Multiple Myeloma, Other Plasma Cell Disorders, and Primary Amyloidosis
Rachid Baz
Mohamad A. Hussein
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 production of a monoclonal protein.1 To efficiently utilize the newly introduced therapeutic classes and new refined compounds in the current classes, it is crucial to understand the diseases’ pathophysiology and their interaction with the microenvironment. The later term is a complex cellular, humoral, and supportive cell environment. The potency of the new compounds has resulted in many patients achieving deep responses; unfortunately, there is a group of patients that continue to succumb to their disease within the first 2 years of diagnosis. The term “minimal residual disease” (MRD) has been suggested as a measure of outcome to different regimens especially in the newly diagnosed setting where high response rates are the norm. Minimal residual disease continues to be vaguely defined and in reality describes the outcome of one component of the disease—a single clone. Perhaps a better term at this stage is “minimal residual clone”—MRC. The pathophysiology of plasma cell dyscrasia, clonal diversity, evolution, and mutation, as well as how all these complex yet integrated components interact with the microenvironment, is beyond the scope of this chapter but is critical in the understanding of the evolving therapeutic field.
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
A monoclonal protein (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 when 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 used, 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 or a measured excess of one of the light chains. Although some investigators have correlated changes in the free light chain induced by therapy with outcomes and the use of the serum free light chain test has been incorporated in the International Myeloma Working Group (IMWG) 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.
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 when 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 used, 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 or a measured excess of one of the light chains. Although some investigators have correlated changes in the free light chain induced by therapy with outcomes and the use of the serum free light chain test has been incorporated in the International Myeloma Working Group (IMWG) 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
Monoclonal gammopathy of uncertain significance (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 depends 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 a lower risk of MGUS may be followed up on a yearly or biannual basis, patients with a 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 may 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.
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 depends 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 a lower risk of MGUS may be followed up on a yearly or biannual basis, patients with a 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 may 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
A. General considerations and aims of therapy2
1. Diagnosis
Multiple myeloma (MM) is a clonal B-cell tumor of slowly proliferating plasma cells within the bone marrow. Table 24.1 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 24.2). Its use has fallen out of favor owing to difficulties inherent to its use. A more practical staging system is the International Staging System, which is illustrated in Table 24.3. 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.
a. End organ damage. The IMWG 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. The conventional criteria defining organ damage are anemia, renal failure, hypercalcemia, or lytic bony disease. More recently, the IMWG suggested that patients with 60% or greater bone marrow plasmacytosis, a free light chain ratio of 100 or greater, and positron emission tomography (PET) or magnetic resonance imaging (MRI)-defined lesions may also warrant initiation of systemic
therapy given the high likelihood of progression to symptomatic myeloma, although the benefits of early treatment initiation have not been demonstrated in this subgroup.
therapy given the high likelihood of progression to symptomatic myeloma, although the benefits of early treatment initiation have not been demonstrated in this subgroup.
TABLE 24.1 Diagnostic Criteria of MGUS and MM | ||||||||||||||||||
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TABLE 24.2 Durie-Salmon Staging System | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TABLE 24.3 ISS System for Multiple Myeloma | |||||||||||||||
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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 in clinical trials aimed at preventing or retarding the progression to active disease.
2. Epidemiology
The annual incidence of MM is 4 per 100,000 population, with a peak incidence between the sixth and seventh decades 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, which imparts an increased incidence of MM.
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 approach is to transform the disease into a chronic process by using frequent sequential 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 either 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 enrollment in clinical trials and referral to a tertiary care center.
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 either 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 enrollment in clinical trials and referral to a tertiary care center.
In addition to the management of the malignant plasma cell clone, particular attention must be paid 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 24.4 illustrates the uniform response criteria as defined by the IMWG.
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 the IMWG 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. More recently, several gene expression profiling (GEP) signatures have been introduced into the clinical arena. For instance, a commercial 70 gene GEP, MyPRS (Myeloma Prognostic Risk Signature),8 is available in the United States and provides information regarding the molecular subtype of myeloma as well as a prognostic score that identifies a subset of patients with high-risk disease. Although the prognostic utility of this test has been validated in multiple data sets, it remains unclear whether it has predictive value and impacts treatment decisions. Patients with high-risk disease continue to experience poor outcomes and should be considered for clinical trials, if possible.
prognosticators. Nonhyperdiploid karyotypes are frequently associated with immunoglobulin heavy chain rearrangements and worse clinical outcomes. More recently, several gene expression profiling (GEP) signatures have been introduced into the clinical arena. For instance, a commercial 70 gene GEP, MyPRS (Myeloma Prognostic Risk Signature),8 is available in the United States and provides information regarding the molecular subtype of myeloma as well as a prognostic score that identifies a subset of patients with high-risk disease. Although the prognostic utility of this test has been validated in multiple data sets, it remains unclear whether it has predictive value and impacts treatment decisions. Patients with high-risk disease continue to experience poor outcomes and should be considered for clinical trials, if possible.
TABLE 24.4 Uniform Response Criteria as Defined by the IMWG | ||||||||||||||||
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B. Treatment—standard regimens
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 zoledronic acid or pamidronate) is recommended for nearly every patient with symptomatic myeloma with adequate renal function, particularly in those with bony disease (see Section III.F.1). 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, especially in patients with high light chain burden or borderline renal function. In addition, because of the increased awareness of osteonecrosis of the jaw, a rare complication of bisphosphonate therapy, a dental evaluation prior to starting therapy should be considered when feasible.
2. Systemic therapy for the newly diagnosed patient—approach to therapy
Although a plethora of therapeutic options for the treatment of patients with newly diagnosed MM are available, there is no standard first-line therapy. In this text, we will define non-highdose therapy as traditional therapy and high-dose therapy with
stem cell rescue as intensive therapy. As therapy for MM does not result in cures, treatment recommendations are often individualized and based on a patient’s comorbidities, performance status, and preference, as well as disease characteristics. For example, if high-dose therapy is considered during the course of therapy, avoidance of agents, such as melphalan and other alkylating agents, that impair stem cell collection is important. In the patient with significant symptoms from the disease, the choice of highly active first-line therapy that results in rapid responses is reasonable. Similarly, in patients with renal dysfunction at presentation, the choice of agents with a safe renal profile is recommended (e.g., bortezomib-based therapy).
stem cell rescue as intensive therapy. As therapy for MM does not result in cures, treatment recommendations are often individualized and based on a patient’s comorbidities, performance status, and preference, as well as disease characteristics. For example, if high-dose therapy is considered during the course of therapy, avoidance of agents, such as melphalan and other alkylating agents, that impair stem cell collection is important. In the patient with significant symptoms from the disease, the choice of highly active first-line therapy that results in rapid responses is reasonable. Similarly, in patients with renal dysfunction at presentation, the choice of agents with a safe renal profile is recommended (e.g., bortezomib-based therapy).
Patients with poor prognostic factors at presentation [chromosome 13 deletion by metaphase cytogenetics or t(4;14), deletion 17p, high β2 microglobulin, or increased plasma cell labeling index] fare poorly with all traditional therapies. Accordingly, these patients are best managed by enrollment in clinical trials. Alternatively, it is intuitive, though unproven, that intensive therapy (combination novel agent induction therapy followed by consideration of high-dose therapy and consolidation with novel agents as well as maintenance) would result in improved outcomes. While some reports suggest that bortezomib-based therapy overcomes the negative implications of high-risk disease, these observations are based on small numbers and relatively short follow-up, and other investigations did not confirm these findings.
For patients eligible for intensive therapy, the use of dexamethasone in combination with an immunomodulator (lenalidomide) and a proteasome inhibitor (bortezomib) is a reasonable consideration. Alternatively, bortezomib, cyclophosphamide and dexamethasone can be considered, especially for patients with renal insufficiency. The randomized phase II trial noted a similarly high response rate with either regimen. Such induction therapy is usually continued for four to eight cycles until a plateau phase is reached, at which time, high-dose therapy or maintenance therapy is initiated.
Although many patients over the age of 65 years remain excellent candidates for intensive therapy, high-dose therapy may not be appropriate for some; therapy with lenalidomide and low-dose dexamethasone, or bortezomib and low-dose dexamethasone can be considered standard of care. Specifically, the FIRST trial9 has demonstrated the superiority of continued lenalidomide-dexamethasone over a fixed duration of the same therapy (18 months) or a combination of melphalan, prednisone and thalidomide. Furthermore, the addition of melphalan or cyclophosphamide to the lenalidomide-dexamethasone backbone did not improve outcomes in the elderly population. In addition,
there are similar outcomes with bortezomib-dexamethasone as compared with those with bortezomib-melphalan-prednisone or bortezomib-thalidomide-dexamethasone in this patient population. In some circumstances, it is reasonable to consider a more intensive combination (bortezomib-dexamethasone with either lenalidomide or cyclophosphamide) in elderly patients with higher tumor burden.
there are similar outcomes with bortezomib-dexamethasone as compared with those with bortezomib-melphalan-prednisone or bortezomib-thalidomide-dexamethasone in this patient population. In some circumstances, it is reasonable to consider a more intensive combination (bortezomib-dexamethasone with either lenalidomide or cyclophosphamide) in elderly patients with higher tumor burden.
3. Traditional chemotherapy recommendations
While numerous additional chemotherapeutic regimens have been described, only agents commonly used in the treatment of MM are reviewed below.
a. Dexamethasone10 is considered the standard corticosteroid for many induction regimens for MM. The Eastern Cooperative Oncology Group study comparing lenalidomide and low-dose dexamethasone with lenalidomide and high-dose dexamethasone demonstrated a survival benefit in the lower dose of dexamethasone. This was more pronounced in patients older than 65 years, but was noted in all age groups. High-dose dexamethasone, for a few cycles, in combination with lenalidomide remains reasonable in younger patients with high disease burden.
High-dose dexamethasone is given at a dose of 40 mg by mouth (PO) on days 1 to 4, 9 to 12, and 17 to 20. Cycles are repeated every 28 days. Low-dose dexamethasone consists of 40 mg PO weekly or on days 1 to 4 of a 28-day cycle. Significant early toxicities include hyperglycemia, dyspepsia, fatigue, and muscle weakness. Additionally, patients often report agitation and insomnia. Longer-term toxicities include increased infections, cataract, osteoporosis, and avascular necrosis of femoral heads. As a single agent in patients with newly diagnosed myeloma, responses are observed in about 50% of patients, and the median time to response is approximately 1 month. However, the median duration of response is only 6 months. As such, single-agent dexamethasone is generally not the treatment of choice.
b. Melphalan and prednisone (MP)9 has fallen out of favor, with the availability of novel agents, and combinations of thalidomide or bortezomib with MP have resulted in superior survival than MP alone. Nonetheless, MP remains a reasonable option for very elderly patients with many comorbidities. MP results in about a 50% overall response rate (ORR) in patients with newly diagnosed myeloma, and a median time to progression of about 15 months. While a number of different dosages and schedules for MP exist, we recommend the following:
Melphalan 9 mg/m2 PO on days 1 to 4, and
Prednisone 100 mg PO on days 1 to 4.
For reliable absorption, melphalan should be taken on an empty stomach. Repeat the cycle every 4 to 6 weeks, depending on recovery of counts. MP is usually given in six to nine cycles, and treatment beyond 1 year does increase risks of myelodysplasia. Responses to MP tend to occur slower on average, making this a less attractive regimen in patients with significant symptoms. On the other hand, MP is well tolerated in patients with myeloma, with myelosuppression being the most significant adverse event. MP should not be used in patients who are candidates for intensive therapy as it may impair stem cell collection.
c. Cyclophosphamide and prednisone (CP)11 is a forgotten alternative to MP. Cyclophosphamide does not need dose adjustments for renal failure, making it a useful agent in patients with a decreased performance status and/or comorbidities. It results in a response rate of about 50% and a progression-free survival (PFS) of 12 to 15 months in treatment-naïve patients. CP is given as follows:
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