I. INTRODUCTION
A. Types of plasma cell dyscrasias
Plasma cell dyscrasias represent a heterogeneous group of conditions characterized by an increased number of plasma cells or by the productions of a monoclonal protein. The following plasma cell dyscrasias will be discussed in this chapter: monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), Waldenström macroglobulinemia (WM), amyloidosis, and solitary plasmacytomas. Light chain deposition disease, heavy chain diseases, immunoglobulin D MM, nonsecretory MM, osteosclerotic myeloma or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome and primary plasma cell leukemia are beyond the scope of this text.
B. Monoclonal protein (M-protein)
An M-protein is detected in the serum, urine, or both of most patients with plasma cell dyscrasias. The so-called M-protein is thought to be a measure of plasma cell burden, although a correlation is not always evident. A notable discordance between the M-protein and disease burden could be noted in heavily pretreated patients where the malignant cells might have dedifferentiated and have become less secretory or nonsecretory. This is often accompanied by an increase in the serum lactate dehydrogenase. Exceptions aside, most plasma cell dyscrasias are best followed by serial measurements of the M-protein and parameters of end organ dysfunction. Current standard criteria rely on changes
in the M-protein for determining response and progression after treatment. The basic immunoglobulin (Ig) unit comprises two identical heavy chains (G, A, M, D or E) and two identical light chains (kappa or lambda). The serum protein electrophoresis is used to quantify the monoclonal component of the globulin; it fails to do so, however, when the concentration of the latter is low because of lack of secretion or if the M-protein is excreted in the urine. If there is a high clinical suspicion for the presence of an M-protein despite a negative serum protein electrophoresis, an immunoelectrophoresis should be performed on both the serum and the urine, as up to 15% of patients may have a negative serum immunofixation with positive urine immunofixation. The urinary light-chain excretion (expressed in grams per 24 hours) is used to follow the urinary M-protein. This is calculated from the 24-hour urine protein and the percent contribution of light chain to proteinuria on the urine protein electrophoresis. It is critical to assess the percent contribution of the light chain to the proteinuria especially in patients with other comorbidities such as hypertension and diabetes mellitus, where the patient could present with an M-protein with the proteinuria consisting mainly of albumin secondary to the other medical processes. Newer assays for serum free light chain are becoming increasingly available and often result in the detection of increased free light chains in the serum of many patients with nonsecretory MM (negative immune fixation of the serum and urine) and amyloid light-chain (AL) amyloidosis. The latter assay does not demonstrate monoclonality of the light chain but relies on the ratio of kappa to lambda light chain to infer an excess of one of the light chains. While some investigators have correlated changes in the free light chain induced by therapy with outcomes and the use of the serum, and the free light-chain test has been incorporated in the International Myeloma Working Group response criteria, the precise role of these markers beyond their contribution to the diagnosis has not been thoroughly validated. Infections, autoimmune disorders, and poor renal function make interpretation of the free light-chain assay difficult.
II. MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE (MGUS)
MGUS is usually characterized by a low M-protein (less than 3 g/dL), the absence of bone lesions, less than 10% plasma cells on the bone marrow biopsy, and the absence of attributable end organ damage such as anemia, hypercalcemia, and renal dysfunction. The prevalence of MGUS increases with age and has been described in as many as 3% of all individuals over 70 years of age. The rate of progression from MGUS to MM or other lymphoproliferative disorders varies based on several factors, the most notable of which is the level of the serum M-protein. A high serum M-protein (≥1.5 g/dL), a higher bone marrow plasma
cell burden, and possibly an abnormal kappa to lambda ratio on free light-chain testing puts select patients at higher risk of progression to MM. While patients with lower risk MGUS may be followed on a yearly or biannual basis, patients with higher risk of progression probably benefit from closer follow-up and may be eligible for enrollment in prevention clinical trials. In a small number of patients, MGUS could be associated with peripheral neuropathy. The majority of patients with MGUS and peripheral neuropathy in association with an Ig M-protein have anti-myelin-associated glycoprotein antibodies. This group of patients responds favorably to therapy with single-agent rituximab.
III. MULTIPLE MYELOMA (MM)
A. General considerations and aims of therapy
1. Diagnosis. MM is a clonal B-cell tumor of slowly proliferating plasma cells within the bone marrow. Table 23.1 illustrates diagnostic criteria required for a diagnosis of MM. The Durie and Salmon staging system was initially used for the staging of patients with MM (Table 23.2). Its use has fallen out of favor due to difficulties inherent to its use. A staging system is the International Staging System, which is illustrated in Table 23.3. It relies on the serum β2-microglobulin and on serum albumin. It was found to accurately prognosticate patient outcomes.
With the increased awareness, an increasing number of patients are being diagnosed with monoclonal gammopathy incidentally, and the decision to monitor or actively treat has become difficult with the old nomenclature.
TABLE 23.1 Diagnostic Criteria of MGUS and Multiple Myeloma
MGUS
Asymptomatic MM
Symptomatic MM
Serum M-protein <30 g/L and clonal bone marrow plasmacytosis <10%
Serum M-protein ≥30 g/L or clonal bone marrow plasmacytosis ≥10%
M protein in the serum or urine and clonal bone marrow plasmacytosis or plasmacytoma
No other B-cell lymphopro-liferative disorder
No related organ and tissue impairment
Related organ and tissue impairment*
No related organ and tissue impairment
M-protein, monoclonal protein; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma.
* Related organ tissue impairment includes the following:
▪ Hypercalcemia
▪ Renal dysfunction
▪ Anemia: hemoglobin 2 g/dL below the lower limit of normal
▪ Lytic bone lesions (solitary plasmacytoma requires >30% plasma cells)
▪ Symptomatic hyperviscosity
▪ Amyloidosis (requires >30% plasma cells)
▪ Recurrent bacterial infections (>2/year).
TABLE 23.2 Durie-Salmon Staging System
Stage*
Criteria
I
All of the following:
Hemoglobin >10 g/dL
Serum calcium value normal (≤12 mg/dL)
On radiograph, normal bone structure or solitary bone plasmacytoma only
Low M-component production rates
IgG value <5 g/dL
IgA value <3 g/dL
Urine light-chain M component on electrophoresis <4 g/24 hours
II
Fitting neither stage I nor stage III
III
One or more of the following:
Hemoglobin <8.5 g/dL
Serum calcium value >12 mg/dL
Advanced lytic bone lesions
High monoclonal component production rates
IgG value >7 g/dL
IgA value >5 g/dL
Urine light-chain M component on electrophoresis >12 g/24 hours
IG, immunglobulin.
* Stages I, II, and III are further designated A for serum creatinine <2 and B for serum creatinine ≥2. From Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975:36:842.
TABLE 233 ISS Staging System for Multiple Myeloma
Better response to therapy
Stage I Factors:
beta-2 microglobulin <3.5 mg/dL
Albumin ≥3.5 g/dL
Most favorable prognosis
Stage II Factors:
beta-2 microglobulin <3.5 mg/dL
Albumin <3.5 g/dL or beta-2 microglobulin ≥3.5-<5.5 mg/dL
Lesser response to therapy
Stage III Factors:
beta-2 microglobulin ≥5.5 mg/dL
Less favorable prognosis
ISS, International Staging System.
a. End organ damage. The International Myeloma Working Group has presented the concept of MM with active or inactive disease based on the presence or absence of end organ damage, respectively.
b. Criteria defining end organ damage are anemia, renal failure, hypercalcemia, severe osteoporosis or lytic bony disease, or other organ abnormality that is attributable to the plasma cell dyscrasia.
c. Patients without end organ damage (MGUS or inactive myeloma) should be monitored carefully as early intervention does not affect the outcome of the disease. Patients with inactive MM should be considered for enrollment clinical trials aimed at preventing or retarding the progression to active disease.
d. Alternatively, patients who meet the criteria for MGUS but demonstrate end organ damage related to the plasma cell dyscrasia must be classified as active MM and should receive active therapy.
2. Epidemiology. The annual incidence of MM is 4 per 100,000 population, with a peak incidence between the sixth and seventh decade of life. Patients of African-American descent have an incidence of MGUS and MM approaching twice the incidence for Caucasians in the United States. Several agents have been strongly associated with the development of MM, ionizing radiation being the most commonly described risk factor. Nickel, agricultural chemicals, petroleum products, and other aromatic hydrocarbons, benzene, and silicon have been considered potential risk factors as well. One particular note is made for Agent Orange exposure by Vietnam veterans imparting an increased incidence of MM.
3. Goals of therapy. Despite recent advances in the treatment of MM, the disease remains incurable. Accordingly, therapy is aimed at improving symptoms and preventing complications of the disease, thus improving quality of life and survival. These goals could be achieved with different approaches: one aim is to transform the disease into a chronic process by using frequent low morbidity therapies, while the other approach attempts to eradicate the disease with intensive therapy. The cure versus control paradigm remains a subject of considerable debate, and it remains unclear which treatment methodology is superior. However, there is evidence that certain subgroups of patients might benefit from one or the other approach, and therapy aimed at control of the myeloma may be inappropriate for patients with more aggressive risk features. Because of these uncertainties and because standard first-line therapy is not well defined, patients with MM,
regardless of age, stage of disease, or number of previous therapies, must be considered for clinical trials enrollment.
In addition to the management of the malignant plasma cell clone, particular attention must be made to end organ dysfunction including skeletal health, prevention of infections, and thrombotic, neuronal, and renal complications. Accordingly, response to therapy is based on changes to the M-protein concentration, the percentage of plasma cells in the bone marrow, as well as monitoring end organs for improvement in function. The cooperative oncology groups in the United States and Europe have adopted different cutoffs to define response. Table 23.4 illustrates the uniform response criteria as defined by the International Myeloma Working Group.
4. Prognostic factors. Severe anemia, hypercalcemia, advanced lytic lesions, and very high M-protein are all associated with a high tumor burden and a poor survival and are the basis of the Durie and Salmon staging system. Renal failure, although not clearly correlated with disease burden, is associated with worse outcomes. Other established clinical poor prognostic factors include the following: advanced age, poor performance status at presentation, high serum lactate dehydrogenase level, lower platelet counts, bone marrow with greater than 50% plasma cells, greater than 2% bone marrow plasmablasts, high plasma cell labeling index, elevated serum β2-microglobulin, and low serum albumin. The latter two are the basis for the Southwest Oncology Group (SWOG) and International Myeloma Working Group staging systems. The identification of cytogenetic prognostic factors using metaphase karyotyping relies on cellular growth, which is difficult as the MM plasma cells have a low in vitro proliferative rate and thus such information is available only in 20% to 40% of the patients. The presence of abnormalities with this method, however, is meaningful. Genomic prognostic factors include the deletion of chromosome 13, translocation of the immunoglobulin heavy chain [t(4;14), t(14;16)], and loss of 17p13. The t(11;14), on the other hand, is not thought to portend a worse outcome. Recently, interphase fluorescence in situ hybridization (FISH) has been used to detect specific cytogenetic abnormalities. Even though FISH analysis is more sensitive at detecting certain abnormalities such as chromosome 13, this might not be clinically meaningful without other additional poor prognosticators. Nonhyperdiploid karyotypes are frequently associated with immunoglobulin heavy chain rearrangements and worse clinical outcomes.
B. Initial treatment
1. General measures. Patients with a new diagnosis of MM occasionally have associated complications that require immediate attention, such as hypercalcemia, renal failure, severe cytopenias, and spinal cord compression. These complications should be promptly identified and managed either simultaneously or before the start of therapy. Alternatively, asymptomatic patients and those with smoldering MM may be followed without specific therapy until clear evidence of progression. Ambulation and hydration should be maintained throughout the initial therapy. Avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs), aminoglycosides, and intravenous contrast agents is important for renal health. If radiologic procedures involving the use of intravenous contrast agents are to be considered, appropriate hydration and the use of N-acetyl-cysteine should be considered. The use of bisphosphonates (either pamidronate or zoledronic acid) is recommended for nearly every patient with myeloma with normal renal function, in particularly those with bony disease (see Section III.C.5). The authors recommend holding the initiation of the bisphosphonates in the first cycle of therapy to help decrease renal complications from the use of these agents. In addition, because of the increased awareness for osteonecrosis of the jaw, a rare complication of bisphosphonate therapy, a dental evaluation prior to starting therapy should be considered.
TABLE 23.4 Uniform Response Criteria as Defined by the International Myeloma Working Group
CR
▪
Negative immunofixation on the serum and urine, and
▪
Disappearance of any soft-tissue plasmacytomas, and
▪
No more than 5% plasma cells in the bone marrow (confirmation with repeat bone marrow is not needed)
Stringent CR
▪
CR as defined above, and
▪
Normal serum FLC ratio, and
▪
Absence of clonal cells in the bone marrow by immunohistochemistry or immunofluorescence, based on a κ/λ ratio of >4:1 or <1:2 performed on a minimum of 100 plasma cells (confirmation with repeat bone marrow is not needed)
Very good partial remission
▪
Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or
▪
At least 90% reduction in serum M-protein plus urine M-protein level of <100 mg per 24 hours
Partial remission
▪
At least 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90%, or to <200 mg per 24 hours
▪
If the serum and urine M-protein are unmeasurable,* a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria
▪
In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size of soft-tissue plasmacytomas is also required
Stable disease
▪
Not meeting criteria for CR, very good partial remission, partial remission, or progressive disease
Progressive disease
▪
Increase of ≥25% from baseline in serum monoclonal component and disease the absolute increase must be ≥0.5 g/dL If the starting monoclonal component is ≥5 g/dL, increases ≥1 g/dL are sufficient to define relapse.
▪
Increase of ≥25% from baseline in urine monoclonal component, and the absolute increase must be ≥200 mg/24 hours
▪
Only in patients without measurable serum and urine M-protein levels: increase of ≥25% from baseline in the difference between involved and uninvolved FLC levels, and the absolute difference must be >10 mg/dL
▪
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Multiple Myeloma, Other Plasma Cell Disorders, and Primary Amyloidosis
Multiple Myeloma, Other Plasma Cell Disorders, and Primary Amyloidosis
Rachid Baz
Mohamad A. Hussein
