Casey B. Williams and Timothy R. McGuire
Multiple myeloma (MM) is a cancer that develops in plasma cells, leading to excessive production of a monoclonal immunoglobulin.
Most patients have skeletal involvement at the time of diagnosis with associated bone pain and fractures. Anemia, hypercalcemia, and renal failure may also be present. A bone marrow biopsy with 10% or more plasma cells and an M-protein spike on plasma or urine electrophoresis confirms the diagnosis.
Most patients require treatment after diagnosis, but treatment can be deferred in patients with smoldering (asymptomatic) MM. In patients with symptomatic disease, treatment produces benefits in various measures of survival and quality of life.
Thalidomide, lenalidomide, or bortezomib plus dexamethasone are commonly used induction regimens. They produce higher complete remission rates compared with the classic regimens of melphalan plus prednisone and VAD (vincristine, doxorubicin, and dexamethasone). The increased response rate is at the expense of significant grade III and IV toxicity, which can include myelosuppression, venous thromboembolism (VTE), and neuropathy depending on the regimen used. These novel agents can be added to chemotherapy (melphalan, liposomal doxorubicin, cyclophosphamide, or VAD-like chemotherapy) as part of induction and results in substantially higher response rates. Novel agents can also be combined to produce more active regimens.
Bortezomib-based regimens are commonly used to treat newly diagnosed patients with high-risk disease and patients with relapsed MM.
Lenalidomide is more potent and better tolerated than thalidomide and is the most commonly used immunomodulatory drug.
A host of new drugs are being studied and integrated into treatment of relapsed MM, including carfilzomib, pomalidomide, vorinostat, and bendamustine. Carfilzomib is a very active agent and is currently being studied as induction therapy in newly diagnosed patients.
Melphalan plus prednisone is not used in transplant candidates as part of induction but commonly used in transplant-ineligible patients combined with thalidomide, lenalidomide, or bortezomib.
Autologous hematopoietic stem cell transplantation (HSCT) is used after induction in patients with reasonably good performance status to maximize complete remissions and prolong survival. Combining autologous HSCT with allogeneic HSCT must be considered investigational and should be performed under clinical trial.
Maintenance therapies can be used in both transplant-eligible and -ineligible patients. Current regimens usually include lenalidomide or bortezomib with the intent of increasing response rates and progression-free survival.
Bisphosphonates are used to treat bone disease associated with MM, which results in decreased pain and skeletal-related events and improvement in quality of life.
Salvage therapy for patients with relapsed or refractory MM can include any of the prior listed therapies, depending on performance status of the patient, risk category of the patient, and prior treatments used for induction.
Multiple myeloma (MM) is a genetically complex and an increasingly more common hematologic malignancy that develops in plasma cells or immunoglobulin-producing B lymphocytes.1,2 The plasma cells produce excessive monoclonal immunoglobulins that can be measured in the plasma or urine. As a result of the various bone-mobilizing cytokines secreted from the MM clone and bone marrow stromal cells, patients often have skeletal involvement at diagnosis. MM is often sensitive to chemotherapy initially, but drug resistance develops relatively rapidly. Although therapy is not currently curative, MM has been a remarkable example of bench-to-bedside translation in new drug development. In particular, the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide target MM cells in the bone marrow microenvironment and have improved outcomes.
EPIDEMIOLOGY AND ETIOLOGY
In the United States, it is estimated that 22,350 cases of MM will be diagnosed in 2013, with 10,710 deaths. It is a disease that affects older adults with a median age at diagnosis of 66 years. MM occurs more frequently in males and African Americans.3 Additionally, individuals with a first-degree relative with MM have a 3.7-fold increased risk of developing this malignancy than those with unaffected relatives.4,5
Epidemiologic data from the United States have demonstrated associations with MM and individuals who work in agriculture.6 Studies have shown an increased incidence of lymphohematopoietic cancers associated with lifetime exposure to alchalor, a commonly used pesticide. Other occupational groups associated with the development of MM include miners, carpenters and wood workers, sheet-metal workers, and furniture makers.1,4 Radiation exposure has also been historically linked to the development of MM, but existing evidence is inconclusive.7
Although the pathogenesis of MM has not been fully elucidated and the role of antigen stimulation in the pathogenesis of the disease remains controversial, the understanding of the cellular events underlying the development of MM is becoming clearer. Decades of research and improved scientific techniques have enabled closer examination of the changes that occur during the development of normal and abnormal B cells.
Multiple myeloma is a genetically heterogeneous disease that belongs to a group of related diseases called paraproteinemias that are characterized by abnormal clonal plasma cell infiltration in the bone marrow. A precursor condition called monoclonal gammopathy of undetermined significance (MGUS) is associated with monoclonal immunoglobulin in the blood (≤3 g/dL [≤30 g/L]) without clinical manifestations of the complications of MM.8,9 The conversion rate of MGUS to MM is about 1% per year. The molecular changes associated with the conversion of MGUS to MM are not clear, but genome-wide studies have identified several candidate genes associated with disease progression.2,9,10 Distinct from MGUS, which is a premalignant syndrome, smoldering MM is an asymptomatic disease with a low tumor burden and an indolent course.1,4 In patients with smoldering MM, the risk of progression is about 10% per year for the first 5 years after diagnosis, about 3% per year for the next 5 years, and about 1% per year for the next 10 years.11
Although both MGUS and smoldering MM lack the clinical features of MM, they share many of the same genetic features. A characteristic feature of MM cells is the requirement for an intimate relationship with the bone marrow microenvironment, where plasma cells are nurtured in specialized niches that maintain and promote their long-term survival.12 In early MM, the balance between apoptotic and antiapoptotic genes is disrupted with overexpression of antiapoptotic genes. As the disease progresses, a greater number of gene products that confer resistance, such as mutated p53, are overexpressed.13Molecules such as interleukin-6 (IL-6) and the transcriptional regulator nuclear factor kappa B (NF-κ B) also stimulate clonal growth and promote resistance to therapy. Given their imprecise but important role in initiation and progression of MM, IL-6 and NF-κ B are targets for both old and new therapies.13,14
MM is characterized by the accumulation of malignant plasma cells in the bone marrow and the production of a monoclonal immunoglobulin (M protein). These proteins, secreted by the malignant clone, are frequently referred to as paraproteins.1,4 Both MM and normal plasma cells are produced from differentiated B cells after antigen stimulation. Whereas normal plasma cells will die within days to weeks after differentiation, MM plasma cells are immortalized.1,4 MM cells are seldom seen in large quantities in the peripheral blood because of their interaction with bone marrow stromal cells. This interaction between MM cells and bone marrow stroma is mediated by adhesion molecules within an abnormal bone marrow microenvironment and is required for growth and disease progression.14 Figure 113-1 shows several of the factors involved in disease pathogenesis and progression and potential targets for thalidomide, lenalidomide, pomalidomide, bortezomib, and carfilzomib.
FIGURE 113-1 Sites of action for thalidomide, lenalidomide, pomalidomide, bortezomib, and carfilzomib.
Over the next several years, our current understanding of the pathogenesis of MM and the tumor-specific mutations that drive tumor development and proliferation should improve dramatically. Whole-genome sequencing may lead to improvements in clinical practice. The sequencing of the MM genome in 38 patients was recently published and revealed that mechanisms previously suspected to have a role in the biology of MM like NF-κ B may have much broader roles than previously suspected.15 Additionally, the discovery of potential new mechanisms of transformation and progression such as mutations in the oncogenic kinase BRAF may lead to new therapeutic approaches in the future.16,17
Most patients with MM present with complaints of bone pain and fatigue at diagnosis. About 10% to 20% of patients are asymptomatic at the time of diagnosis and have what is called smoldering MM.4,11 Unfortunately, most patients show evidence of end-organ damage at the time of diagnosis. Initial laboratory evaluation often reveals hypercalcemia, renal insufficiency, anemia, and abnormalities in various disease markers, such as albumin and β2-microglobulin. Skeletal evaluation shows gross abnormalities in most patients. Bone scans show abnormalities that often include lytic lesions, osteoporosis, and fractures. This group of findings (hypercalcemia, renal insufficiency, anemia, and bone lesions) is often referred by the acronym CRAB.4,8 A bone marrow biopsy with 10% or more plasma cells and an M-protein spike on plasma or urine electrophoresis confirms the diagnosis.8,18 Immunofixation is more sensitive and identifies the M-protein isotype being secreted. In a minority of patients, no M protein can be detected in the plasma but is found in the urine, requiring that urine be examined as part of a complete diagnostic workup. About 60% of patients have intact monoclonal immunoglobulin G (IgG), 20% have monoclonal IgA, and the remaining 20% secrete only monoclonal light chains. Antibodies are composed of two light chains where antigen binds and two heavy chains. Light-chain immunoglobulin alone can be secreted by the MM clone. Free monoclonal light chains in the urine are called Bence Jones proteins because they were first described by Dr. Henry Bence Jones and are primarily responsible for MM-associated renal failure.1,4 In addition, serum IgG light chain can be measured with a free light chain assay (Freelite). This assay has several advantages compared with serum protein and urine electrophoresis, particularly increased sensitivity, and the free light chain ratio that may add valuable information on likelihood of disease progression.19
As discussed earlier, the skeleton is involved at the time of diagnosis in most patients with MM.4,8 The effects of MM on the skeleton result from the abnormal production of cytokines, including IL-1, IL-6, tumor necrosis factor-α (TNF-α), and the receptor for activation of NF-κ B ligand (RANK-L). Bone disease is the net effect of the activation of osteoclasts and inhibition of osteoblastogenesis.20 In addition, patients are frequently anemic from infiltration of the bone marrow with the MM clone and poor erythropoietin response. Patients can have clinically important hypercalcemia, which results from calcium mobilization from the bone. Renal failure can occur as a result of high protein load from the monoclonal protein secretion as well as dehydration.
CLINICAL PRESENTATION Multiple Myeloma
• 80% of patients present with symptomatic disease
Signs and Symptoms
• Bone pain (fractures, lytic lesions)
• Fatigue (anemia)
• Infection (reduced polyclonal response)
• Neurologic symptoms (nerve compression)
• Polyuria (hypercalcemia)
• Nausea and vomiting (hypercalcemia)
• Elevated paraproteins
• Plasma electrophoresis
• Urine electrophoresis
• Elevated serum creatinine
• Low hemoglobin
• Low albumin
• Elevated β2-microglobulin
• Elevated C-reactive protein
• ≥10% plasma cells
• Chromosome 13 deletion
• Translocation (4;14)
• Del (17p)
STAGING AND PROGNOSTIC FACTORS
Some patients with MM are asymptomatic and have no evidence of end-organ damage at the time of diagnosis. As discussed previously, these patients are categorized as having smoldering (asymptomatic) MM.21 Most patients have evidence of end-organ damage (hypercalcemia [>10.5 g/dL (>2.63 mmol/L)], renal impairment [>2.0 mg/dL (>177 μmol/L)], anemia [<10 g/dL (<100 g/L; 6.21 mmol/L) or >2 g/dL (>20 g/L; 1.24 mmol/L) below normal]), or bone disease at the time of diagnosis and are categorized as having active (symptomatic) disease. Patients with asymptomatic disease have an indolent course with a median survival time of about 5 years.11,21
The International Staging System (ISS) uses serum β2-microglobulin and albumin concentrations to stage patients.22 These two routine laboratory tests are powerful prognostic discriminators. The ISS predicts survival in patients treated with either conventional treatment or autologous hematopoietic stem cell transplantation (HSCT). An older staging system, Durie-Salmon, uses hemoglobin, serum calcium, bone involvement, and M protein to categorize patients in one of three stages. Table 113-1 describes the ISS and median survival times for each of the three ISS stages.
TABLE 113-1 The International Staging System for Multiple Myeloma
Several adverse prognostic factors have been proposed for MM, including chromosome 13 deletion and other cytogenetic abnormalities (e.g., 17p deletion, t(4,14)), elevated β2-microglobulin, elevated C-reactive protein, high plasma cell labeling index, low albumin, and high bone marrow microvessel density.1,4,8 These prognostic factors generally represent the underlying pathologic changes associated with MM, including genetic damage (chromosome 13 and 17 abnormalities), proinflammatory changes (C-reactive protein), tumor load (β2-microglobulin), and dysregulated cellular growth (labeling index and marrow microvessel density).
The current goal of therapy in MM is to prolong progression-free survival (PFS) and overall survival and improve quality of life. The initial goal of induction therapy in newly diagnosed patients with more active (symptomatic) and advanced disease (stages II and III) is to obtain at least a major response.4,8,18 This is usually followed by consolidation and maintenance therapy, both of which can extend and often improve induction responses. With the integration of novel agents into therapy, PFS and overall survival have steadily improved, and responses have increased in frequency, depth, and duration. Unfortunately, there is no convincing evidence that patients are cured of their disease.
In asymptomatic patients with smoldering MM, watchful waiting is the most common practice despite a systematic review that suggests early treatment with chemotherapy slows disease progression and may decrease vertebral compression.11,21 The benefits of chemotherapy in this setting are generally offset by the absence of convincing evidence that early treatment improves overall survival and the risk of treatment-related adverse events. With the availability of new novel agents, progression of this form of MM may be delayed. The National Comprehensive Cancer Network (NCCN) guidelines currently recommend watchful waiting for smoldering MM.23
Initial management of symptomatic MM depends on the presence or absence of high-risk features of the disease (i.e., cytogenetics), patient age, renal function, performance status, and whether autologous HSCT is planned. Although current treatments are not curative, the median survival time has increased significantly from about 7 months to 24 to 36 months in high-risk disease patients and 6 to 7 years or more in patients with standard-risk disease, primarily as a result of improved treatment of symptomatic MM and supportive care.4,23
All patients with symptomatic MM are treated with initial induction therapy. Although there is no standard initial or induction therapy, the regimens differ depending on whether the patient is a candidate for autologous HSCT (Table 113-2). The age restriction for autologous HSCT has changed because of low transplant-related mortality, but autologous HSCT is generally reserved for patients younger than 65 years of age.
TABLE 113-2 Drug Therapy in Newly Diagnosed Multiple Myeloma
For many years, the choice of induction therapy in autologous HSCT candidates included VAD (vincristine, doxorubicin, and dexamethasone) as the standard therapy. In the last 10 years, combination regimens such as dexamethasone combined with thalidomide, lenalidomide, or bortezomib and dexamethasone combined with bortezomib and lenalidomide or thalidomide have become common. The use of VAD chemotherapy before autologous HSCT is now obsolete given data that suggest superior outcomes in patients receiving newer drug combinations.23,24
The Mayo Clinic recommends a risk-adapted approach to initial therapy in which treatment is guided by cytogenetics and gene expression profiling.25 In contrast to the single institution guidelines of Mayo Clinic, the NCCN recommendations are based on the opinions of experts from many nationally recognized cancer centers (Table 113-2).23 The Mayo Clinic and NCCN guidelines both recommend the use of newer novel agents as initial therapy; these guidelines are discussed later in Recommendations for Initial Therapy section.
Induction therapy is usually continued until maximum response is achieved. Patients who are candidates for autologous HSCT then undergo hematopoietic stem cell collection. Most patients undergo autologous HSCT at that time, but some patients may decide to delay the procedure. Patients who are not candidates for autologous HSCT usually receive several cycles of consolidation therapy, although the optimal duration of therapy after maximum response is achieved is unknown. Single-agent maintenance therapy may be given in both transplant-eligible and -ineligible patients.
Clinical response to therapy is generally defined by a reduction in paraprotein in blood and urine.4 Clinical complete remission (CR) is defined as elimination of plasma paraprotein as measured by electrophoresis and immunofixation and plasma cells (≤5%) in the bone marrow. A specialized type of complete remission, called stringent complete response (sCR), is defined by normal free light chain and negative immunofixation. Complete remissions are uncommon in MM, and lesser responses, including partial response (PR), near complete response (nCR), and very good partial response (VGPR), are more commonly attained. Although the nCR term is less commonly used in current trials, it was used in several important studies. These lesser responses can be important because they may correlate with improved survival. Table 113-3 describes the most common types of responses that are used clinically.23
TABLE 113-3 Definition of Clinical Response in Multiple Myeloma
Pharmacotherapy of Multiple Myeloma
The current treatment of MM relies heavily on integration of novel agents, including thalidomide, lenalidomide, bortezomib, carfilzomib, and pomalidomide. These novel agents have revolutionized the treatment of MM, greatly increasing responses and survival with acceptable but different toxicity profiles compared with conventional chemotherapy-based regimens previously used in MM. Tables 113-4 and 113-5 show dosing and monitoring parameters for the novel agents used in the treatment of MM. Dose reductions in elderly patients and in patients with adverse events are often required.24
TABLE 113-4 Dosing of Novel Agents in Multiple Myeloma
TABLE 113-5 Adverse Reactions and Monitoring Parameters for Novel Agents in Multiple Myeloma
As previously discussed, two of the common conventional chemotherapy regimens used historically to treat MM are melphalan plus prednisone (MP) and VAD.4,26 Despite more active combinations, MP and VAD remain listed as options as initial therapy in patients with MM.23 Because conventional-dose melphalan has an adverse effect on stem cell mobilization and subsequent autologous HSCT, the use of melphalan is limited to patients ineligible for autologous HSCT. Melphalan has also been associated with the development of myelodysplastic syndromes.27 The original use of VAD chemotherapy as initial treatment became more common because of these concerns with melphalan. However, the slightly higher response rates with VAD and similar combination chemotherapy did not translate into improved survival compared with MP, and VAD is now rarely used in MM.23
Because dexamethasone accounts for most of the antimyeloma activity of VAD (Table 113-6), dexamethasone was used alone as initial therapy. However, one study reported that MP produced similar response rates and survival compared with dexamethasone. The higher rate of infection and central nervous system toxicity in patients treated with dexamethasone led these investigators to conclude that high-dose dexamethasone be used with caution as initial therapy, particularly in older patients.28 In current regimens, newer agents (thalidomide, bortezomib, lenalidomide, carfilzomib) are combined with dexamethasone or the MP backbone to maximize initial response rates.4,8,23,26,29Doxorubicin, which also is included in VAD chemotherapy, is recognized as highly active antimyeloma chemotherapy. Current regimens can combine doxorubicin in the liposomal form with various novel agents producing regimens with some of the highest responses seen in MM patients.
TABLE 113-6 Initial Therapies for Multiple Myeloma
Thalidomide was first used clinically in Europe in the late 1950s as a sedative and antiemetic but its use was largely abandoned when teratogenicity was reported. Its immunomodulatory effects became evident with its use in Hansen disease (or leprosy), and it continues to be used for this rare indication. These clinical benefits are thought to be related to the anti-TNF activity of thalidomide. As a result of the role of inflammatory cytokines in the pathophysiology of MM, thalidomide was first studied in refractory MM in 1999. The observation that thalidomide had activity against myeloma rejuvenated it as an important therapeutic agent.30
Thalidomide and other IMiDs have multiple immune effects, including inhibition of inflammatory mediators, antiangiogenic activity, and T cell–modulating activity. Thalidomide destabilizes TNF-αmessenger RNA, which leads to increased destruction of the transcripts and reduction in TNF-α production. One potential explanation for thalidomide’s antimyeloma activity is inhibition of TNF-mediated NF-κ B activation, which results in increased apoptosis of the MM clone. Thalidomide also has TNF-independent effects on NFκ B; it protects the cytosolic inhibitor of NFκ B (Iκ B) and prevents signal transduction to the nucleus, resulting in a decline in MM growth factors.30,31
Myeloma bone marrow has a high rate of neovascularization, which makes it susceptible to antiangiogenic therapy. Bone marrow microvessel density has been identified as an independent prognostic factor in MM.32 One explanation for the angiogenesis that occurs in MM is the paracrine release of TNF-α by the myeloma clone and bone marrow stromal cells, which leads to the release of angiogenic factors, including vascular endothelial growth factor (VEGF), IL-8, basic fibroblast growth factor, and IL-1, through NF-κ B induction. Thalidomide treatment can reduce bone marrow microvessel density, which may contribute to its antimyeloma activity.
The role of TNF-α inhibition is supported by the observation that TNF-α polymorphisms may predict for thalidomide response in patients with MM.33 High producers of TNF-α had significantly higher response rates and improved survival with thalidomide therapy compared with patients without the hypersecretory phenotype. These results may be explained by inhibition of TNF-α as a required growth factor in patients with the TNF-αhypersecretory phenotype. The authors commented that larger studies are required to confirm and explain these results. Figure 113-1 shows that thalidomide inhibits proliferation and angiogenesis, stimulates T lymphocytes, and modifies the cytokine-secreting ability of bone marrow stromal cells.
Single-agent thalidomide has been extensively evaluated in refractory MM in which it produces overall response rates (including minor responses) in about 30% of patients.34 Although minor and partial responses are the most common types of responses, these end points are associated with improved survival.35
With the activity of thalidomide in refractory MM established, subsequent studies evaluated its activity in newly diagnosed patients and in combination with other therapies, including dexamethasone and chemotherapy. Partial response rates with single-agent thalidomide in untreated patients are about 30% to 40%.36 When dexamethasone is added to thalidomide in untreated patients, response rates (≥PR) increase to about 70% to 80%.37 The higher response rate with thalidomide plus dexamethasone has made this an attractive combination for initial therapy. However, the higher rate of thromboembolism with this combination (15%–20%) when used in newly diagnosed patients is a concern.37,38
The addition of thalidomide to chemotherapy also increases response rates (Table 113-6). Three published randomized controlled trials in newly diagnosed MM showed that the addition of thalidomide to MP improved response.39,40 In the first randomized trial, the overall CR rate with melphalan, prednisone, and thalidomide (MPT) was about 15% compared with 4% with MP. With a median follow-up time of about 3 years, patients in the MPT group had significantly improved PFS but not overall survival.39 The second randomized trial was stopped early because MPT showed clear improvements over the other treatment arm. Results of this trial reported significantly improved median PFS (27.5 vs. 17.8 months) and overall survival (51.6 vs. 33.2 months) with MPT compared with MP.40 A third trial compared MPT with MP in patients older than 75 years of age. Patients on MPT had superior PFS and overall survival at the cost of increased peripheral neuropathy and neutropenia.41 Based on these impressive results, some have previously recommended that MPT be the new standard induction therapy in older patients ineligible for autologous HSCT. However, it is not possible to define a single standard regimen in this setting because of the number of highly active combination regimens and the lack of head-to-head comparative trials. The increased response rate of MPT is at the expense of higher rates of grades 3 and 4 toxicity, particularly venous thromboembolism (VTE), peripheral neuropathy, and infection.40,41
The combination of thalidomide, dexamethasone, and pegylated liposomal doxorubicin produces a high overall response rate of 98% and a complete remission rate of 34%. The major grades 3 and 4 toxicities were VTE (14%) and infection (22%). However, toxicity was acceptable, even in patients older than 65 years of age.42 Although the activity of doxorubicin and thalidomide compares favorably with other combinations, one disadvantage of this regimen is that pegylated liposomal doxorubicin requires IV administration.
Thalidomide dose correlates with response and toxicity. In one large trial of single-agent thalidomide, a higher response rate was observed when more than 42 g of thalidomide was administered over a 3-month period, which is equivalent to a daily dose of about 450 mg.35 As expected, the higher dose was associated with higher rates of thalidomide-related toxicity. When thalidomide is combined with chemotherapy, thalidomide doses of 100 mg/day are associated with high CR rates.39,42,43 Neuropathy, one of the important dose-limiting toxicities, may correlate with cumulative thalidomide doses. Thalidomide-induced neuropathy is usually, but not always, reversible and is associated with demyelinating changes in peripheral neurons. About 10% to 20% of patients are unable to tolerate thalidomide, and neuropathy is often the toxicity associated with discontinuation of therapy.35,41 Unfortunately, no effective methods have been identified to prevent or treat thalidomide-induced neuropathy.
Other common toxicities associated with thalidomide include constipation, sedation, and rash. Although these toxicities can be problematic, they rarely require discontinuation of thalidomide treatment. Stimulant laxatives can be used to prevent severe constipation. The severity of constipation and sedation declines over time in many patients.44
The rate of VTE with single-agent thalidomide is relatively low (<5%) and may not exceed the baseline incidence for MM patients. VTE prophylaxis is not recommended in patients receiving single-agent thalidomide.44 When thalidomide is combined with dexamethasone, MP, or doxorubicin, the risk of thrombosis is elevated. The underlying mechanism for thrombosis in these patients is unknown, but rates in several studies of combination therapy were as high as 10% to 30%.39–41,45 VTE prophylaxis is recommended and potential preventive strategies include therapeutic doses of warfarin, fixed-dose warfarin, low-molecular-weight heparin (LMWH), or aspirin depending on the patient’s risk for VTE. Fixed-dose warfarin and 100 mg aspirin was recently compared with LMWH in MM patients on thalidomide combinations. Fixed-dose warfarin and 100 mg aspirin showed similar efficacy to LMWH in lowering a composite measure of VTE and cardiac events. However, when only grade 3 to 4 VTEs were evaluated, aspirin prophylaxis was similar to LMWH, but fixed-dose warfarin was inferior.46 Warfarin is not a popular choice for VTE prophylaxis because fixed-dose warfarin remains controversial, and therapeutic warfarin is associated with bleeding complications. The evidence suggests low-dose aspirin is effective prophylaxis, but it should be reserved for patients in whom LMWH is not feasible and in whom there is a low to moderate risk of developing VTE.45–47
Bortezomib is a proteasome inhibitor approved for use in newly diagnosed and relapsed or refractory MM. The proteasome is a protease complex responsible for degrading cytosolic proteins that are conjugated to ubiquitin. Ubiquitin is a 8.5-kD polypeptide that tags various proteins for destruction.48 By reversibly binding to the chymotrypsin site in the catalytic core of the 26S proteasome, bortezomib inhibits the degradation of these targeted proteins.
In MM, NF-κ B activity is increased, resulting in increased transcription of inflammatory cytokines such as IL-6 and TNF-α, which are involved in the pathogenesis and progression of MM. In the cytosol, NF-κ B is bound to and inhibited by Iκ B. The proteasome degrades Iκ B. When the proteasome is inhibited with bortezomib, cytosolic concentrations of Iκ B remain high, and NF-κ B is retained in the cytosol as an inactive complex. The resulting inhibition of the NF-κ B signal leads to a reduction in cytokine production and growth inhibition of the MM clone. Other proteins involved in cell-cycle regulation and apoptotic signaling that may be affected by bortezomib include p53, JNK proteins, and caspase 3.48
In phase I studies in patients with refractory hematologic malignancies, bortezomib was administered twice weekly for 2 consecutive weeks followed by 1 week of rest. The responses observed in those studies included a CR in one of eight patients who completed the first course of therapy and minor responses in two patients. These responses were impressive for a phase I trial and confirmed the promising activity in preclinical studies.49
Patients with refractory MM were then enrolled in a phase II trial and received 1.3 mg/m2 of bortezomib twice weekly for 2 weeks followed by 1 week of rest. Patients received up to 8 cycles. The overall response rate was 35% (includes minor responses) with seven (3.6%) patients achieving a CR.50 Based on the phase I and II studies, bortezomib was approved in May 2003 under the Food and Drug Administration’s (FDA’s) accelerated approval process for relapsed or refractory MM in patients who had failed at least two prior therapies.
Subsequently, a large phase III study (Assessment of Proteasome Inhibition for Extending Remissions [APEX] trial) demonstrated that bortezomib had superior activity compared with high-dose dexamethasone in relapsed MM.51 Bortezomib-treated patients had higher complete and partial response rates (38% vs. 18%), longer median time to progression (6.2 vs. 3.5 months), and improved 1-year overall survival (80% vs. 66%) compared with patients receiving dexamethasone. The differences in each of these end points were statistically significant. The results from this study led to expanded FDA approval in 2005 to include patients who had relapsed after one therapy.
Combination therapy with bortezomib has shown promising results in relapsed MM. It was reported that relapsed patients who had suboptimal response to bortezomib alone may respond after the addition of dexamethasone. Subsequent studies reported improved results with the combination of bortezomib and corticosteroids with the CR and nCR rate ranging between 5% and 15%.52 The inclusion of bortezomib in three- to four-drug combinations, which may include doxorubicin, melphalan, thalidomide, and lenalidomide, produce CR and nCR rates of 10% to 50% in relapsed MM.48,52
A number of studies have investigated bortezomib in newly diagnosed patients (Table 113-6). Bortezomib alone produces about a 40% response rate with about 3% of patients obtaining a complete remission. When combined with dexamethasone, the overall response rate increases to about 90% (CR plus PR) with CR rates of 5% to 20%.53,54 In a phase II study of bortezomib combined with MP (MPB) in newly diagnosed elderly MM patients, the overall response rates of 89% and CR rates of 32% are among the highest reported rates with induction therapies.55 Subsequently, MPB was compared with MP in the large phase III VISTA (Velcade as Initial Standard Therapy in multiple myeloma) trial. The overall response and CR rates, time to progression, and overall survival were significantly better in the MPB group. Based on these results, bortezomib received FDA approval in 2008 as first-line therapy in newly diagnosed patients with MM. The improvement in response came at the expense of greater serious adverse effects, including neuropathy, gastrointestinal toxicity, and herpes zoster. However, treatment-related mortality was not different between MPB and MP groups.56 An update of this study reported a continued survival benefit after 5 years of follow-up.57
Bortezomib can cause significant toxicity, the most common being mild to moderate fatigue and gastrointestinal toxicities. Neuropathy occurs frequently and is the most common cause of discontinuation of therapy. In the VISTA trial, the rate of neuropathy was 44% in the MPB group versus 5% in the MP group.56 However, the MPB and MP groups had similar rates of therapy discontinuation at about 15%. Other important toxicities included thrombocytopenia, fever, neutropenia, and infection. An increased risk of shingles has been reported in bortezomib-treated patients, and the NCCN guidelines recommend that herpes zoster prophylaxis be considered.23 VTE prophylaxis is not required with bortezomib when it is combined with MP based on the results of the VISTA trial, which reported low rates of VTE and nearly identical rates in the MPB versus MP group.56
Bortezomib plus dexamethasone has more recently been added to cyclophosphamide or lenalidomide, resulting in high response rates and improved PFS.25 The use of bortezomib has become more convenient with the new subcutaneous regimens.58 In a phase III trial in relapsed MM, therapeutic equivalence was found between IV and subcutaneous routes of administration.58,59 In addition, subcutaneous administration offers the potential advantage of administration in patients without IV access and perhaps improved safety profile, particularly less peripheral neuropathy.
Lenalidomide is a thalidomide analog that shares a similar mechanism of action with thalidomide but is significantly more potent. Because of differences in the toxicity profile compared with thalidomide, the use of lenalidomide has increased. In phase I studies, patients with relapsed, refractory MM were found to have a maximum tolerated dose of lenalidomide of 25 mg/day, and this dose was the most commonly used dose in subsequent phase II and III studies.60
The addition of lenalidomide to high-dose dexamethasone has been shown to increase response rate and prolong survival in patients with relapsed MM. In 2006, lenalidomide received FDA approval in relapsed-refractory MM based on the results of two randomized controlled trials.61,62 One trial was conducted in North America, and the other trial was conducted outside of North America. In both trials, patients were randomized to receive a combination of either lenalidomide (25 mg/day on days 1 to 21 of a 28-day cycle) and high-dose dexamethasone or an identical lenalidomide placebo and high-dose dexamethasone. In the North American trial, patients in the lenalidomide and dexamethasone group had overall and CR rates of 61% and 14% compared with 20% and 0.6% in the dexamethasone alone group (P < 0.001).61 These improved response rates translated into longer median overall survival time in the lenalidomide and dexamethasone group (29.6 vs. 20.5 months). Similar results were reported in the trial conducted outside of the United States.62
Lenalidomide has been extensively studied as initial therapy in newly diagnosed MM (Table 113-6). Preliminary results of phase I and phase II studies of lenalidomide plus dexamethasone report an overall response rate of 90% and a CR rate of 18%.63 These rates may be higher than those reported with thalidomide plus dexamethasone. Lenalidomide causes less neurotoxicity and constipation but more myelosuppression than thalidomide.64 When used as part of combination therapy, the risk of VTE with lenalidomide is similar to that observed with thalidomide, and VTE prophylaxis is recommended. Results from a phase III trial in newly diagnosed MM reported that patients randomized to lenalidomide plus high-dose dexamethasone had a 26% incidence of VTE compared with a 12% rate in those randomized to the lenalidomide plus low-dose dexamethasone arm.65,66 That trial also reported a superior 2-year overall survival rate in the lenalidomide plus low-dose dexamethasone group (87% vs. 75%), and this regimen could become the new standard induction regimen for older patients ineligible for autologous HSCT. The improved survival in the low-dose dexamethasone arm is related to lower mortality from adverse events, particularly VTE. Excess deaths in the high-dose dexamethasone group usually occurred in the first 4 months and in elderly patients. The low risk of VTE in the lenalidomide plus low-dose dexamethasone arm may allow for VTE prophylaxis with low-dose aspirin alone.65,66 These results have led to a category 1 NCCN recommendation in MM patients not eligible for transplant.23
Carfilzomib is the first second-generation proteasome inhibitor to receive accelerated approval from the FDA in July 2012 as treatment for patients with MM who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy.
The schedules for administration of carfilzomib are based on the results of preclinical and phase I and II studies and are different from those for bortezomib. Based on studies in preclinical murine models, which showed more potent, yet tolerable, proteasome inhibition with two consecutive daily doses, carfilzomib entered phase I clinical testing with two schedules: 5 consecutive days of 14-day cycle and 2 consecutive days weekly of a 28-day cycle.67–69The schedule that used 2 consecutive days of dosing showed better tolerability and allowed increases in carfilzomib doses. A subsequent multivariate analysis of three phase II trials showed a dose–response relationship in MM patients. The initial study used a 20 mg/m2 fixed dose in every cycle and showed fourfold less response when compared with increasing to 27 mg/m2 in the following cycle in patients who could tolerate the initial dose.70Collectively, subsequent clinical trials have generally adopted the administration schedule of day 1, 2, 8, 9, 15, 16, 22, and 23 of 28-day cycles with carfilzomib, starting at 20 mg/m2 IV over 2 to 10 minutes on the first cycle/week and increased to 27 mg/m2 or more afterward depending on tolerability. In addition, the results from phase Ib/II studies showed that prolonged infusion (30 min) is better tolerated and that the carfilzomib dose can be increased up to 56 mg/m2.71
The most mature safety data for carfilzomib comes from the compiled results of three phase II studies. The most frequently reported adverse events included fatigue (55%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%). The most common grade 3 or greater adverse events were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), pneumonia (11%), and neutropenia (10%). Grade 2 elevation of creatinine was reported in 25% of patients and was improved with the use of hydration and dexamethasone as premedication. Most of these events were manageable.72
The single-agent activity of carfilzomib is based on phase II studies of 266 relapsed and refractory MM patients who had received a median of five previous therapies.73 Patients received carfilzomib 20 mg/m2IV over 2 to 10 minutes twice weekly on 2 consecutive days with dexamethasone premedication for 3 of 4 weeks in cycle 1 and then 27 mg/m2 in subsequent cycles until disease progression, unacceptable toxicity, or completion of a maximum of 12 cycles. The primary end point of overall response rate (≥PR) was 22.9%, and the median duration of response was 7.8 months (95% confidence interval [CI] 5.6–9.2 months). In patients who were refractory or intolerant to both bortezomib and lenalidomide, 37% obtained clinical benefit. In patients refractory to both bortezomib and lenalidomide, the overall response rate (≥PR) was 15.4%. Moreover, unfavorable cytogenetic characteristics did not appear to adversely impact response rates. The median overall survival time was 15.6 months compared with the median of 9 months typically seen in this setting. An additional large multicenter trial in relapsed/refractory MM patients investigated variable dosing in bortezomib-naïve patients and those previously treated with bortezomib; the overall response rate reported as 52.2% in bortezomib-naïve patients in the 20/27 mg/m2 dose cohort.74 Importantly, these studies demonstrated that carfilzomib had a rapid time to response (0.5–1.0 months).74,75
The activity of carfilzomib combination regimens as first-line treatment is impressive. A phase I/II study of carfilzomib in combination with lenalidomide and dexamethasone enrolled 53 newly diagnosed patients treated with carfilzomib 20, 20/27, or 20/36 mg/m2 in phase I and expansion to phase II at a 20/36 mg/m2 dose.76 The overall response rate (≥PR) was 94%. The responses were rapid and increased in depth with additional cycles of therapy, with 62% and 42% of patients achieving a CR and sCR, respectively. In 36 patients who completed induction, 78% reached at least nCR and 61% sCR. At a median follow-up time of 13 months, the estimated 24-month PFS was 92%. The three-drug regimen did not adversely affect stem cell collection, but was associated with peripheral neuropathy, which was predominately grade 1 or 2 and observed in 23% of patients.
Three randomized phase III trials are ongoing in relapsed myeloma. The CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma (ASPIRE) trial compares lenalidomide and dexamethasone with lenalidomide, dexamethasone, and carfilzomib; the CarFilzOmib for AdvanCed Refractory MUltiple Myeloma European Study (FOCUS) trial compares carfilzomib monotherapy to best supportive care; and the RandomizEd, OpeNLabel, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients with Relapsed Multiple Myeloma (ENDEAVOR) trial compares carfilzomib and dexamethasone with bortezomib and dexamethasone.
Drugs in Development
Pomalidomide is the newest in the immunomodulatory class of antimyeloma drugs. It was recently granted accelerated approval by the FDA in relapsed MM. In a phase II trial, the combination of pomalidomide with dexamethasone produced good overall response rates (35%) in heavily pretreated relapsed and refractory MM. Toxicity profile was reasonable and consisted mainly of manageable myelosuppression. Pomalidomide is currently being evaluated in phase III trials.77
Recommendations for Initial Therapy
The Mayo Clinic Guidelines uses a risk-adapted approach that categorizes patients into risk groups based on cytogenetics and gene expression profiling. In high-risk patients, the combination of bortezomib, lenalidomide, and dexamethasone is recommended as induction therapy.25 In intermediate-risk patients, the combination of bortezomib, cyclophosphamide, and dexamethasone is recommended as induction therapy. In both high- and intermediate-risk patients, induction therapy for 4 months is recommended in transplant-eligible patients and for 1 year in transplant-ineligible patients. In the largest group, standard-risk patients, lenalidomide and low-dose dexamethasone or bortezomib, cyclophosphamide, and dexamethasone are recommended for 4 cycles in transplant-eligible patients followed by transplant, but transplant can be delayed depending on patient preference. Transplant-ineligible standard-risk patients should receive lenalidomide and low-dose dexamethasone, with dexamethasone dose reduction or discontinuation after 1 year Other options for induction therapy in these patients is MPT or a bortezomib-based regimen (in patients with renal insufficiency). Many patients receive maintenance therapy with bortezomib or lenalidomide after transplant (in transplant-eligible patients) or induction therapy (in transplant-ineligible patients).
Initial therapy in the NCCN guidelines is based on transplant eligibility. In patients ineligible for autologous HSCT, thalidomide, lenalidomide, or bortezomib is added to chemotherapy as initial therapy. MP forms the backbone to which these newer drugs are added if the patient is not a candidate for autologous HSCT. As previously discussed, MPT produces high response rates, and MPB produce equal or better results.37 Based on the results of phase III trials demonstrating superiority of MPT over MP, many suggested that MPT was the preferred induction regimen in patients who were ineligible for autologous HSCT. However, the results of the VISTA trial, the continuous lenalidomide trial, in which MPL induction is followed by lenalidomide maintenance, and a phase II trial comparing MP with MPL in newly diagnosed patients supports the addition of MPB and MPL as two additional preferred induction regimens.56,78,79 MPB, MPL, and MPT are listed as NCCN category 1 recommendations.23 Bortezomib-containing regimens (i.e., MPB) may be particularly useful in MM patients with high-risk cytogenetics (t(4;14), 17p-). The preferred combination (MPT, MPB, or MPL) is currently unclear and will require randomized controlled trials that compare these combinations. Carfilzomib-based therapy will have an important role in heavily pretreated refractory MM and is being evaluated in ongoing phase III trials as induction therapy for newly diagnosed MM patients.
If autologous HSCT is planned after induction therapy, melphalan should be avoided, and thalidomide, bortezomib, or lenalidomide can be added to dexamethasone or VAD-like chemotherapy. The NCCN guidelines list several induction therapy options (Table 113-2). Because there is no standard induction regimen, clinicians can select from a wide range of possible induction regimens.29 Many clinicians recommend lenalidomide or bortezomib and dexamethasone as two-drug induction regimens or bortezomib, dexamethasone, and either cyclophosphamide, doxorubicin, or lenalidomide as three-drug regimens for patients who are autologous HSCT candidates.
Patients with high-risk cytogenetics may benefit from bortezomib-containing induction regimens because of its activity in these high-risk patients.14,25 Because patients with high-risk cytogenetics may have poorer outcomes after autologous HSCT, bortezomib-containing regimens should be considered in this group of patients.14,25
Novel agents, such as thalidomide, bortezomib, and lenalidomide, are now routinely used in combination with dexamethasone or chemotherapy as induction therapy. There is no standard induction therapy, and decisions are made based on physician preference and individual characteristics of the patient. Some experts recommend a risk-adapted approach that tailors the treatment-based cytogenetics and gene expression profiling.
Autologous Hematopoietic Stem Cell Transplantation
Although MM is a chemosensitive tumor with significant response rates after treatment with conventional chemotherapy, CR rates have historically been low, and response durations have been short. In an attempt to improve outcomes with chemotherapy, high-dose chemotherapy regimens with stem cell support have been used after initial induction therapy. The intent of the induction therapy before transplant is to reduce tumor burden. With the newer combinations being used as induction, higher rates of quality responses (CR, VGPR, nCR) can be obtained, and recent data suggest that obtaining quality responses during induction improves the outcomes associated with autologous HSCT.80
Several well-designed, randomized, controlled trials have evaluated the role of high-dose chemotherapy followed by autologous HSCT. In these trials, previously untreated patients were randomized to induction therapy alone versus the same induction therapy followed by high-dose chemotherapy and autologous HSCT. The results generally showed that autologous HSCT improved PFS with a more variable effect on overall survival.81–83 No survival plateau was observed in the group treated with autologous HSCT, which suggests that few, if any, patients are cured of their disease. Despite this variable effect on overall survival, MM has become the leading indication for autologous HSCT in the United States.
A systematic review of autologous HSCT in newly diagnosed MM was published in 2007.83 The review pooled results from nine studies comprising 2,411 patients randomized to either autologous HSCT or standard-dose chemotherapy. The combined hazard ratio for overall survival with autologous HSCT was 0.92 (95% CI, 0.74–1.13) and for PFS was 0.75 (95% CI, 0.59–0.96). These results indicate that high-dose therapy with autologous HSCT significantly improves PFS but does not significantly improve overall survival. This benefit in PFS was at the risk of greater transplant-related mortality. Patients who received autologous HSCT had a threefold higher risk of treatment-related death compared with conventional dose chemotherapy. The authors concluded that for every 26 patients who received a transplant, there would be one excess death from autologous HSCT compared with conventional chemotherapy. It should be noted that these trials used an induction of VAD or VAD-like chemotherapy, which is inferior to the modern induction therapies described previously.
Two of the randomized trials comparing autologous HSCT with standard therapy in newly diagnosed MM included in the systematic review were updated and illustrate the divergent results seen with autologous HSCT. Barlogie et al. reported that PFS and overall survival were equivalent between the high- and conventional-dose groups.84 This is different than the conclusions of the systematic review, which reported a significant improvement in PFS. The contrary results of this study may be due to the use of total-body irradiation plus melphalan rather than the more commonly used high-dose melphalan alone. However, several other studies that used total-body irradiation in addition to melphalan have reported variable results, which suggest that the differences in the preparative regimen do not fully explain these negative results. In the second updated study, Fermand et al. reported a benefit in event-free survival (EFS) but no benefit in overall survival. These results were consistent with the systematic review. This study used standard high-dose melphalan and compared it with conventional therapy in previously untreated patients.85
Although the use of autologous HSCT as consolidation therapy has become standard of care in patients younger than age 65 years, it is associated with higher treatment-related mortality, and there is no convincing evidence that it improves overall survival. The widespread adoption of autologous HSCT as standard therapy is related to the significant improvement in PFS. But as conventional therapy continues to improve, response rates, PFS, and overall survival may equal or exceed results seen with autologous HSCT perhaps without the risk of transplant-related mortality.86
The role of autologous HSCT as consolidation therapy has been questioned because newer combinations produce results similar to transplantation with lower risk of mortality. However, many investigators continue to believe that the use of autologous HSCT as a scheduled sequential therapy after induction therapy is a logical approach to treating MM and offers the patient the greatest chance of prolonged PFS.
Induction regimens containing at least one of the novel agents may make a significant difference in outcomes after autologous HSCT.87 Also, the use of these novel agents in induction may reduce the number of patients who require a second transplant because of the higher proportion of patients achieving major responses (CR, nCR, or VGPR) after the combination of novel induction regimen and the first transplant. A randomized phase III trial performed by the French group compared bortezomib in combination with dexamethasone with VAD as induction before autologous HSCT.88 Patients were randomized to one of four arms, which included either bortezomib plus dexamethasone or VAD. All arms underwent autologous HSCT with melphalan preparation (200 mg/m2). Postinduction CR and nCR rates were 15% in the bortezomib-containing arms compared to 6% in those receiving VAD. PFS was superior in the patients in whom autologous HSCT was preceded by bortezomib plus dexamethasone induction. Also, the proportion of patients requiring a second transplant was significantly lower in the bortezomib plus dexamethasone arm because of the higher rates of acquiring at least a VGPR in the bortezomib plus dexamethasone group. Two other studies that used bortezomib-based induction before autologous HSCT showed similar benefit.87
Most patients are treated with autologous HSCT as consolidation therapy after a short course of induction chemotherapy. However, a smaller number of patients receive autologous HSCT as salvage therapy after patients have failed conventional treatments. A study in the early 1990s compared autologous HSCT with chemotherapy in previously treated MM patients.89 The results of that study showed that high-dose therapy was no better than VAD alone. However, other studies reported benefit from autologous HSCT in both primary treatment failures and relapsed MM.90,91 The NCCN guidelines list autologous HSCT as one of the acceptable options in the salvage setting. Responses to autologous HSCT in the salvage setting can occur even in patients who have relapsed after prior successful autologous HSCT.23
The optimal timing of autologous HSCT (early vs. late) in MM was investigated in a randomized controlled trial. Patients were randomized to early (n = 91) or late transplantation (n = 94), and no significant difference in 5-year overall survival was observed between the groups.92 EFS, however, was significantly longer in the early transplantation group (39 months vs. 13 months). In an analysis that factors in the time without symptoms, treatment, or treatment toxicity (TWisTT), patients receiving early transplantation had a longer time in a state associated with good quality of life (27.8 vs. 22.3 months). The results of this study support early autologous HSCT because of its effects on EFS and quality of life. The often long period of disease response after autologous HSCT without ongoing treatment must be considered as newer combinations are considered as upfront therapy to replace autologous HSCT. Although these new combinations may produce equivalent responses, they require prolonged treatment, which may lead to decline in quality of life and can make these therapies more expensive than autologous HSCT.
A specialized form of autologous HSCT, tandem transplantation, involves the use of two separate autologous HSCT procedures separated by a rest period of several months. In a meta-analysis, six randomized controlled trials (N= 1,803) were included, and the authors concluded that although overall response was superior with tandem transplant, overall survival was not superior compared with single transplant. Higher transplant-related mortality was observed in patients receiving tandem transplant.93
Transplant-related mortality is generally low for autologous HSCT but is higher in patients receiving tandem transplants (2.7% vs. 4.8%). About 10% to 15% of patients who did not achieve a CR with the first transplant attained it with the second transplant.94 Because of this increased risk of mortality with tandem transplants, it would be helpful to identify patients who would benefit most from the second transplant. Two French studies reported that patients who did not achieve at least a VGPR after the first transplant benefited most from the second transplant.95,96 One of these studies reported an estimated 7-year overall survival rate of 21% in the single-transplant arm and a 42% survival rate in the double-transplant arm.95
The primary conclusion from the current data on autologous HSCT as consolidation therapy in MM is that it should be used in younger patients with good performance status. Before transplant, all patients should receive induction therapy to reduce tumor burden. Because of higher transplant-related mortality, a second autologous HSCT should only be considered in patients who do not achieve a VGPR or better with the first autologous HSCT. However, a recent systematic review concluded that the evidence is sufficiently biased that no conclusion can be made regarding tandem versus single transplants. It is further limited by the fact that none of the trials used modern induction regimens. Definitive recommendations on tandem transplant will require well-designed trials that limit selection bias and use modern induction regimens.97
Because of the controversy surrounding the potential value of upfront autologous HSCT in an era of novel induction therapy, some experts recommend a risk-adapted approach to treatment. For example, the Mayo Clinic categorizes newly diagnosed patients as high risk, intermediate risk, or standard risk based on cytogenetics and gene expression profiling of the malignant clone. Transplant-eligible intermediate- and high-risk patients are offered autologous HSCT after bortezomib-based induction therapy, while standard-risk patients are given the option of autologous HSCT followed by maintenance therapy or induction followed by maintenance therapy.25
Even with the advances in induction therapy and autologous HSCT, most patients eventually progress within 3 to 5 years, suggesting that effective maintenance therapy is needed to control or delay disease progression. The International Myeloma Working Group has published a consensus document on maintenance therapy in MM.98
Historically, variable efficacy and high toxicities have been reported with interferon-α (IFN-α) and dexamethasone maintenance, and neither drug can be recommended outside of a clinical trial.23 IFN-α at one time was considered to be maintenance of choice after autologous HSCT based on data from a randomized trial showing superior PFS and overall survival after autologous HSCT.99 A meta-analysis supports the benefit of IFN-α maintenance, but the benefit is limited by high toxicity and intolerance.100 A randomized trial conducted by the Southwest Oncology Group evaluated the benefit of prednisone maintenance therapy in 125 patients.101 Patients who received high-dose steroids had significantly longer PFS and overall survival but similar to IFN-α at the expense of high toxicity. Although IFN-α or corticosteroid maintenance has not been widely adopted because of toxicity, these therapies served as proof of principle and led to trials evaluating thalidomide, lenalidomide, and bortezomib.
Thalidomide has been studied as maintenance after autologous HSCT. Results of three separate phase III studies showed that thalidomide improves overall survival. In the largest study, 597 patients were randomized to receive no maintenance, pamidronate alone, or the combination of thalidomide plus pamidronate. Patients randomized to the thalidomide plus pamidronate group had significantly longer event-free and overall survival compared with those who received no thalidomide.102 The median duration of thalidomide maintenance was 15 months, and the average dose was 200 mg/day. Nearly 40% of patients had to discontinue thalidomide as a consequence of toxicity. In a subgroup analysis, patients with deletion of chromosome 13 did not benefit, and other maintenance therapies need to be evaluated for this high-risk group. This effect of adverse cytogenetics predicting nonresponse to thalidomide maintenance was recently confirmed in a randomized study and accompanying meta-analysis.103
In another approach, investigators at the University of Arkansas used thalidomide in both induction and maintenance as part of the Total Therapy II trial.104 Thalidomide increased CR and VGPR rates. In addition, EFS was improved in the thalidomide arm, including patients with adverse cytogenetics. The differences between the Arkansas group and other groups regarding response in patients with adverse cytogenetics may be related to different approaches to cytogenetic and molecular risk assessment. This group indicated that outcome with thalidomide was not related to cumulative dose, which may allow clinicians to limit the duration of thalidomide therapy and therefore reduce toxicity.104
Thalidomide maintenance has also been used after induction in elderly patients who were not candidates for autologous HSCT. The results in this setting are not clear and remain controversial. Despite evidence that thalidomide maintenance after autologous HSCT can improve outcomes, it is not widely used because of the adverse toxicity profile.105
Lenalidomide has largely replaced thalidomide as maintenance therapy because it is better tolerated than thalidomide. Two recently published randomized trials have investigated the use of lenalidomide maintenance after autologous HSCT. Both trials reported a significant improvement in PFS with lenalidomide maintenance compared with placebo.106,107 Although lenalidomide was well tolerated, a significant increase in secondary malignancies was observed in the lenalidomide maintenance arm compared with placebo. In patients who are not candidates for autologous HSCT, lenalidomide maintenance has also been shown to improve PFS and was relatively well tolerated in this older group of patients.79
Bortezomib maintenance after autologous HSCT has been studied and compared with thalidomide maintenance, but interpretation of the data is complicated by the use of different induction therapies in the thalidomide (VAD) and bortezomib (PAD) maintenance arms.108 The study did report a significant improvement in response rates in the bortezomib induction and maintenance arm compared with thalidomide induction and maintenance. Bortezomib was better tolerated than thalidomide, with 30% of the thalidomide group stopping therapy because of intolerance compared with 11% in the bortezomib group. The use of bortezomib maintenance in patients who are not candidates for autologous HSCT has not been extensively studied. Preliminary data indicate significantly improved response rates with bortezomib maintenance after the use of bortezomib-containing induction.
In summary, the NCCN guidelines do not strongly recommend the use of dexamethasone or IFN-α maintenance (category 2B). Thalidomide maintenance is given a category 1 recommendation in the NCCN guidelines, but it does not have a favorable adverse effect profile.23 Lenalidomide maintenance is given a category 1 recommendation, both in patients who undergo autologous HSCT and those who are not transplant eligible. Bortezomib maintenance received a category 2A recommendation in both transplant-eligible and -ineligible patients. Both lenalidomide and bortezomib are relatively well tolerated. However, the clinical benefits of maintenance must be weighed against the risk of secondary malignancies for lenalidomide and infections for bortezomib.23,109
The Mayo Clinic guidelines recommend bortezomib-based maintenance in high- and intermediate-risk patients regardless of their eligibility for autologous HSCT.25 Lenalidomide maintenance should be considered in standard-risk patients after autologous HSCT for a maximum of 2 years.
Allogeneic Hematopoietic Stem Cell Transplantation
Allogeneic HSCT uses a stem cell source other than the patient him- or herself and is therefore a transplant across immunologic barriers. The major posttransplant complications associated with transplanting across these barriers are graft failure and acute and chronic graft-versus-host disease (GVHD). Acute or chronic GVHD may be associated with a graft-versus-myeloma effect. The graft-versus-myeloma effect, which is mediated by antitumor effector cells from the GVHD reaction, reduces relapse risk and may offer the patient the best chance for long-term disease-free survival.110 Unlike autologous HSCT, which is simply a method of increasing the dose intensity of chemotherapy, allogeneic HSCT is a form of immune therapy. This is best illustrated by nonmyeloablative allogeneic HSCT in which reduced-intensity preparation provides immunosuppression, so the graft is not rejected, but little or no antitumor activity yet long-term disease-free survival can be achieved as a result of graft-versus-tumor effect.111
Despite data reporting lower relapse rates in MM patients, myeloablative allogeneic HSCT is associated with high transplant-related mortality rates (20%–50%), leading to overall survival rates similar to those for autologous HSCT.111 The reasons for the high transplant-related mortality rates in allogeneic HSCT are not entirely clear. One possible explanation is that MM patients come to transplantation heavily pretreated, at an older age, and with greater existing organ damage compared with patients with other cancers. However, a study was closed prematurely in MM patients younger than 55 years of age with minimal pretreatment because of an unacceptably high transplant-related mortality rate (∼50%), suggesting that these explanations do not completely account for the high mortality rate.94
With the high transplant-related mortality rate associated with myeloablative allogeneic HSCT, the use of nonmyeloablative allogeneic HSCT is an attractive option to reduce early posttransplant mortality. Two conclusions can be made based on the available data regarding the use of nonmyeloablative allogeneic HSCT in MM patients. First, the transplant-related mortality rate associated with nonmyeloablative allogeneic HSCT is lower than that reported with myeloablative allogeneic HSCT. Second, the cytoreductive activity of the reduced-intensity preparation may be insufficient for the graft-versus-myeloma effect to have its full impact. Most immune therapies, including the graft-versus-myeloma reaction, are most effective when patients have minimal residual disease, and nonmyeloablative allogeneic HSCT may have insufficient antitumor activity to achieve important tumor reduction. The need for cytoreduction may be accomplished by autologous HSCT preceding the reduced-intensity allogeneic HSCT procedure. The trials investigating this novel approach have produced conflicting results. These studies compared tandem autologous HSCT with single autologous HSCT followed by reduced-intensity allogeneic HSCT. Three trials reported no differences in event-free or overall survival between tandem autologous HSCT and single autologous HSCT followed by reduced-intensity allogeneic HSCT.112–114Other trials reported significantly improved event-free and overall survival when autologous HSCT was combined with reduced-intensity allogeneic HSCT.115,116 The conflicting results of these various trials may relate to the inclusion of particularly high-risk patients and the use of more aggressive immunosuppression in the negative trials. In most of the trials, the transplant-related mortality rate was higher in the combined autologous HSCT and reduced-intensity allogeneic HSCT arm compared with tandem autologous HSCT. Because of the variability of these results, the combined use of autologous and allogeneic HSCT should only be performed as part of an investigational protocol.
Along with anti-MM therapy, supportive care measures are aggressively used to stabilize skeletal abnormalities. Bisphosphonates have been used for more than a decade in the management of MM. The clinical benefits of bisphosphonates must be weighed against some of the serious adverse events such as osteonecrosis of the jaw (ONJ) and renal failure.
Bisphosphonates have a major role in the treatment of bone-related complications associated with MM. Bone resorption is a manifestation of the disease process and is mediated in part by inflammatory molecules, including IL-6, IL-1, and TNF-α.1 Bone disease is not seen in MGUS but occurs in about 80% of MM patients at diagnosis. Although the classic cytokine mediators of bone loss are important, a newer view involves excessive production of RANK-L, which activates NF-κ B through receptor activator of nuclear factor-κB (RANK).117 As previously stated, NF-κ B is a transcriptional regulator that increases the production of various inflammatory molecules. Normally, RANK-L–mediated activation is in equilibrium with osteoprotegerin, which inhibits NF-κ B activation by serving as a decoy receptor for RANK-L.117 In the bone marrow of MM patients, excess RANK-L is produced particularly from stromal cells, which, when coupled with a decline in osteoprotegerin from both stromal cells and osteoblasts, leads to osteoclast activation and bone destruction. Macrophage inflammatory protein α1, macrophage colony-stimulating factor, and VEGF may also play important roles in MM bone disease by stimulating the production and activation of osteoclasts.118 Macrophage inflammatory protein α1 is also an important chemotactic factor released by MM cells; it attracts osteoclast precursors, enabling myeloma cells to influence the maturation and activation of osteoclasts, which suggests that antimyeloma drugs, particularly lenalidomide and bortezomib, can have a beneficial effect on MM bone disease.119Although MM bone disease may involve many cell types and many soluble and cell-bound molecules, it is useful to simplify its pathophysiology and consider it to be an imbalance between RANK-L and osteoprotegerin.
Activation of osteoclasts leads to a net loss of bone mass and to many of the common clinical features of MM, including fractures, hypercalcemia, and bone pain. The bone resorption is influenced by the MM cells in proximity to the osteolytic lesions and is associated with recruitment of osteoclasts.120 The disruptive effect on skeletal integrity can lead to direct mortality but more commonly has a major impact on morbidity and quality of life.
Bisphosphonates are analogs of endogenous pyrophosphate but are more resistant to hydrolysis than pyrophosphate. Similar to endogenous pyrophosphate, the bisphosphonates bind to crystalline calcium in the bone and are then phagocytized by osteoclasts.121 The best described effect of the bisphosphonates is the inhibition of osteoclast activity, which likely occurs by direct osteoclast cytotoxicity.122 In addition to osteoclast inhibition, bisphosphonates may also promote apoptosis in MM cells. This effect may result from the inhibition of the mevalonic acid pathway, which produces several molecules required for growth of the MM clone.123 In addition, other potential antimyeloma effects of bisphosphonates may include modifying the cytokine microenvironment, inhibiting the adhesion of MM cells to bone marrow matrix cells, and inhibiting angiogenesis.124 Although it is possible that bisphosphonates have an antimyeloma effect, there is little direct clinical evidence to support this activity.
The use of bisphosphonates in MM is based on the results of several large, randomized, controlled trials. In the pamidronate study, the drug was compared with placebo in a group of MM patients undergoing their first or second course of chemotherapy.125 Several clinical end points were found to be positively impacted by pamidronate therapy. The investigators reported that patients in the pamidronate group had a lower risk of skeletal-related events, lower pain scores, and improved quality of life. Importantly, a survival advantage was observed in the pamidronate-treated patients who had already received one or more courses of antimyeloma chemotherapy. This finding of improved survival in subgroup analysis is part of the circumstantial evidence to propose an antimyeloma effect for the bisphosphonates.
Guidelines for the use of zoledronic acid in MM are based partly on a randomized study in MM and breast cancer. In patients with bone metastases, zoledronic acid was compared with pamidronate with the intent of demonstrating clinical equipoise.126 The study did show equivalence between pamidronate and zoledronic acid. The lack of a placebo arm because of ethical concerns complicates interpretation of this study. Despite this limitation, pamidronate and zoledronic acid appear to have equivalent clinical benefit in stabilizing the skeleton.
Other randomized, controlled trials have been conducted, and the results of these trials were pooled in a recent systematic review.127 Twenty randomized trials were included, which accounted for 6,692 MM patients. The risk of vertebral fractures and pain was significantly lower in the bisphosphonate-treated patients, and there was no difference between zolendronic acid or pamidronate. Given that the aggregate data in the systematic review agreed with the large controlled studies described earlier, the effect on vertebral fractures and pain are well-supported benefits of bisphosphonate therapy. An overall survival benefit associated with bisphosphonate use in MM patients remains unclear, but this meta-analysis reported that zolendronic acid improved overall survival compared with placebo. In a recent randomized controlled trial comparing zolendronic and clodronate, there was a 16% reduction in mortality rate in the zolendronic arm which may suggest an antimyeloma effect associated with zolendronic acid.128,129
Osteonecrosis of the jaw is characterized by an area of exposed necrotic bone and often affects the mandible and the maxilla, but it can also affect the soft palate. Treatment of ONJ involves surgical debridement and antimicrobial therapy and is often suboptimal.130 The development of ONJ may be related to dental disease and tooth extraction and appears to be more common with zoledronic acid than with pamidronate. The incidence of ONJ is unknown but may be as high as 10% in MM patients receiving zoledronic acid for extended periods of time. Because observational studies suggested the risk of ONJ during the first 2 years of pamidronate was low, the Mayo Clinic guidelines in 2006 recommended monthly infusions of pamidronate for 2 years after diagnosis of symptomatic MM.131
A subsequent longitudinal cohort study supported many of the conclusions of the Mayo Clinic recommendations. These investigators concluded that ibandronate and pamidronate were safer alternatives to zolendronic acid and that dental procedures and dentures were risk factors for the development of ONJ. They recommended a comprehensive dental examination with management of dental problems before initiating bisphosphonate therapy but made no recommendation on which agent is preferred.132
A strong recommendation on a preferred bisphosphonate based on ONJ incidence is likely not warranted. A recent meta-analysis found no difference between the bisphosphonate used and the risk of ONJ.127
Pamidronate and zoledronic acid are usually well tolerated. Flulike symptoms can occur after the administration of bisphosphonates. Acute renal impairment can occur with both agents and is related to both infusion time and dose. For zoledronic acid, the risk of acute renal impairment is higher with the 8-mg dose (vs. 4 mg) and when the duration of infusion is 5 minutes (vs. 15 minutes). Patients with moderate renal impairment (creatinine clearance: 30–60 mL/min [0.5–1.0 mL/s]) should have their dose of zoledronic acid adjusted downward by 25% (3 mg). This recommendation was included in the zoledronic acid package insert and is based on a greater renal toxicity in patients with preexisting renal impairment.133 Randomized studies suggest that renal effects are similar between pamidronate and zoledronic acid, and patients on bisphosphonate therapy should have serum creatinine measured at baseline and then periodically thereafter.134
Clinical practice guidelines for the use of bisphosphonates in MM were published in 2007 by an expert panel under the auspices of the American Society of Clinical Oncology Health Services Research Committee.129 The evidence-based guidelines remain relevant and recommend that symptomatic MM patients be placed on bisphosphonate therapy at the time of diagnosis to reduce pain and skeletal-related events and to improve quality of life. No firm recommendation was made on the duration of bisphosphonate therapy and whether pamidronate or zolendronic acid is preferred. However, the expert panel recommended a duration of bisphosphonate use of 2 years in patients with responsive or stable disease. Reinstituting bisphosphonate therapy at relapse or progression is at the discretion of the clinician.
Although the NCCN recommends upfront bisphosphonate therapy in symptomatic MM, many controversies remain, including whether an antimyeloma effect exists; how long patients should remain on this expensive therapy; and, most important, the risk of ONJ.
Although bisphosphonates are indicated in MM patients with bone disease, controversies surrounding the selection of the best agent and duration of therapy remain. Because of the risk of ONJ in MM patients, a cautious approach on bisphosphonate use is prudent. Some experts recommend that the duration of bisphosphonate therapy should be limited to 2 years. The preference of pamidronate over zoledronic acid is also controversial given that ONJ has also been reported with pamidronate, and the higher risk of ONJ with zoledronic acid is based on observational studies rather than head-to-head randomized comparisons.
Denosumab, a RANK-L antagonist, was recently compared with zolendronic acid in cancer patients with bone metastases, including a relatively small number of MM patients.135 Denosumab was determined to be noninferior with rates of ONJ similar between the two groups. The authors concluded that denosumab was a reasonable therapy in cancer patients with bone disease and required no monitoring of renal function. However, this study was not sufficient evidence for the routine use of denosumab in MM patients given that MM patients were a relatively small subgroup in this study and outcomes were worse in the MM patients receiving denosumab. Although denosumab is FDA approved for use in patients with solid tumors, it is not approved for use in patients with MM.
Relapsed or Refractory Disease
A variety of factors must be considered when determining the most appropriate therapy for an individual who relapses, including the type and duration of previous therapies, presence or absence of adverse prognostic factors, toxicity of prior therapies (e.g., peripheral neuropathy), organ dysfunction (e.g., renal impairment), and how much time has elapsed from initial response to relapse.26 The same drugs used to treat MM initially can also be used as salvage therapy in MM patients who have relapsed. Patients who relapse more than 6 months after initial induction therapy can have that induction therapy repeated.25 Bortezomib is an effective salvage therapy. When bortezomib was compared with high-dose dexamethasone, response rates were 43% versus 18%, respectively.51 The activity of bortezomib in patients with high-risk cytogenetics is particularly useful because high-risk patients are more likely to relapse and require salvage therapy. The addition of dexamethasone to patients who progress on single-agent bortezomib has been shown to improved response.52
The combination of bortezomib and pegylated liposomal doxorubicin is another active regimen in relapsed or refractory MM. In a phase III trial, patients randomized to the bortezomib and pegylated liposomal doxorubicin arm had significantly longer median time to progression (9.3 vs. 6.5 months; hazard ratio = 0.55; 95% CI, 0.43–0.71) and 15-month survival rate (76% vs. 65%) compared with patients randomized to receive bortezomib alone.136 It is interesting to note that the overall (complete and partial) response rate was only slightly higher in the bortezomib and pegylated liposomal doxorubicin group (44% vs. 41%). Based on the results of this study, the combination of bortezomib and pegylated liposomal doxorubicin received FDA approval in 2007 for patients with previously treated MM and is listed as a category 1 recommendation in the NCCN guidelines.23 As expected, patients who received the combination experienced more adverse effects. Prior use of IMiDs or high-dose chemotherapy does not appear to affect bortezomib activity in relapsed MM. A phase III trial reported that bortezomib with or without dexamethasone had activity in relapsed or refractory disease despite prior thalidomide therapy or autologous HSCT.137
Lenalidomide also has received a category 1 recommendation when combined with dexamethasone in relapsed or refractory patients.61,62 The combination of lenalidomide plus dexamethasone increased response rate compared with dexamethasone alone but came at the cost of increased grade 3 and 4 hematologic toxicity. Based on the activity of bortezomib and lenalidomide in the setting of relapsed or refractory disease, a phase II trial of these two novel agents combined with dexamethasone showed good response rates and a relatively good toxicity profile (primarily grade 3 hematologic toxicity).138
As previously discussed, questions remain on the optimal timing for autologous HSCT. For patients who are eligible for autologous HSCT and did not receive transplant as part of initial therapy, it is appropriate to offer autologous HSCT at first relapse. It is important to emphasize that although higher quality of life was realized when autologous HSCT was used as consolidation therapy, there was no difference in overall survival based on timing of transplant.92 The use of salvage autologous HSCT in patients who received a prior autologous HSCT seemed to be most beneficial in patients who had a response of greater than 24 months after initial autologous HSCT.139 In patients with relapsed or refractory MM, autologous HSCT followed by nonmyeloablative allogeneic HSCT has potential benefit but at the expense of increased transplant-related mortality requiring treatment only be performed as part of a clinical protocol.
The treatment of relapsed-refractory patients can be with active agents in combination or single agents used sequentially. With the growing number of highly active agents, combination salvage therapy has become predominant. The NCCN has three category 1 recommendations: single-agent bortezomib, bortezomib plus liposomal doxorubicin, and lenalidomide plus dexamethasone. The combined use of bortezomib with lenalidomide has not yet been given a category 1 recommendation but remains a category 2A recommendation in the NCCN Guidelines.23 Treatment decisions for individual patients with relapsed disease may potentially be improved by taking into account patient-specific information such as the type of previous therapies, adverse cytogenetics, and end-organ dysfunction. For example, in patients with relapsed MM, combined bortezomib and liposomal doxorubicin has shown improved time to progression compared with bortezomib alone, including in patients who had received prior anthracyclines, lenalidomide, and thalidomide.136 In contrast, treatment with lenalidomide and dexamethasone resulted in a significantly shorter time to progression in patients who had previously been treated with thalidomide compared with thalidomide-naïve patients.61,62
Carfilzomib is indicated in patients who have received bortezomib and lenalidomide salvage and have progressive disease. The FDA approval in this group of relapsed or refractory patients was based on a phase II study in patients, 80% of whom were refractory to both bortezomib and lenalidomide, which showed an overall response rate of 25%.23,73 Based on these impressive results, phase III trials comparing carfilzomib combinations with lenalidomide or bortezomib plus dexamethasone in a group of previously treated relapsed MM patients are ongoing. Single-agent carfilzomib is also being compared with supportive care in patients who had received at least three prior therapies.23
Bendamustine is a highly active chemotherapeutic agent in MM with overall response rates in variously treated relapsed patients of 30% to 55%. Toxicity has been largely hematologic and manageable.23Bendamustine has been combined with novel agents to further improve response. Bendamustine was added to lenalidomide and dexamethasone in a phase II trial that reported a more than 50% response rate with nearly half being VGPR.140 The NCCN has given both single agent bendamustine and the bendamustine, lenalidomide, and dexamethasone combination a category 2A recommendation.23
Vorinostat is an inhibitor of histone deacetylase and modifies the expression of genes involved in tumor progression and has good activity in relapsed MM when combined with bortezomib. The results of phase II trials have been encouraging, and the NCCN has given vorinostat and bortezomib combinations a category 2A recommendation in relapsed MM.23,141
The NCCN guidelines offer many options for salvage therapy, including thalidomide, lenalidomide, or bortezomib with or without dexamethasone or chemotherapy (Table 113-7). Newer agents such as ponalidomide, carfilzomib, bendamustine, and vorinostat are being integrated into therapy. In addition, autologous HSCT has a role as salvage therapy.23 Therapy should be selected based on disease and patient risk factors and previous treatment. Despite clear progress, most salvage therapies produce less than a 50% response rate, and new drugs and drug combinations are needed.
TABLE 113-7 Salvage Therapy in Multiple Myeloma
Therapy for MM is personalized based on staging (e.g., ISS), cytogenetics, gene expression profiling, performance status of the patient, age of the patient, and preexisting risk for drug toxicity. Personalized therapy has been driven by the explosion of new treatment options in MM and a better understanding of the MM biology and therapeutic targets. As described previously, the Mayo Clinic recommends a risk-adapted approach that tailors therapy based on risk category (e.g., high, intermediate, or standard).
The use of a risk-adapted approach is reasonable in newly diagnosed patients. MM is currently not curable, and the disease will evolve as the disease progresses, which will require evaluation of biomarkers at times of relapse and progression to tailor therapy in each stage of the disease.
In addition to molecular characteristics of the tumor, a number of patient-related factors guide personalized treatment. For example, older patients with poor performance status would not be candidates for autologous HSCT. Patients with preexisting severe peripheral neuropathy would be less likely to receive thalidomide or bortezomib because of neurotoxicity. Patients with risk factors for VTE would be more likely to receive bortezomib-containing combinations because the risk of VTE is lower compared with thalidomide or lenalidomide combinations. Patients with preexisting renal failure may be less likely to receive lenalidomide because it requires dose adjustment based on renal function. With personalized therapy, patients will have the opportunity to benefit from the use of novel agents.
EVALUATION OF THERAPEUTIC OUTCOMES
Because MM is currently not a curable disease, the goals of therapy are to prolong survival and to improve quality of life. Patients with asymptomatic MM are usually followed and not treated. Asymptomatic patients are assessed every 3 to 6 months for disease progression, which would then require therapy. Assessment involves measurement of M protein in blood and urine and laboratory tests that include complete blood count, serum creatinine, and calcium. Patients are treated as the disease produces symptoms. Disease response is defined by a decline in M protein. After completion of the initial course of therapy and response is obtained, patients should be monitored every 3 months. Bone surveys are performed yearly or as required because of changes in symptoms. Various other tests, including bone marrow biopsy, magnetic resonance imaging, and positron emission tomography, or computed tomography scan, are performed on an as-needed basis to evaluate disease status.
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