-protein (mainly IgG-γ or IgA-γ), and skin changes (hyperpigmentation, thickening, hypertrichosis). Various other signs, such as cachexia, fever, edema, clubbing, and telangiectasia, can also occur. Autoantibodies to peripheral nerve components are absent. The syndrome appears to be the result of marked activation of the proinflammatory cytokines. Patients with POEMS syndrome, particularly those associated with Castleman disease, have been found to contain HHV-8.
d. Hypercalcemia. About 10% of patients with MM present with hypercalcemia, and 10% develop it during the course of their disease. This complication results from enhanced bone resorption, resulting in the release of calcium into the circulation. Hypercalcemia is a major cause of renal failure among patients with MM, and normalization of the serum calcium often reverses the renal dysfunction. Avoid bed rest and immobilization because these factors can contribute to both the development and worsening of hypercalcemia. Serum alkaline phosphatase levels are usually normal but may be increased with recalcification of fractures. It is important to remind patients who are on calcium and vitamin D supplements to discontinue these supplements until the calcium level is under control.
4. Protein abnormalities
a. Frequency. The incidence of monoclonal immunoglobulins in MM and in comparison to MGUS is shown in Table 22.2.
b. Increased excretion of κ or λ light chains in the urine depends on the rate of unbalanced synthesis of excess light chains, plasma volume, degradation rate, renal catabolism, and urine volume. Monoclonal light chains in the urine are present in two-thirds of all patients with MM and present without an M-protein in the serum in 25%.
c. Serum free light chains are identified in MM patients and, importantly, in many patients with otherwise “nonsecretory” disease.
d. Normal immunoglobulins are usually decreased in the serum of patients with MM and are occasionally decreased in patients with MGUS. The mechanism of inhibition of their synthesis is unknown. Older series showed a high rate of infection with encapsulated organisms that was thought to be related to patients’ marked decrease in normal serum immunoglobulins. The risk for infection, however, largely occurs during chemotherapy-induced neutropenia or during the terminal stages of the disease.
e. Other plasma alterations (see Section IX.A). Hyperviscosity is unusual in MM (<5% of patients).
Table 22.2 Frequency of Monoclonal Immunoglobulins in MM and MGUS
MM, multiple myeloma; MGUS, monoclonal gammopathy of undetermined significance
5. Renal dysfunction, both acute and chronic, occurs at diagnosis in 15% to 20% of cases and develops during their course in most patients with MM. Many patients have renal dysfunction from causes other than MM owing to comorbid diseases such as diabetes mellitus or hypertension, urinary tract infections, nephrotoxic medications, or dehydration. Patients with MM secreting urinary light chains commonly present with renal failure. The most important causes of renal dysfunction in these MM patients are hypercalcemia and myeloma kidney.
a. Myeloma kidney is generally attributed to the deposition of κ and λ chains in the distal and collecting tubules, which is where the light chains are catabolized. The tubules dilate, apparently obstructed by casts surrounded by multinucleated giant cells, and undergo cellular atrophy. Glomerular basement membrane disease also occurs in most patients with myeloma kidney. In most instances, proteinuria contains monoclonal light chains only. These abnormalities occur slightly more commonly in MM associated with λ chain production.
Malignant myeloma is the most common cause of the adult Fanconi syndrome (aminoaciduria, glycosuria, phosphaturia, and electrolyte loss in the urine). Fanconi syndrome may precede the recognition of MM by many years.
b. Amyloidosis also develops commonly in MM. It affects the glomeruli and results in nonselective proteinuria.
c. Inconstant findings that may aggravate renal function include pyelonephritis, metabolic abnormalities in addition to hypercalcemia (nephrocalcinosis and hyperuricemia), glomerulosclerosis, and focal myeloma cell infiltration. Renal tubular acidosis occasionally occurs. Nephrotic syndrome is rare in MM unless amyloidosis supervenes. Recent studies suggest, however, that chronic administration of IV pamidronate may also be associated with nephrotic syndrome (see below).
d. Intravenous contrast-dye studies should be done with caution (if at all) because patients with MM are more susceptible to renal dysfunction after such studies, particularly if they are dehydrated.
6. Neurologic dysfunction often develops in MM and is the result of several pathogenetic mechanisms.
a. Central nervous system (CNS). Spinal cord and nerve root compression develops in about 15% of patients and is usually caused by epidural plasmacytoma. Amyloidosis is a rare cause of epidural masses. Collapse of vertebral bodies can also cause spinal cord compression but, more likely, produces radicular symptoms secondary to nerve root compression. Cranial nerve palsies can develop from tumor occlusion of calvarial foramina. Intracerebral and meningeal plasmacytomas are rare.
With the longer survival of myeloma patients, meningeal myeloma seems to be occurring more frequently than had been previously observed. Furthermore, many of the newer anti-MM agents are recognized to cause fatigue and cognitive dysfunction.
b. Peripheral neuropathy. The carpal tunnel syndrome, which is usually the result of amyloid infiltration of the flexor retinaculum of the wrist (causing entrapment of the median nerve), is a common peripheral neuropathy in MM. Infiltration of nerve fibers and vasa nervorum with amyloid can also produce peripheral neuropathy. Additionally, peripheral neuropathy may be associated with monoclonal immunoglobulins to myelin-associated glycoproteins (see Section IX.B). Rarely, patients with MM and POEMS syndrome develop a characteristic peripheral neuropathy. The most common cause of peripheral neuropathy in patients with MM is from treatment with drugs such as thalidomide, bortezomib, or arsenic trioxide.
c. Neurologic paraneoplastic syndromes (see Chapter 32, Section V)
III. DIAGNOSIS
A. Symptoms. Fatigue, weakness, and weight loss are common in both MM and WM.
1. Skeletal pain occurs in 70% of patients with MM at the time of diagnosis but is rare in patients with WM.
2. Symptoms of hypercalcemia (see Chapter 27, Section I) are present in about 10% of patients with MM at the time of diagnosis and develop in another 10% later in the course of the disease.
3. Hyperviscosity syndrome symptoms (bleeding, neurologic dysfunction, visual disturbances, or congestive heart failure) are present in about 50% of patients with WM and in <5% of patients with MM (see Section IX.A.1).
4. Cold sensitivity may occur in patients with cryoglobulins, especially in WM (see Section IX.A.2).
B. Physical findings
1. Hepatosplenomegaly is present in 40% of patients with WM at the time of diagnosis and is uncommon in MM except with the POEMS variant.
2. Lymphadenopathy occurs in 30% of patients with WM but is rare in patients with MM except late in the disease.
3. Bone tenderness in patients with MM often signifies recent fracture or subperiosteal infiltration with malignant cells.
4. Neurologic abnormalities are frequent in MM; neurologic abnormalities in WM are caused by hyperviscosity or demyelination.
5. Purpura signifies thrombocytopenia in MM and hyperviscosity syndrome in WM. Occasionally, patients with MM will develop coagulopathies associated with purpura.
C. Laboratory studies. The following studies should be obtained in the investigation of patients with suspected plasma cell neoplasms:
1. Routine studies. CBC, blood urea nitrogen, creatinine, electrolytes, calcium, albumin, and total protein
2. Serum proteins evaluated with PEP, immunoelectrophoresis (IEP), and quantitative immunoglobulins (QIG). Because of the inherent variability of results of these tests, it is critical to perform all of these tests in diagnosing and following response to therapy. The following assays are also useful:
a. Serum β2-microglobulin (β2m) reflects tumor mass and is a standard measure of tumor burden in MM.
b. C-reactive protein (CRP) is a surrogate marker for interleukin-6 (IL-6), which is a prime stimulator of myeloma growth.
c. Lactic dehydrogenase (LDH), which may be a measure of tumor burden in lymphoma-like or plasmablastic myeloma
d. Serum viscosity, if hyperviscosity is suspected
e. Free light chains may be measured in the serum, especially among patients with “nonsecretory disease” or with changing renal function among patients with only the presence of urinary paraprotein (see below).
3. Urine light chains. Twenty-four–hour excretion of protein and PEP and IEP of a specimen concentrated 100- to 200-fold (urine dipsticks are usually not sufficiently sensitive to detect light chains, and Bence-Jones protein assays are unreliable). About 20% of patients with MM have urinary M-proteins only, and 20% to 30% of patients will show the presence of both serum and urine M-protein. It is important to measure both the urine and the serum M-proteins on an ongoing basis to determine the patient’s response to treatment.
Approximately 1% to 2% of patients with myeloma do not show the presence of serum or urine M-protein. This occurrence appears to result largely from aberrant rearrangements of the immunoglobulin genes that normally produce antibodies in the malignant plasma cells.
4. Bone marrow aspiration and biopsy are necessary to establish the diagnosis. Bone marrow findings are discussed in Section II.A. Flow cytometry may help confirm the diagnosis. Cytogenetic studies may detect abnormalities. Biopsy of a solitary osteolytic lesion, masses, skin nodules, or enlarged lymph nodes may be necessary in selected cases.
Because myeloma can be a “patchy disease” in the bone marrow, there is marked heterogeneity in different parts of the bone marrow in terms of the percentage of tumor involvement. It is important to recognize that the use of the bone marrow aspirate and biopsy to establish the severity or progression of the patient’s MM is of limited use.
5. Evaluation of the skeleton
a. Complete skeletal radiographic survey, including skull and long bones, is required in all patients suspected of having MM.
b. MRI of the spine may be necessary in some patients if there is a paraspinal mass or signs of cord or nerve root compression or solitary plasmacytoma of bone. This will determine if there is spinal cord involvement and can help to determine the extent of myeloma involvement in the spine. It has become more important to evaluate the spine accurately with the development of several surgical techniques that help immensely in controlling back pain caused by compression fractures from bone loss in patients with MM.
c. Computed tomography scan (avoiding the use of contrast dyes) for evaluation of suspected extradural extraosseous plasmacytoma
d. Positron emission tomography (PET) scans occasionally may be helpful to evaluate extent of disease. The routine use of PET scans cannot yet be recommended to follow patients with MM. However, PET CT scans may be useful to help identify possible additional lesions among patients with an initial diagnosis of solitary plasmacytoma and aid in following patients with nonsecretory disease.
e. Bone scans are of limited usefulness in MM because most lesions are osteolytic, and bone scans require perilesional osteoblastic activity to be positive. Positive bone scans in MM usually indicate regions of fracture or arthritis, except in the rare event of osteoblastic myeloma.
f. Bone densitometry studies may be useful at diagnosis and are especially useful among MM patients without obvious osteolytic disease on plain films but who manifest osteopenia or osteoporosis. These assessments may identify patients who could benefit from bisphosphonate therapy. Patients with MGUS appear to be at high risk for osteopenia and osteoporosis; one should strongly consider baseline assessment of bone density in this high-risk group.
g. Bone formation and resorption markers may predict risk of skeletal complications but should not be performed routinely.
6. Special studies. Serum viscosity, cryoglobulins, and rectal biopsy or analysis of joint effusions for amyloid are obtained when indicated.
D. Protein studies. Some serum immunoglobulin properties that have clinical relevance are listed in Table 22.1. Kinetic studies of protein synthesis in animals and humans show tumor burden to be closely correlated with the quantity of M-protein in the blood (approximately 1 g/dL corresponds to 100 g of tumor and 1 × 1011 plasma cells).
1. Protein electrophoresis is extremely valuable for recognizing cases of monoclonal gammopathies and for following quantitative changes in spikes. PEP, however, is only a presumptive screening test; IEP must be done to establish the diagnosis of monoclonal gammopathy. Examples of serum and urine PEP patterns are shown in Figure 22.1.
Figure 22.1. Electrophoresis patterns. Alb, albumin.
SERUM. Normal: The point of application of serum is indicated. Polyclonal hypergammaglobulinemia: occurs in many conditions. Benign immunoglobulin G (IgG) gammopathy: normal levels of albumin and gamma globulins plus a peak in the γ region. Pseudoparaproteinemia: small peaks in β or α regions (see Section IX.C).
URINE. Myeloma: typical homogeneous peak of light chains (LC) in γ region. Nephrotic syndrome: panproteinuria. Benign IgG gammopathy: normal pattern in urine.
a. M-proteins appear as tall, narrow, sharply defined peaks (spikes) that reflect their structural homogeneity. They are usually located in the γ or γ–β region. Monoclonal peaks in the α or α–β region are usually not caused by M-proteins but by reactant proteins (see Section IX.C).
b. IgG spikes are usually tall, narrow, and located in the β region. IgA spikes are usually broader because the molecule tends to form polymers of different sizes; they are located in the β region. IgM spikes are usually located near the point of origin. IgD spikes usually cause only slight deflections in the pattern because the protein is present in a relatively small concentration.
c. Light chains are not ordinarily found in the serum because light chains are rapidly catabolized by the kidney or excreted in the urine. Light chain spikes may be found in the serum of patients with renal insufficiency or in instances in which polymerization of light chains has occurred. Recent studies have used this assay to establish a more stringent complete response among MM patients.
(1) The normal ratio of κ-to-γ chains in humans is 2:1. This normal ratio is usually maintained when excretion of light chains is owing to renal disease but is significantly altered when the excretion is caused by malignant gammopathies.
(2) Urinary excretion of monoclonal light chains is found in 50% to 60% of patients with MM and in 10% to 20% of patients with WM. Patients with MGUS may also show light chains in the urine, but the amount of monoclonal urinary protein is usually <1 g/24 h.
(3) The free lite assay is able to assess free light chains in the serum of a patient with myeloma. This assay can be important for following patients who have deteriorating renal function (more accurately than 24-hour urine paraprotein levels, which may be unreliable for patients with kidney dysfunction and oliguria) or who have nonsecretory myeloma (a serum light chain may be detected and followed). The usefulness of this assay in following patients long term has not yet been clearly demonstrated, however.
2. IEP determines the exact heavy chain class (γ, α, μ, δ, ε) and light chain type (κ, λ) of the M-protein and distinguishes polyclonal and monoclonal increases in gamma globulins. IEP is more sensitive than PEP for low-concentration or heterogeneous globulin mixtures.
3. QIG estimations are excellent for measuring normal or decreased immunoglobulin levels and are useful for distinguishing MGUS from MM. QIG are unreliable, however, if levels are markedly increased or if protein aggregation has occurred. The variability in QIG estimation with assays measured in the same laboratory over time makes it imperative that both QIG and serum PEP be done to assess the response of patients to therapy.
4. Serum viscosity. The rate of descent of serum at 37°C through a calibrated capillary tube is compared with that of distilled water. Plasma is not used because elevated levels of fibrinogen can markedly affect the results. Normal values for serum viscosity ratios range from 1.4 to 1.9. Symptoms usually do not develop unless the serum viscosity >4.
E. Differentiation of plasma cell dyscrasias. In the absence of biopsy proof of malignant disease, differentiating MGUS from early malignant disease may be impossible at the initial examination. To establish the diagnosis, serial evaluations of the patient and M-protein level must be done for several months or years. Table 22.3 indicates the important data that need repeated observation. These data predict benign or malignant monoclonal gammopathy, but none is diagnostic by itself; patients with MGUS may slowly progress to MM. About 25% of patients with MGUS progress to MM or a related B-cell malignancy (WM, lymphoma, or amyloidosis). The most important findings that suggest malignant disease are significant and progressive increases in the serum M-protein or urinary light chain concentration.
Table 22.3 Protein Variables for Predicting Benign Versus Malignant Monoclonal Gammopathy
MM, multiple myeloma; WM, Waldenström macroglobulinemia.
1. IgM monoclonal gammopathies may be benign or owing to WM, lymphoproliferative disorders, or epithelial tumors that can present with a serum abnormality years before the neoplasm becomes evident. Thus, the division of IgM gammopathies into MGUS, primary or Waldenström macroglobulinemia, and secondary macroglobulinemia is at times arbitrary. A very small percentage of patients with myeloma present with an IgM monoclonal gammopathy; these patients have typical features of myeloma with osteolytic bone disease, renal dysfunction, or both.
2. IgG, IgA, and IgD monoclonal gammopathies: diagnostic criteria for MM. To establish the diagnosis of MM, invasion or destruction of normal tissues by the uncontrolled growth of plasma cells must be proved by biopsy. High concentrations of monoclonal serum immunoglobulins (>3.5 g/dL for IgG and >2 mg/dL for IgA) or urinary light chains (>1 g/d) are nearly diagnostic of MM. MM, however, often remains subclinical or indolent (so-called smoldering myeloma) for many years. If the diagnosis of MM cannot be proved, the working diagnosis becomes MGUS, and the patient is examined at regular intervals to detect changes in clinical or laboratory findings.
IV. STAGING SYSTEMS AND PROGNOSTIC FACTORS
A. Staging systems for MM. Distinguishing patients with low, intermediate, and high volumes of tumor mass before institution of therapy is useful for prognosis: 1 × 1012 cells correspond to 1 kg of tumor, and 3 to 5 × 1012cells are usually incompatible with life in the average-sized patient.
1. The classic Salmon-Durie staging system for MM is shown in Table 22.4.
Table 22.4 Salmon-Durie Staging System for Multiple Myeloma
UPEP, urine protein electrophoresis
2. The International Staging System (ISS) has replaced the Salmon-Durie system. The ISS involves measurement of serum β2m and albumin. The ISS consists of the following stages in the order of worsening prognosis:
Stage I: serum β2 m <3.5 mg/L and serum albumin ≥3.5 g/L
Stage II: neither stage I nor III
Stage III: serum β2 m ≥5.5 mg/L
3. Serum β2m is the light chain moiety of classic human leukocyte antigens (HLA) and is found on the surface membranes of most nucleolated cells. Patients with MM and higher initial values of β2m appear to have a worse prognosis. Despite the high correlation of β2m levels with renal function, β2m has emerged as an important independent prognostic factor.
a. Elevated β2m levels are also found in patients with acute or chronic myelocytic leukemia, lymphoproliferative disorders, myeloproliferative disorders, myelodysplastic syndromes, benign or malignant liver diseases, and autoimmune diseases.
b. Serum albumin also is decreased among patients with poor outcome and represents an assessment of nutritional status as well as pro-MM cytokine activity.
B. Prognostic factors
1. MGUS. If a patient with the presumptive diagnosis of MGUS remains stable for 2 years, the chance for malignant disease is about 20%.
2. WM. Median survival has dramatically improved among these patients with most patients now living more than 7 years and many living more than 10 years. The development of complications, such as hyperviscosity, hemorrhage, or infection, contributes to death. In fact, studies are now showing that many deaths may be attributed to myelodysplasia and secondary leukemias from drugs, especially purine analogs, that are used to treat WM. Age >60 years, male gender, reduced IgM levels, and hemoglobin <10 g/dL are associated with shortened survival time.
3. MM. The overall median survival of MM patients has dramatically improved during the past decade and, in some studies, has been more than 10 years. The prognosis in MM is improving with the wide array of new agents available to treat patients.
a. Tumor mass. Patients with a low tumor mass have a median survival time of 3.5 to 10 years. Patients with a high tumor mass have a median survival time of 0.5 to 3 years, but recent studies suggest that this is improving.
b. C-reactive protein and IL-6. Elevated IL-6 levels may possibly portend a poor prognosis. CRP levels appear to reflect IL-6 serum levels, but most patients with MM do not have elevated CRP levels.
c. Labeling index (LI). The LI is indicative of the percentage of cells undergoing mitosis. A high LI (>3%) is associated with a poor prognosis in MM.
d. Cytogenetic abnormalities
(1) Abnormalities associated with a poor prognosis.
(a) Abnormalities involving loss of chromosome 17p remain a poor prognostic factor regardless of treatment.
(b) The absence of chromosome 13 is no longer considered an independent prognostic factor in MM. Its presence is often associated with other poor prognostic chromosomal abnormalities.
(c) Following the introduction of bortezomib and lenalidomide combination therapies, abnormalities involving chromosome 4 or 16 are no longer considered poor prognostic factors.
(d) Abnormality of chromosome 14
(e) Gains on the long arm of chromosome 1
(2) Abnormalities associated with a good prognosis. Chromosome anomalies previously thought to predict a better outcome, such as those involving chromosome 11, are no longer considered to be predictive of improved survival.
e. Renal function previously was thought to be an important prognostic factor. Increasing degrees of azotemia were associated with progressively shorter life expectancies. Advances in plasmapheresis, dialysis, and supportive care have diminished this prognostic factor. The outcome for patients whose renal function normalizes with initial therapy is not different from that for patients who present with normal renal function.
f. Response to therapy. Whether the depth of response to therapy is related to overall survival is controversial. Only patients who show progressive disease during initial therapy definitely have a worse outcome. In general, the extent of response from initial therapy, as long as the patient does not show disease progression, is not a very good prognostic factor. Paradoxically, patients who respond too rapidly to therapy with melphalan and prednisone (>50% reduction in <3 months) have a poor prognosis. However, complete disappearance of the paraprotein predicts an improved survival in some but not all studies. Certainly, long-term maintenance of a complete disappearance of the M-protein is associated with an improved outcome.
g. Immunoglobulin class. Although earlier studies suggested that patients with IgD or λ light chain disease had a worse prognosis, analyses of prognostic factors in large MM trials have not shown the paraprotein type to be a prognostic factor.
h. Other prognostic factors. The presence of a p53 deletion, plasmablastic morphology, higher numbers of circulating monoclonal plasma cells, or higher serum levels of LDH, soluble IL-6 receptor, or syndecan-1 also predict a poor outcome. In early stage disease, the pattern and number of MRI abnormalities predict both progression to symptomatic disease and overall survival. The gene-expression profiling pattern may predict outcome as well.
V. PREVENTION AND EARLY DETECTION
The availability of PEP and of screening chemistry panels has probably resulted in earlier detection of monoclonal gammopathies. If IEP were used for screening populations, the incidence of MGUS might well double, but survival would not be affected.
VI. MANAGEMENT OF WM
A. Diagnosis
1. Diagnostic criteria for WM
a. IgM monoclonal gammopathy of any concentration
b. Bone marrow infiltration by small lymphocytes, plasmacytoid lymphocytes, and plasma cells in a diffuse, interstitial, or nodular pattern
c. The immunophenotype is positive for surface immunoglobulin, CD19, and CD20 and is negative for CD5, CD10, and CD23.
2. Additional workup at presentation
a. Chest x-ray study and CT scan of chest, abdomen, and pelvis
b. Serum viscosity, cold agglutinins, and cryocrit
c. Hepatitis serology
B. Treatment. Patients with asymptomatic disease, without anemia, hyperviscosity, renal insufficiency, or neurologic abnormalities, should be monitored for clinical status and by PEP until disease progression is confirmed.
1. Indications for treatment
a. Anemia, pancytopenia
b. Symptomatic hyperviscosity, cryoglobulinemia, or neuropathy
c. Bulky lymphadenopathy or symptomatic organomegaly
d. Amyloidosis
e. Cryoglobulinemia
f. Cold agglutinin disease
g. Transformation to another aggressive B-cell malignancy
2. Treatment alternatives. Patients are treated similarly to low-grade lymphomas (see Chapter 21). Hyperviscosity is relieved by plasmapheresis because >70% of the protein is in the plasma rather than the tissues (see Section IX.A), but it is required only in a few patients with very high IgM levels.
a. Treatment options for WM patients have changed dramatically during the past several years. Although alkylating agents were considered the initial therapy of choice, this is no longer the case. Current treatment options include rituximab, bortezomib, immunomodulatory agents, and purine analogs. Many patients can be started on rituximab alone, or if more serious disease exists, rituximab may be combined with bortezomib and dexamethasone, or cyclophosphamide and fludarabine, or cladribine.
b. Patients with WM should be treated with only several courses of these agents because decreases in M-protein can occur for many months after discontinuing therapy. In addition, treatment with rituximab may be associated with an initial rise in IgM, the so-called “flare” response, followed by a drop in serum IgM levels and tumor burden. Plasmapheresis should be considered for patients showing a very high pretreatment IgM level or a significant increase in IgM during the first 2 months of anti-CD20 treatment.
c. If progressive disease develops >6 months following treatment, the same therapy can be repeated. If progressive disease develops in <6 months, the alternative class of drugs should be tried. These may include other bortezomib/rituximab combinations including anthracyclines or bendamustine. Immunomodulatory agents, including thalidomide or lenalidomide with steroids, may also be tried.
VII. MANAGEMENT OF MGUS AND SOLITARY, SMOLDERING, OR STAGE I MM
A. MGUS. Patients should have PEP studies every 3 months for the first year, every 6 months for the next 2 years, and then every 6-12 months thereafter. Patients with MGUS should not be treated with cytotoxic agents. Only patients showing significant rises in M-protein levels should have additional diagnostic studies (bone marrow aspirate and biopsy, skeletal survey). It may be useful to obtain periodic bone density studies on these patients because of their higher risk to develop bone loss and fractures. Intermittent treatment with IV zoledronic acid may improve bone density, although its impact on fracture risk remains unknown.
B. Solitary osseous plasmacytoma is potentially curable and is treated with at least 4,500 cGy of RT to the involved field. It is important to recognize that many patients treated for a solitary osseous plasmacytoma actually have systemic disease. These patients may benefit from PET CT scan to identify possible additional disease that may require systemic therapy; the presence of additional lesions suggests that these patients are at high risk to develop MM. This should be taken into consideration before an attempt is made at curative local RT.
The M-protein is measured every 3 to 6 months as indicated. Radiologic skeletal survey is performed annually or when symptoms develop. Disease that is refractory to RT (<50% reduction in the M-protein) or that progresses is treated as for stage II or III MM.
C. Solitary extraosseous plasmacytoma is also potentially curable and is treated with surgery, at least 4,500 cGy of RT to the involved field, or both. The M-protein is followed and measured every 3 months for 1 year, then annually. CT scans should be repeated every 6 months for the first year and thereafter as indicated clinically. Disease that is refractory to RT (<50% reduction in the M-protein) or that progresses is treated as for stage II or III MM.
D. Systemic smoldering or stage I myeloma
1. Definition of smoldering MM
a. M-protein component:
IgG >3.5 g/dL and <5.0 g/dL
IgA >2.0 g/dL and <3.0 g/dL
Urinary light chains <1.0 g/24 h
b. Plasma cell infiltration of bone marrow is >10% but <20%
c. No anemia, renal failure, or hypercalcemia
d. No bone lesions on skeletal survey
2. Clinical course. The disease progresses in most patients, but patients may do well for many months or years before progression occurs. The risk is highest (10% per year) during the first 5 years, 3% per year during the next 5 years, and 1% per year after 10 years of follow-up. Significant risk factors for more rapid progression to symptomatic disease include a level of paraprotein >3 g/dL, the IgA subtype, increased numbers of circulating plasma cells, increased ratio of bone marrow abnormal versus normal plasma cells, and bone marrow showing >10% plasma cells.
3. Treatment. Patients are observed without treatment until the disease progresses to symptomatic or active disease (anemia, hypercalcemia, renal insufficiency, bone lesions) or associated amyloidosis. Several clinical trials are underway attempting to slow the progression of disease with the use of single-agent thalidomide or lenalidomide. In addition, clinical trials are investigating the use of cyclo-oxygenase 2 (COX-2) inhibitors and IL-1 antagonists to treat this small group of patients with myeloma. Treatment with monthly intravenous bisphosphonates has been shown to reduce the risk of skeletal complications in these patients, but these drugs have not delayed the time to progressive disease; however, these studies involved a relatively short treatment period (1 year) with bisphosphonates. Among patients with severe bone loss demonstrated on bone densitometry, it is certainly reasonable to consider treatment with these antibone resorptive drugs.
VIII. MANAGEMENT OF STAGE II OR III MM
Maximizing ambulation, administration of chemotherapy, glucocorticoids, bisphosphonates, stem cell transplantation (SCT), and RT have been the mainstays of treatment. Newer agents, such as bortezomib, thalidomide, and lenalidomide, have shown efficacy in the treatment of these patients in both first-line and relapsed or refractory disease settings. Notably, the newer agents show higher response rates when combined with glucocorticoids or cytotoxic agents.
A. Older chemotherapy regimens for MM. Several alkylating agents (melphalan, cyclophosphamide, chlorambucil, and nitrosoureas) are equally effective in producing responses. Refractoriness to one alkylating agent is often associated with responsiveness to another alkylating agent. Exposure to myelotoxic agents (particularly alkylating agents) should, however, be limited to avoid compromising stem cell reserve before stem cell harvest in patients who may be candidates for SCT.
Treatment should continue for two cycles beyond maximal response; but, continued therapy does not prolong the duration of the plateau phase. Traditional older regimens for MM are as follows:
1. Dexamethasone alone: 40 mg PO daily for 4 days every other week
2. M&P (cycle frequency is 4 to 6 weeks)
Melphalan: 10 mg/m2 PO on days 1 through 4
Prednisone: 60 mg/m2 PO on days 1 through 4
3. VAD (cycle frequency is 4 weeks)
Vincristine: 0.4 mg/d for 4 days by continuous IV infusion
Doxorubicin (Adriamycin): 9 mg/m2/d for 4 days by continuous IV infusion
Dexamethasone: 40 mg PO on days 1 through 4, 9 through 13, and 17 through 21
4. EC (cycle frequency is every 4 weeks)
Etoposide: 100 mg/m2 IV on days 1 through 3
Cyclophosphamide: 1,000 mg/m2 IV on day 1
5. DVD (cycle frequency every 4 weeks)
Doxil (liposomal doxorubicin): 30 to 40 mg/m2 IV on day 1
Vincristine: 2 mg IV on day 1
Dexamethasone: 40 mg PO on days 1 through 4
6. Other regimens
a. M-2 protocol (cycle frequency is 5 to 6 weeks)
Melphalan: 0.25 mg/kg PO on days 1 through 4
Prednisone: 1 mg/kg PO on days 1 through 7
Vincristine: 0.03 mg/kg IV on day 1
BCNU (carmustine): 1 mg/kg IV on day 1
Cyclophosphamide: 10 mg/kg IV on day 1
b. VBAP (cycle frequency is 3 weeks)
Vincristine: 1 mg IV on day 1
BCNU (carmustine): 30 mg/m2 IV on day 1
Doxorubicin (Adriamycin): 30 mg/m2 IV on day 1
Prednisone: 100 mg PO on days 1 through 4
7. Response rates to older regimens
a. Response rates to daily low-dose, single alkylating-agent therapy is about 30% and appear to be equivalent to pulse therapy given every 4 to 6 weeks. The addition of prednisone to an alkylating-agent regimen (e.g., M&P) increases the response rate to 50% to 60%.
b. Responses to VAD occur more rapidly and are somewhat more frequent than to M&P. The duration of response to up-front VAD chemotherapy is approximately 15 to 18 months and of similar duration for other up-front regimens.
c. Corticosteroids alone (dexamethasone) may produce response and survival rates nearly equivalent to those achieved with infusional VAD or M&P.
d. Other combination chemotherapy regimens have not been shown to improve survival when compared with M&P. Durable complete responses to these regimens are rare.
B. Newer regimens for the treatment of MM
1. IMID-regimens. The mechanisms of action of the IMID (thalidomide [Thalomid] and lenalidomide [Revlimid]) are incompletely understood but are thought to be immunomodulatory and antiangiogenic. Both agents are very active in MM but differ in their toxicity profile. The dose-limiting side effects are neurologic (somnolence, peripheral neuropathy) for thalidomide and myelosuppression (mainly thrombocytopenia) for lenalidomide. Both agents are teratogenic and thrombophilic.
a. Thalidomide (with or without dexamethasone or other steroids): a dose of 100 mg PO daily at night is as effective, but with fewer neuropathic effects, than higher doses.
b. MPT (cycle frequency is every 4 weeks)
Melphalan: 4 mg/m2 daily on days 1 through 7
Prednisone: 40 mg/m2 daily on days 1 through 7
Thalidomide: 100 mg daily at night
c. MPR (cycle frequency every 28 days)
Melphalan: 9 mg/m2 (0.18 mg/kg) PO daily on days 1 through 4
Prednisone: 2 mg/kg PO daily on days 1 through 4
Revlimid (lenalidomide): 10 mg PO daily on days 1 through 21
d. Rev/Dex (cycle frequency is every 4 weeks)
Revlimid (lenalidomide): 25 mg PO daily for 21 days followed by a 7-day rest period
Dexamethasone: 40 mg PO weekly
e. BiRD (cycle frequency every 4 weeks)
Biaxin (clarithromycin): 500 mg orally twice daily
Revlimid (lenalidomide): 25 mg daily on days 1 through 21
Dexamethasone: 40 mg orally on days 1, 8, 15, and 22
f. BTD (daily)
Biaxin (clarithromycin): 500 mg PO twice daily
Thalidomide: 100 to 200 mg PO at bedtime
Dexamethasone: 40 mg PO weekly
g. Response rates
(1) Thalidomide as a single agent leads to durable responses in one-third of relapsing patients. The response rate to thalidomide plus dexamethasone is 60% with a 15% complete response rate. Thalidomide alone is associated with a 30% response rate even after progression of disease following autologous SCT. Although this agent used up front with dexamethasone improves response rate and progression-free survival compared with dexamethasone alone, no improvement is seen in overall survival, an observation that may reflect patients failing steroids alone receive thalidomide at the time of progressive disease. However, several recent studies show superior survival when thalidomide is added to oral melphalan and prednisone in previously untreated elderly patients with MM who were not transplant candidates.
(2) Lenalidomide with dexamethasone is also associated with a 60% response rate and approximately 20% complete response. The number of lenalidomide combination therapies is rapidly increasing, and they demonstrate higher response rates with some of these new regimens approaching 100% (e.g., RVD below).
2. Bortezomib (Velcade) regimens. Dose-limiting side effects of bortezomib are peripheral neuropathy (predominantly sensory) and myelosuppression (especially thrombocytopenia). Fatigue, fever, and gastrointestinal (GI) side effects are also common.
a. Bortezomib (Velcade): 1 or 1.3 mg/m2 IV bolus (IVB) on days 1, 4, 8, and 11; cycle frequency is every 3 weeks
b. Bortezomib/Dex (cycle frequency is every 3 weeks)
Bortezomib: 1.3 mg/m2 IVB days 1, 4, 8, and 11
Dexamethasone: 40 mg PO weekly
c. BAM (cycle frequency is every 4 weeks)
Bortezomib: 1 mg/m2 IVB on days 1, 4, 8, and 11
Ascorbic acid: 1 g PO daily on days 1 through 4
Melphalan: 0.1 mg/kg PO daily days 1 through 4
d. BMP (cycle frequency is every 6 weeks)
Bortezomib: 1.3 mg/m2 IVB on days 1, 4, 8, 11, 22, 25, 29, and 32
Melphalan: 9 mg/m2 PO daily on days 1 through 4
Prednisone: 60 mg/m2 PO daily on days 1 through 4
e. CYBOR-D (cycle frequency every 4 weeks)
Cyclophosphamide: 300 mg/m2 PO on days 1, 8, 15, and 22
Bortezomib: 1.3 mg/m2 IVB on days 1, 4, 8, and 11
Dexamethasone: 40 mg PO on days 1 through 4, 9 through 13, 17 through 20, and 11
f. Doxil/Velcade (cycle frequency every 3 weeks)
Doxil (liposomal doxorubicin): 30 mg/m2 IV on day 4
Velcade: 1.3 mg/m2 IVB on days 1, 4, 8, and 11
g. DVD (cycle frequency every 4 weeks)
Doxil: 5 mg/m2 IV on days 1, 4, 8, and 11
Velcade: 1 mg/m2 IVB on days 1, 4, 8, and 11
Dexamethasone: 40 mg IV on days 1, 4, 8, and 11
h. DVD-R (cycle frequency every 4 weeks)
Doxil: 4 mg/m2 IV on days 1, 4, 8, and 11
Velcade: 1 mg/m2 IVB on days 1, 4, 8, and 11
Dexamethasone: 40 mg IV on days 1, 4, 8, and 11
Revlimid (lenalidomide): 10 mg PO daily on days 1 through 14
i. RVD (cycle frequency every 3 weeks)
Revlimid: 25 mg PO daily on days 1 through 14
Velcade: 1.3 mg/m2 IVB on days 1, 4, 8, and 11
Dexamethasone: 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12
j. Treanda/Velcade (cycle frequency every 4 weeks)
Treanda (bendamustine): 90 mg/m2 IV on days 1 and 4
Velcade: 1 mg/m2 IVB on days 1, 4, 8, and 11
k. Bortezomib scheduling. Bortezomib given IV weekly at either 1.3 mg/m2 or 1.6 mg/m2 appears to show similar response rates as when the drug is given on days 1, 4, 8, and 11 of each cycle.
l. Response rates. Although bortezomib as a single agent shows a 30% response rate, adding steroids increases the response rate to >50%. Adding melphalan to bortezomib increases the response rate to nearly 70%. The three drug combination of RVD or these three drugs combined with liposomal doxorubicin (Doxil) have been associated with response rates of well over 90%.
C. Duration of therapy. Patients should be treated until a plateau phase (stabilization of M-protein levels for several months) is achieved. Continuation of chemotherapy beyond plateau phase has not been demonstrated to prolong survival but does increase the risk for secondary malignancies, especially acute leukemia. Few data exist on how long to continue the newer agents such as bortezomib and the IMIDs once a maximal response is achieved, but most patients remain on these agents albeit at often a reduced or less frequent dosing schedule until disease progression occurs. Concerns have arisen regarding the risk of secondary malignancies among patients receiving long-term lenalidomide treatment, especially when patients have also been exposed to melphalan-based therapies.
1. For patients with disease that responds or stabilizes following therapy, choices are observation without further therapy until disease progression occurs, maintenance therapy, or high-dose regimens with SCT. No treatment while watching disease parameters is a justifiable option.
2. Maintenance therapy is controversial. Some studies have reported that maintenance therapy with prednisone (50 mg PO every other day) or recombinant interferon-α (IFN-α) prolongs the response to conventional therapy in patients who have a near complete response or in those with IgA or light chain myeloma. The use of prednisone (50 mg PO every other day) as maintenance therapy after even a minor response to VAD was shown to improve significantly both progression-free and overall survival without significant toxicity.
Although remissions are sustained longer with the addition of IFN to prednisone, a significant survival benefit for maintenance therapy with this cytokine after conventional therapy has not been demonstrated. Maintenance therapy with IFN alone has yielded inconsistent results. One recent study suggests the combination of thalidomide and pamidronate following tandem transplant may improve overall survival. Another study suggests that the addition of thalidomide to oral glucocorticoids as maintenance therapy following autologous SCT improves overall survival compared to glucocorticoids alone. Maintenance single-agent lenalidomide has been shown to prolong progression-free survival both following MPR treatment for elderly, nontransplant candidates as well as following autologous SCT, but its impact on overall survival remains to be determined.
D. High-dose regimens have generally contained myeloablative doses of alkylating agents with or without total-body irradiation (TBI). TBI is generally not given to patients who received prior local RT and is associated with a higher degree of treatment-related morbidity and mortality. In fact, TBI is no longer recommended as part of the conditioning regimen for MM patients outside of a clinical trial because of the associated higher mortality rates with this modality compared to chemotherapy-based regimens. Most institutions currently use high-dose IV melphalan as the sole treatment for patients having myeloablation for their MM.
With high-dose regimens, the response rates are higher, and a significant proportion of patients show elimination of the M-protein. All candidates for this intensive therapy must have sufficient cardiac, pulmonary, hepatic, and renal function. However, the newer regimens for MM without high-dose therapy are producing complete response rates and durable remissions that are in some cases higher than observed without this additional intensive therapy. It remains to be determined whether using these newer regimens prior to high-dose therapy improve overall survival for MM patients.
1. High-dose therapy with autologous peripheral blood SCT in some studies is associated with increased rates of complete remission, improved event-free survival, and increased overall survival when compared with conventional chemotherapy, particularly in patients <60 years of age. Other studies, however, have not shown a difference in overall survival despite the higher complete remission rate among patients who have high-dose therapy.
Stem cells are harvested from the blood of patients at the time of maximal response to conventional chemotherapy. Autologous peripheral blood SCT is not curative. Improvements in supportive care have reduced the treatment-related mortality rate to 1% to 2% in most centers.
A study in France suggests that patients having a tandem transplant approach (two sequential autologous SCT) may have an improved outcome compared with those having a single transplant. The intensity of chemotherapy in that study was suboptimal, however; thus, the superiority of double compared with single SCT is questionable. Other studies have not confirmed the benefit of double transplant for this patient population.
2. Allogeneic SCT is associated with high treatment-related mortality rates (nearly 40%); thus, the use of this procedure has been reduced to primarily clinical trials for younger patients who have a compatible donor. Studies have used donor leukocyte infusions with some reduction in M-protein levels but also with significant graft-versus-host disease toxicity. Some centers are now performing tandem (double) transplantationsfor these patients (autologous SCT followed by allogeneic SCT). A study suggests a high complete remission rate when patients have this latter approach, but the long-term outcome of these patients is yet to be determined, and the risk of chronic graft-versus-host disease is high and associated with a significant treatment-related mortality.
3. Autologous bone marrow transplantation. Because many tumor cells are found in the autograft, attempts have been made to purge autografts of tumor using stem cell selection. Although this procedure successfully eliminates tumor cells in the autograft, it does not improve overall survival, probably because of the relatively high tumor burden remaining in the patient even after myeloablative chemotherapy.
E. Considerations for choices of treatment for MM
1. Treatment choices for initial therapy of MM have greatly increased recently as a result of the introduction of bortezomib, thalidomide, and lenalidomide in the first-line setting. Because these regimens have not been evaluated against each other and response rates and progression-free survival are similar between the different regimens, choice of initial therapy must take into account the severity of the myeloma and the patient’s work- and lifestyle and comorbid conditions.
a. Although long-term use of alkylating agents is associated with permanent stem cell toxicity, short courses with lower doses in the newer regimens are unlikely to have an impact on stem cell function.
b. Thalidomide-containing regimens, including thalidomide and dexamethasone or MPT, are oral and convenient, but they are associated with irreversible neuropathy and a high risk of thromboembolic events, requiring many patients to receive long-term anticoagulation prophylaxis. Similarly, Rev/Dex is also associated with significant risk of thromboembolic effects and also marrow suppression.
c. Bortezomib-containing regimens, including Velcade/Dex, BAM, DVD, RVD, and VMP, are also associated with neurotoxicity, but the effects are generally reversible.
2. SCT.Patients who are considering high-dose chemotherapy with hematopoietic support may receive these up-front regimens for several months and then have stem cell collection, high-dose chemotherapy, and stem cell infusion.
3. Patients who relapse may be considered for another treatment with the same new agent (bortezomib, thalidomide, or lenalidomide) with a different chemotherapeutic agent or for another new agent alone or in combination with steroids or chemotherapy. In addition, although arsenic trioxide shows only modest activity as a single agent, it is very active in combination with melphalan and IV ascorbic acid. The EC combination and single-agent therapy with topotecan or vinorelbine show moderate activity in relapsing patients; however, the duration of responses with these combinations is extremely brief.
4. Patients with disease progression following therapy can be treated with ESHAP (see Appendix D3), cyclophosphamide with VAD, thalidomide, lenalidomide, bortezomib, or arsenic trioxide. As a single agent in these circumstances, bortezomib is associated with a 35% response rate, about 5% of which are complete responses. The addition of bortezomib or arsenic trioxide to small doses of melphalan, cyclophosphamide, or anthracyclines can produce responses even among patients who were previously resistant to these chemotherapeutic agents. The combination of thalidomide and bortezomib has also been associated with a high response rate. It is important to recognize these observations in planning therapy for relapsing patients who have been previously treated with chemotherapeutic agents.
F. Supportive care is extremely important in MM. Bed rest is often necessary because of the painful bony lesions or fractures. Bed rest, however, further promotes bone demineralization, which may lead to hypercalcemia.
1. Bisphosphonates (pamidronate, 90 mg IV over >2 hours, or zoledronic acid, 4 mg IV over 15 minutes) given monthly are indicated for all patients with stage II or III MM (and perhaps stage I as well). These agents have significantly decreased the incidence of skeletal complications in this disease. Bisphosphonates reduce pain and analgesic usage and prevent the deterioration of quality of life compared with placebo. Bisphosphonates are also discussed in Chapter 33, Section I.E.2.
a. A recent large randomized study shows that monthly zoledronic acid not only reduced skeletal complications but also improved overall survival compared to a weaker oral bisphosphonate, clodronate, administered daily among previously untreated MM patients who also required anti-MM treatment.
b. It is important to recognize that these agents occasionally are associated with renal dysfunction. Pamidronate more often will cause a glomerular lesion initially associated with proteinuria, which may be at nephrotic levels. By contrast, zoledronic acid more often causes tubular dysfunction and, thus, is not often associated with albuminuria.
c. Bisphosphonates are associated with an increased risk of osteonecrosis of the jaw (ONJ). This complication occurs more frequently among patients who have had recent dental surgery or trauma, poor dental hygiene, or who abuse alcohol or use tobacco. Before initiating bisphosphonate treatment, patients should have a complete dental examination and any dental extractions or removal of jawbone(s) should be completed several months before initiating these drugs to reduce the risk of ONJ.
The course of ONJ is variable and many patients do not show worsening of the condition, although this can occur. No studies have evaluated whether discontinuing these drugs among patients with this complication affects the course of ONJ. It is clear that surgical intervention to treat this problem should be kept to a minimum and undertaken only by dental professionals experienced with this problem.
d. Reports of atypical fractures of the femurs and of the metatarsal bones of the feet have been made among patients who receive long-term bisphosphonate treatment.
2. Skeletal complications
a. Surgery for MM is restricted to orthopedic procedures (also see Chapter 33, Sections I.H and I.I). Fractures of long bones usually require fixation with a medullary pin and postoperative irradiation. Sometimes, impending fractures with large osteolytic lesions of the femoral head are internally fixed prophylactically. If the diagnosis of the underlying disease is in doubt, acute spinal cord compression or vertebral fracture may make laminectomy necessary. Either vertebroplasty or kyphoplasty should be considered for symptomatic vertebral compression fractures. Kyphoplasty may reverse the compression fracture and can lead to immediate and sustained pain relief for patients with symptomatic vertebral compression fractures, especially when they occur in either the thoracic or the lumbar spine. The risk of leakage of the cement appears to be lower with this procedure than with vertebroplasty, although these procedures have not been compared with one another in any randomized trials. However, a recent randomized study shows the superiority of immediate kyphoplasty to nonsurgical management for cancer patients with vertebral compression fractures, and myeloma was the most common type of cancer among enrolled patients.
b. RT in low doses is useful for palliation of lesions that are localized or that cause spinal cord or nerve root compression. Small subcutaneous tumors or small painful lesions in bone may be treated with only a single dose of 800 cGy. Large osteolytic lesions in long bones should be irradiated before a fracture occurs. Large lytic lesions or paraspinous masses rarely need >2,000 cGy given over 5 days. Many patients, however, will have significant pain relief with effective treatment of their underlying myeloma. In some patients, it may be prudent to wait before initiating RT to relieve pain. Because of the radiosensitizing effects of several anti-MM agents including anthracyclines (such as doxorubicin and its liposomal formulation) and bortezomib, use of these drugs may have to be delayed during the period of time that the patient undergoes RT.
c. Back pain is relieved by RT unless the pain is caused by compression fracture. Because spinal cord compression is a common complication in MM, the physician should not hesitate to order an MRI or CT myelo-gram in patients with MM who have new or changing back pain. This should be treated emergently if it occurs (see Chapter 32, Section III).
The use of RT to the spine should be done judiciously. The spine represents a large reservoir for the production of normal bone marrow, and thus, its compromise with RT must be taken into consideration among patients who will require myelotoxic treatment for their underlying disease. Given the high response rates approaching 100% with some of the newer anti-MM regimens, treating patients with cord compression with systemic therapy alone is being done with increasing frequency.
d. Pain relief may be achieved with focal RT. Analgesics should be prescribed in a regimen that gives the most consistent pain relief. Nonsteroidal anti-inflammatory drugs (NSAID) should be avoided to decrease the chances of renal dysfunction. However, often systemic therapy effectively relieves bone pain rapidly without subjecting patients to the side effects of RT.
e. Ambulation should be maximized as early as possible after the onset of fractures or pain. Corsets and braces may be effective in relieving back pain by stabilizing the spine, but often, patients will do just as well with well-designed physical therapy regimens.
f. Calcium and vitamin D deficiencies occur in many patients with myeloma, and serum calcium levels may also be reduced with bisphosphonate treatment. Thus, oral calcium (1,000 mg daily) is recommended. Monitoring of serum calcium is necessary, however, because occasionally patients may develop hypercalcemia.
All patients with MM should have baseline vitamin D levels assessed and their dose of vitamin D adjusted accordingly. Regardless, patients should receive 800 to 1,200 IU daily. It is important to discontinue both calcium and vitamin D supplementation should the patient become hypercalcemic.
g. Fluoride is not effective in increasing bone remineralization in patients with MM; fluoride treatment results only in increased bone density because of fluorosis.
3. Hydration. Patients must be repeatedly reminded to drink 2 to 3 L of liquids daily to promote urinary excretion of light chains, calcium, and uric acid. This simple reminder has been shown to improve survival greatly in some studies.
4. Infections are the foremost cause of death in patients with MM. Infections must be investigated and treated urgently. These patients have similar infections to other cancer patients treated with chemotherapy. In fact, the risk for infection is primarily during periods of chemotherapy-induced neutropenia or in the terminal stages of the disease. Patients receiving bortezomib should receive antiviral prophylaxis as herpes zoster infections occur commonly among patients receiving this drug.
Although the use of prophylactic antibiotics and IVIG may be attempted in patients with recurrent infections, most patients do not require these interventions. IVIG therapy should be considered in cases of recurrent, life-threatening infections.
Pneumococcal and influenza vaccine should also be considered. Because it is a live vaccine, vaccination with the herpes zoster vaccine should be avoided in MM patients.
5. Renal failure is best prevented by hydration, treatment of hyperuricemia and hypercalcemia, and avoidance of both IV contrast media and NSAID. Recent randomized studies have not demonstrated the benefit of plasmapheresis. When renal failure becomes severe, some patients may be candidates for hemodialysis treatment, especially if they have a reasonable prognosis and have not failed initial therapy. Azotemia may improve slowly in these patients; it may take several months for these patients to discontinue dialysis treatment.
IX. SPECIAL CLINICAL PR5OBLEMS IN PATIENTS WITH PLASMA CELL DISORDERS
A. Plasma alterations in patients with M-proteins
1. Hyperviscosity syndrome. The blood cells normally contribute more to the whole-blood viscosity than do plasma proteins. The development of hyperviscosity with M-proteins depends on their concentration and their ability to aggregate or polymerize. WM is typically associated with hyperviscosity. Symptoms usually do not occur unless the serum M-protein concentration exceeds 3 to 4 g/dL and the serum viscosity index exceeds 4.
a. Complications of hyperviscosity include the following:
(1) Bleeding diathesis is manifested by spontaneous bruising, purpura, retinal hemorrhages, epistaxis, or mucosal bleeding. The hemorrhagic diathesis is compounded by thrombocytopenia. Bleeding in the hyperviscosity syndrome appears to be a result of the following:
(a) Interference with coagulation, especially the third stage of coagulation (polymerization of fibrin monomer), resulting in prolongation of clotting times
(b) Impaired platelet function resulting in abnormalities of bleeding times, clot retraction, and other platelet functions
(2) Retinopathy is manifested by venous dilation and segmentation (“link-sausage” appearance), retinal hemorrhages, and papilledema.
(3) Neurologic symptoms, which develop in about 25% of patients, include malaise, focal neurologic defects, stroke, and coma.
(4) Hypervolemia develops with an increase of M-protein concentration, resulting in distention of peripheral blood vessels and increased vascular resistance. Plasma volume expansion may actually lessen the viscosity but may also precipitate congestive heart failure (which occurs in about 10% of patients who have hyperviscosity).
b. Management. Hyperviscosity syndrome is treated by reducing the quantity of M-protein in the serum. Reduction of M-protein concentrations with cytotoxic-agent therapy takes several weeks or months. Symptomatic patients should be treated with plasmapheresis, 4 to 6 units daily, until the viscosity index is <3. Patients with hyperviscosity caused by monoclonal IgM usually respond to plasmapheresis more rapidly than those with IgG or IgA gammopathies because IgM has a predominantly intravascular distribution (Table 22.1). Additionally, an exponential relationship exists between serum viscosity and IgM level so that, for example, a 20% decrease in IgM concentration results in a 100% decrease in serum viscosity. Improvement should be monitored by noting changes in clinical findings, coagulation tests, and serum viscosity determinations.
2. Cold sensitivity may afflict patients with M-proteins (especially IgM) that have physicochemical properties that permit cold precipitation. The cryoglobulins in plasma cell dyscrasias and lymphoproliferative disorders are monoclonal. The cryoglobulins in other disorders (e.g., collagen vascular diseases and viral infections) are circulating soluble immune complexes (IgM–IgG, IgA–IgG, IgG–IgG). Manifestations include cold urticaria, Raynaud phenomenon, and vascular purpura in the absence of severe thrombocytopenia.
3. Cold agglutinins are IgM with a specificity for specific red blood cell antigens (usually Ia) at temperatures <37°C. These proteins may be responsible for a mild extravascular complement-dependent hemolysis and acrocyanosis, but not for other symptoms of cold sensitivity unless cryoglobulins are also present.
4. Pseudohyponatremia may be observed with high levels of M-proteins (plasma water is displaced by the M-protein).
5. Pseudo-low-HDL-cholesterol (HDL-C). Low levels of HDL-C may be found because paraproteins can interfere with HDL-C measurements in various automated analyzers.
6. Anion gaps, noted with measurement of serum electrolytes (serum concentration of sodium chloride bicarbonate), may be decreased in patients with cationic monoclonal proteins. The decreased gap is produced by the increase of chloride and bicarbonate anions.
B. Peripheral neuropathy (PN)
1. PN associated with gammopathy occurs especially in patients with IgM monoclonal gammopathies. About 5% of patients with a sensorimotor neuropathy have an associated monoclonal gammopathy. Nearly 10% of patients with WM or with MGUS and an IgM paraprotein develop a demyelinating peripheral neuropathy. Sural nerve biopsies demonstrate monoclonal IgM deposition on the outer myelin sheath. The antibody can be shown to react with myelin-associated glycoprotein (MAG) in half of the cases. These patients usually have a mostly sensory or ataxic polyneuropathy, whereas patients with non–MAG-reactive antibodies usually have both a sensory and a motor component to their neuropathy. Treatment with plasmapheresis may be effective in some cases. Other forms of treatment have included high doses of glucocorticosteroids, IVIG, and rituximab.
2. PN associated with treatment. PN more often results from treatment of plasma cell disorders with agents such as thalidomide or bortezomib. Most patients receiving thalidomide will develop irreversible neuropathy after 6 months of treatment. Approximately half of patients treated with bortezomib develop treatment-related neuropathy, which occasionally may be painful but is reversible in most cases. The risk of neuropathy with these two agents is directly related to the dose used. Also, longer cycles, changes in schedule (weekly compared to twice weekly), and subcutaneous route of administration are also associated with a reduction in the occurrence and severity of PN with bortezomib administration. Drugs such as gabapentin (Neurontin), pregabalin (Lyrica), duloxetine (Cymbalta), doxepin, and over-the-counter alpha lipoic acid may be helpful to reduce the severity of this complication.
C. Pseudoparaproteinemia. The PEP can detect serum proteins when the concentration >200 mg/dL. In certain situations, a nonimmunoglobulin homogeneous protein concentration may be >300 mg/dL and appears as a spike on PEP. The location of these spikes usually are in the α and β regions but may be in the β–γ region. The differential diagnosis is clarified by review of the clinical picture, the location of the PEP spike, and IEP. Conditions that may produce pseudoparaproteinemia include the following:
1. Hyper-α1-globulinemia (acute-phase reactant in many inflammatory and neoplastic diseases)
2. Hyper-α2-globulinemia (nephrotic syndrome or hemolysis)
3. Hemoglobin–haptoglobin complexes (intravascular hemolysis)
4. Hyperlipidemia
5. Hypertransferrinemia (iron deficiency)
6. Bacterial products
7. Desiccated serum
8. Fibrinogen (if plasma is measured)
D. Pseudomyeloma. Several malignancies, including lymphoma and cancer of the breast, bowel, or biliary tract, can be associated with the production of an M-protein. These same malignancies may produce lytic lesions in the skeleton and induce marrow plasmacytosis. Pseudomyeloma must be distinguished from true myeloma.
E. Therapy-linked acute leukemia is discussed in Chapter 34, Section I.D in “Cytopenia.”
F. Heavy chain diseases (HCD) are rare plasma cell lymphocytic neoplasms characterized by secretion of abnormal heavy chains (γ, α, or μ) without light chains (κ, λ). α-HCD is the most common, and μ-HCD is the rarest. The heavy chains may also be excreted in the urine and detected by urine PEP. Normal immunoglobulin levels are usually suppressed. Diagnosis of these disorders necessitates detailed immunochemical investigation. IEP is the crucial test; it should demonstrate reaction of antisera with the appropriate heavy chain but not with light chains.
1. α-HCD nearly always involves only the α1 subtype of heavy chain and is associated with GI lymphomas.
2. γ-HCD usually affects elderly patients. Generalized lymphadenopathy, hepatosplenomegaly, involvement of Waldeyer ring, fever, pancytopenia, and eosinophilia are common features of the disease. The illness initially resembles granulomatous disease or Hodgkin disease. Biopsies of lymph nodes and bone marrow are rarely diagnostic. The disease has a variable course, developing over a few months to several years. A satisfactory treatment plan has not been established.
3. μ-HCD nearly always occurs in patients with CLL, and the two disorders are treated in the same manner. In μ-HCD, however, lymphadenopathy is infrequent and, in contrast to other HCDs, large amounts of κ light chains are excreted in the urine. The rare disease may be suspected when a patient with CLL has unusual vacuolated plasma cells (characteristic of μ-HCD) in the bone marrow.
G. Amyloidosis may be primary (with or without associated plasma cell or lymphoid neoplasms), secondary to a variety of chronic inflammatory diseases or hereditary disorders (familial Mediterranean fever), or associated with the aging process. The disease is characterized by organ deposition of fibrillar substances of many different types. The fibrils are mostly or exclusively composed of immunoglobulin light chains (especially the λ type) in amyloidosis associated with primary amyloidosis and myeloma, but the fibrils are composed of substances other than light chains in secondary amyloidosis.
1. Organ distribution of amyloid. The various forms of amyloidosis overlap considerably. Secondary amyloidosis affects the kidneys, spleen, liver, or adrenal glands and rarely involves the heart, GI tract, or musculoskeletal system. Primary amyloidosis and amyloidosis associated with MM mostly affect the heart, GI tract, skeletal muscle, ligaments (carpal tunnel syndrome), and periarticular and synovial tissue (articular manifestations) as well as the tongue (macroglossia) and skin. Skin involvement most commonly is located in the periorbital and skin-fold regions and is manifested by spontaneous purpura and ecchymoses, which may be aggravated by coagulation factor X deficiency, which occasionally accompanies amyloidosis; postproctoscopic eyelid ecchymoses are characteristic. Involvement of the respiratory tract, endocrine glands, and peripheral and autonomic nervous systems also occurs.
2. Diagnosis
a. Biopsy of an involved organ (especially the bone marrow, carpal ligament, sural nerve, rectum, or gingivae) must be performed to establish the diagnosis of amyloidosis; liver or renal biopsy may result in hemorrhage. Amyloid deposits have a homogenous eosinophilic appearance on light microscopy. Confirmation is made by the demonstration of specific birefringence by polarized microscopy of specimens stained with Congo red.
b. Monoclonal light chains in the urine are found in both the primary type and in amyloidosis associated with MM. Many patients with primary amyloidosis are found to have developed a plasma cell dyscrasia, if they survive sufficiently long. On the other hand, patients with MM or WM may develop amyloidosis.
3. Prognosis. The prognosis of patients with amyloidosis has improved to 3 to 4 years with the introduction of many new agents, although the prognosis varies greatly depending on the type of amyloid, the sites and extent of organ involvement, and other possible associated plasma cell disease. Patients with primary amyloidosis generally have the worst outcome. Those with cardiac involvement have the worst prognosis, whereas patients with renal disease have a better outcome. Newer prognostic factors include serum uric acid, troponin, and brain-type natriuretic peptide levels.
4. Treatment of amyloidosis is directed at both the affected organs and the underlying process producing the amyloid deposits. Data are insufficient to identify optimal therapy for this plasma cell disorder. Treatment options are similar to MM and include M&P, VAD, moderate high-dose melphalan, newer agents such as bortezemib or IMIDs, and high-dose melphalan with autologous SCT. Results of a randomized study, however, showed no overall survival advantage with high-dose therapy compared with conventional treatment despite the increase in progression-free survival with the more intensive treatment. Recent studies show that thalidomide and lenalidomide, with or without the addition of glucocorticoids and bortezomib, are very effective for patients with amyloidosis and may lead to long-term remissions. The significant neurotoxic side effects of both thalidomide and bortezomib must be considered in choosing these agents for patients with amyloidosis-associated neuropathy.
H. Papular mucinosis (lichen myxedematosus) is a dermatologic condition characterized by cutaneous papules and plaques that result from the deposition of a mucinous material. The disease is often preceded by chronic pyoderma. It demonstrates an M-protein, usually IgG-λ, with a characteristic mobility (slower than any other gamma globulin component), and a strong affinity for normal dermis. Other manifestations of MM (plasmacytosis, osteolysis, and excretion of light chains) are rare. Treatment with melphalan is often beneficial.
Suggested Reading
Multiple Myeloma
Attal M, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003;349:2495.
Berenson JR, et al. Monoclonal gammopathy of undetermined significance: a consensus statement. Brit J Haematol 2010:150:28.
Berenson JR, Crowley JJ, Grogan TM. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 2002;99:3163.
Berenson J, et al. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicenter, randomized controlled trial. Lancet Oncol2011;12:225.
Cavo M, et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood 2011;117:6063.
Child JA, et al. Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003;348:1875.
Dimopoulos MA, et al. Renal impairment in patients with multiple myeloma: A consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol 2010;28:4976.
Greipp PR, et al. International staging system for multiple myeloma. J Clin Oncol 2005;23:3412.
Korde N, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies. Blood 2011;117:5573.
Kyle RA, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78:21.
Kyle RA, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007;356:2582.
Lonial S, Cavanaugh J. Emerging combination treatment strategies combining novel agents in newly diagnosed multiple myeloma. Br J Haematol 2009;145:681.
Maloney DG, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003;102:3447.
Morgan G, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomized controlled trial. Lancet Oncol 2010;376:1989.
Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364:1046.
Raje N, Roodman GD. Advances in the biology and treatment of myeloma bone disease. Clin Cancer Res 2011;17:1278.
Richardson PG, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010;116:679.
San Miguel JF, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359:906.
Shah JJ, Orlowski RZ. Proteasome inhibitors in the treatment of multiple myeloma. Leukemia 2009;23:1964.
Weber D, et al. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003;21:16.
Yeh HS, Berenson JR. Treatment of myeloma bone disease. Clin Cancer Res 2006;12:6279s.
Zhou Y, et al. The molecular characterization and clinical management of multiple myeloma in the post-genome era. Leukemia 2009;23:1941.
Other Topics
Ansell SM, et al. Diagnosis and management of Waldenstrom macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines. Mayo Clin Proc 2010;85:824.
Berenson JR, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;91:1191.
Comenzo R. How I treat amyloidosis. Blood 2009;114:3147.
Dimopoulos MA, et al. Treatment of plasma cell dyscrasias with thalidomide and its derivatives. J Clin Oncol 2003;21:4444.
Merlini G, Stone MJ. Dangerous small B-cell clones. Blood 2006;108:2520.
Merlini G, et al. Amyloidosis: pathogenesis and new therapeutic options. J Clin Oncol 2011;29:1924.
Migliorati CA, et al. Osteonecrosis of the jaw and bisphosphonates in cancer: a narrative review. Nature Rev Endocrinol 2011;7:34.
Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment. Mayo Clin Proc 2006;81:693.
Treon SP, et al. CD20-directed antibody-mediated immunotherapy induces responses and facilitates hematologic recovery in patients with Waldenstrom’s macroglobulinemia. J Immunother 2001;24:272.
Vijay A, Gertz MA. Waldenstrom macroglobulinemia. Blood 2007;109:5096.