Multiple Myeloma
Angela Dispenzieri
Martha Q. Lacy
Shaji Kumar
Multiple myeloma (MM) is a neoplastic plasma cell dyscrasia (PCD) characterized by a clinical pentad: (1) anemia, (2) a monoclonal protein in the serum or urine or both, (3) bone lesions and/or bone pain, (4) hypercalcemia, and (5) renal insufficiency. With the exception of monoclonal gammopathy of undetermined significance (MGUS), it is the most common PCD, with an incidence of about 4.5 per 100,000 per year in the United States. Solitary plasmacytoma and plasma cell leukemia (PCL) are recognized as separate entities and are much less prevalent. The underlying pathogenesis of the plasma cell malignancies is not well understood but is an area of active investigation. At present, according to the WHO (World Health Organization) classification system, there is only one category for MM.1 Results of clinical trials are confounded by this underclassification. Emerging information about the genetic underpinning of the disease, however, will likely change this deficiency.
The interactions among the plasma cells, their antibody product, the local bone and bone marrow environment, and other organs are complex. There is no cure for MM, but there are many effective treatments that prolong and improve the quality of life in patients with the disease.
HISTORY
The Earliest Diagnoses and Diagnostic Methods
Samuel Solley reported the first well-documented case of MM (mollities ossium) in Sarah Newbury in 1844.2, 3 Several years later, William MacIntyre described and recorded the properties of the disease we now call MM in Thomas Alexander McBean.4 Both Drs. MacIntyre and Bence Jones noted and described some of the peculiar urine properties of this same patient. On heating, the urine was found to be “abound in animal matter,” which dissolved on the addition of nitric acid but reappeared after cooling. These urinary proteins became known as Bence Jones proteins.5 MacIntyre and Dalrymple described the post-mortem examination of Mr. McBean’s bones.4 The former described the affected bones as softened and fragile, with their interiors replaced with a soft “gelatinform” blood-red substance. Dalrymple suggested that the disease began in the cancellous bone and extended through the periosteum. The nucleated cells, which formed the bulk of the gelatinous material, were heterogeneous in size and shape, but the majority were round to oval. Many of the larger and more irregular cells frequently contained two or three nuclei.3 The term “multiple myeloma” was coined in 1873 by von Rustizky,6 who independently described a similar patient to emphasize the multiple bone tumors that were present.
In 1889, Professor Otto Kahler7 described a case involving a 46-year-old physician with MM and published a major review of the disease. He described the skeletal pain, albuminuria, pallor, anemia, a precipitable urinary protein, and the findings on necroscopy and linked these findings as part of a clinical syndrome that bears his name (MM has also been referred to as Kahler disease).
In 1898 Weber predicted the usefulness of Roentgen x-rays in establishing the diagnosis3, 8 and later postulated the Bence Jones protein was produced in the bone marrow.9 Wright10 emphasized that MM arose specifically from plasma cells of the marrow, Jacobson11 recognized Bence Jones proteins in the bloodstream, and Walters12 concluded that the Bence Jones protein was probably derived from blood proteins through the action of the abnormal cells in the bone marrow. The technique of bone marrow aspiration13 facilitated the diagnosis of MM.
Serum electrophoresis, described by Tiselius in 1937,14 made it possible to separate serum proteins. Longsworth et al.15 applied electrophoresis to the study of MM and described the tall narrowbased “church spire” peak. The use of filter paper as a support for protein electrophoresis permitted the separation of protein into distinct zones that could be stained with various dyes.16 Paper electrophoresis was supplanted by filter paper in 1957 and most recently by high-resolution electrophoresis on agarose gel. Immunoelectrophoresis17 and immunofixation or direct immunoelectrophoresis18 made it possible to detect small monoclonal light chains not recognizable by electrophoresis. The immunoglobulin free light chain assay has been added to the diagnostic armamentarium to detect circulating free light chains in the majority of patients previously designated nonsecretory.19
Kunkel20 hypothesized that monoclonal proteins were the product of malignant plasma cells and were the equivalent of normal antibodies produced by normal plasma cells. Before 1960, the term “gamma globulin” was used for any protein that migrated in the gamma mobility region of the electrophoretic pattern; however, in 1959, Heremans21 proposed the concept of a family of proteins with antibody activity. In 1961 in a Harvey Lecture,22 Waldenström distinguished between monoclonal and polyclonal hypergammaglobulinemia.
In 1928, Geschickter and Copeland23 reported on the largest case series of MM—13 cases—and reviewed the 412 cases reported in the literature since 1848. They documented a higher incidence in men than women and an overall survival (OS) of about 2 years. They emphasized six features: (1) involvement of the skeletal trunk, (2) pathologic rib fractures, (3) Bence Jones proteinuria in 65% of cases, (4) backache with early paraplegia, (5) anemia in 77% of cases, and (6) chronic renal disease. They did not note abnormalities of blood protein or an increased erythrocyte sedimentation rate.3 In 1931, Magnus-Levy24 described amyloidosis as a complication of MM. Salmon, Durie, and Smith developed methods to quantitate the total body burden of tumor cells25 and to stage patients26 in 1970 and 1975, respectively.
Prior to the discovery in 195027 of salutary effects of adrenocorticotropic hormones on MM (Fig. 98.1), medications used to that point included stibidine and urethane, neither of which had activity upon critical testing.3 During that decade, it was recognized that the adrenocorticotropic hormones cortisone and prednisone were useful agents in patients with MM. Corticosteroids decreased bone pain, improved hypercalcemia, increased hemoglobin values, and decreased abnormal serum and urine globulin concentrations.28 However, it was not until 1967 that high-dose corticosteroids were recognized as effective antineoplastic agents against MM.29
Blokhin et al.30 reported benefits in 3 of 6 patients with MM who were treated with sarcolysin (a racemic mixture of the d– and l-isomers of phenylalanine mustard). Subsequently, the d– and l-isomers were tested separately, and the anti-MM activity was found to reside in the l-isomer, melphalan. Bergsagel et al.31 reported significant improvement in 14 of 24 patients with MM with the use of melphalan; this activity was quickly substantiated by others.32 Similar effectiveness was noted with cyclophosphamide.33 Subsequently, interferon-α (IFN), doxorubicin, carmustine, thalidomide, bortezomib, lenalidomide, bendamustine, and carfilzomib34, 35, 36, 37, 38, 39 have each been reported to have activity as a single agent in MM.
 FIGURE 98.1. Landmark therapeutic innovations. ASCT, autologous stem cell transplant; BCNU, melphalan, cyclophosphamide, and prednisone (M-2 regimen); CCT, conventional chemotherapy; VAD, vincristine, doxorubicin, dexamethasone; VBMCP, vincristine. |
INCIDENCE AND EPIDEMIOLOGY
As described in Chapter 97, recent evidence supports the theory that all MM arises from a preceding MGUS.40 Increasingly it is becoming apparent that there is an increased risk of developing MM or MGUS among first-degree relatives of both MGUS and MM patients.41, 42 Whether this family linkage is due to either genetic susceptibility factors or shared environmental risk factors (or both) is yet to be determined.
Epidemiology of Myeloma
The 2012 annual estimate in the United States for new cases of MM is 21,700 and for deaths is 10,710.43 SEER (Surveillance, Epidemiology, and End Results) data incidence age-adjusted rates from 1992 through 1998 show an overall incidence of 4.5 per 100,000 per year, with the incidence among whites being 4.2 per 100,000 per year and among blacks, 9.3 per 100,000 per year.44 Male-to-female ratio is 1.3 to 1.43 The median age at diagnosis of MM is 71 years. Since the turn of the century, 5-year survival rates in blacks and whites have equalized.43 MM accounts for 1% of all malignancies and 10% of all hematologic malignancies in whites and 20% in African Americans.44 International mortality data reveal that the highest rates of MM occur in Northern Europe, North America, Australia, and New Zealand and the lowest rates are in Japan, Yugoslavia, and Greece.45 Geographic clusters46 and familial clusters47, 48, 49, 50, 51, 52 of MM among first-degree relatives have been documented. Modest increases in MM rates were observed when incidence data from 1973 to 1992 were calculated in nine population-based cancer registries.53 These increases are likely due to a heightened awareness of the disease.
Etiologic Factors
Radiation Exposure
Reports of increased MM incidence and mortality among Japanese atomic bomb survivors have suggested an association between ionizing radiation and MM. Initial evaluations of cancer incidence54 and mortality55 among Japanese atomic bomb survivors suggested an increased risk of MM with increasing radiation dose, an observation that was no longer seen with additional years of follow-up.56 Subsequent data would suggest that the prevalence of MGUS is higher among those younger patients exposed to higher doses of radiation.57
An excess of MM deaths among American radiologists was reported in the 1960s.58 MM risk was considered to be two times higher among radiologists exposed to low doses of radiation than among physicians not exposed to radiation.59 However, among 27,000 Chinese diagnostic radiography workers, no excess incidence of MM was observed in a 30-year period.60 An analysis of 115,000 workers from the combined roster of four different nuclear plants showed a positive association between MM and radiation exposure in older age groups.61 No increases in MM incidence and mortality have been observed among British62 or New Zealand63 military men who participated in atmospheric nuclear weapons testing.
Diagnostic x-ray exposure has not been linked with the development of MM in most epidemiologic studies.64, 65, 66, 67, 68, 69 A large multicenter population-based case-control study showed no evidence of excess risk of MM among individuals who reported exposure for 10 or more diagnostic radiographs.70 One study reported that the overall risk for MM was not high (RR, 1.14), but that there was evidence of increasing risk with exposure to increasing numbers of radiographic procedures.71 Of historic interest is the finding of an association between MM and the use of Thorotrast.65 Studies of the effects of therapeutic irradiation on MM risk have shown conflicting results, but a study of 180,000 women treated for cervical cancer demonstrated no overall excess risk of developing MM.72 Similarly, a study of 14,000 patients suffering from ankylosing spondylitis and treated with radiation revealed no significant increase in the risk of developing MM.73
Workplace Exposures
Several epidemiologic studies have evaluated the risk of MM among agricultural workers, with positive associations reported by many74, 75, 76, 77, 78, 79 but not all of the studies.80, 81, 82 Khuder and Mutgi83 found a relative risk of 1.23 in a meta-analysis of several studies. Workers in various metal occupations and industries have been reported to have an increased MM risk.84, 85, 86
Benzene has been suggested as a possible etiologic agent for MM.87, 88, 89 A comprehensive review of the published literature found no evidence of a link between benzene exposure and MM.90 Subsequently, Sonoda and colleagues91 conducted a meta-analysis of case-control studies and showed no excess risk for the development of MM. A meta-analysis by Wong and Raabe92 of more than 350,000 petroleum workers similarly showed no increased risk.
Cigarette Smoking, Alcohol Consumption, and Diet
Multiple studies to date have found no etiologic role for cigarette smoking or alcohol consumption in the development of MM.93, 94, 95, 96 In contrast, Tavani et al.97 suggested a dietary link for MM and found a higher risk among people consuming large quantities of liver (odds ratio [OR], 2.0) and butter (OR, 2.8), and a lower risk among people consuming large amounts of vegetables (OR, 0.4) No association of MM and consumption of coffee or red meat has been found.97 Brown and colleagues98 looked at diet and nutrition as risk factors for MM among blacks and whites in the United States. Only obesity was associated with increased risk, and obesity was more frequent in black than in white controls. Frequent consumption of cruciferous vegetables, fish, and vitamin C supplements was associated with decreased risk of MM. The authors concluded that the greater use of vitamin C supplements by whites and the higher frequency of obesity among blacks may explain part of the higher incidence of MM among blacks compared with whites in the United States.
Personal use of hair dyes was evaluated as a risk factor for MM,99 including two prospective studies.100, 101 Thun et al.100 found that women using permanent hair dyes are not generally at increased risk of fatal cancer. However, women with prolonged use of dark, particularly black, hair dyes may have increased risk
of fatal non-Hodgkin lymphoma and MM, but these women are a small fraction of hair dye users. A subsequent meta-analysis by Correa et al.102 showed no increased risk.
of fatal non-Hodgkin lymphoma and MM, but these women are a small fraction of hair dye users. A subsequent meta-analysis by Correa et al.102 showed no increased risk.
Socioeconomic Status
Some investigators have reported that there is an inverse relationship between the risk of MM and socioeconomic status,103 and that this inverse correlation may account for a substantial amount of the black and white differential of MM incidence.104 Earlier studies did not show a link between socioeconomic status and MM.105
Chronic Antigenic Stimulation
Repeated or chronic antigenic stimulation of the immune system may lead to MM. Several case-controlled studies have suggested that MM risk is associated with past history of infections, inflammatory conditions, connective tissue disorders, autoimmune illnesses, and allergy-related disorders.94, 106, 107 Patients with the human immunodeficiency virus may have an increased likelihood of developing MM.108, 109 In addition, MM and hepatitis C may be associated.110, 111, 112 The finding of human herpes virus 8 has been suggested as a possible etiologic agent,113 but this has not been confirmed.114, 115, 116, 117 Increased risk for MM has been observed in patients with rheumatoid arthritis.51, 118, 119 Other studies of individuals with these conditions have shown no increased risk of MM.120, 121, 122, 123
CLINICAL MANIFESTATIONS
The symptoms of MM may be nonspecific and include fatigue, bone pain, easy bruisability and bleeding, recurrent infections, manifestations of anemia, hypercalcemia, lytic bone lesions, hyperviscosity, thrombocytopenia, and hypogammaglobulinemia (Fig. 98.2). Weakness, infection, bleeding, and weight loss are reported in as many as 82%, 13%, 13%, and 24% of patients, respectively.124, 125, 126, 127 Hypercalcemia is present in 18% to 30% of patients.124, 125, 126 One to two thirds of patients present with spontaneous bone pain.124, 125, 126 “Tumor fever” is present in less than 1% of presenting patients.
Anemia
The most common clinical feature of MM is anemia. A hemoglobin concentration of less than 120 g/L occurs in 40% to 73% of patients at presentation124, 125, 126 and contributes to the weakness and fatigue observed in as many as 82% of patients.124, 125, 126 The anemia is normochromic, normocytic in most patients, but macrocytosis may be observed as well. When there are high concentrations of serum immunoglobulin, rouleau formation may be observed (Fig. 98.3A). The combination of anemia and hyperproteinemia leads to a marked increase of the erythrocyte sedimentation rate in more than 90% of cases.128
 FIGURE 98.2. Signs and symptoms of 1,027 newly diagnosed myeloma patients seen at the Mayo Clinic from 1985 through 1998. |
The anemia is related partially to direct infiltration and replacement of the bone marrow. Hemoglobin concentration is also correlated directly with the percentage of MM cells in S phase,129 suggesting that the bone marrow cytokine milieu, permissive for MM cell proliferation, is not conducive to efficient erythropoiesis. Cytokines, like tumor necrosis factor-α and IL-1, may inhibit erythropoiesis.130 Fas ligand-mediated erythroid apoptosis is also increased in patients with MM.131 Finally, relative erythropoietin deficiency from MM-induced renal insufficiency also contributes to the observed anemia.
Monoclonal Proteins
The M protein (M component, myeloma protein, or M spike) is a hallmark of the disease; 97% of MM patients have either an intact immunoglobulin or a free light chain that can be detected by protein electrophoresis, immunoelectrophoresis, or immunofixation studies of the serum or urine (Fig. 98.3B,C).124, 126 Those cases without a detectable monoclonal protein have been referred to as nonsecretory MM, which had accounted for approximately 1% to 3% of MM cases. With the immunoglobulin free light chain assay, small free light chain monoclonal proteins heretoforth not seen by aforementioned methods are seen in approximately two thirds of the cases that had been referred to as nonsecretory.19
Historically, monoclonal proteins have had a valuable role in the fields of immunology and molecular biology, for distinguishing MGUS from MM and for calculating MM tumor burden and kinetics.25, 132, 133 Practically, both serum and urine M protein concentrations are used to stage MM patients and to document their response to treatment.
In a series of 1,027 newly diagnosed cases of MM, the immunoglobulin type was IgG, IgA, IgD, and free light chain only (Bence Jones MM) in 52%, 20%, 2%, and 16% of cases, respectively.126 Fewer than 1% of MM cases are IgM; most IgM monoclonal proteins are associated with diagnoses of MGUS, lymphoma, Waldenström macroglobulinemia, or primary systemic amyloidosis.134 A total of 93% of patients have a monoclonal protein detected in their serum. About 90% of MM patients have reduction in at least one of their uninvolved immunoglobulins.134 About 70% have a monoclonal protein—or fragment thereof—detected in the urine.
Histopathology
The bone marrow microenvironment is hospitable to malignant plasma cells that circulate through the blood. There is a complex interaction among the malignant clone, its surrounding stromal cells, and the remaining immune cells. The morphologic and immunologic phenotypes of MM cells can vary, and they often resemble normal plasma cells. Plasma cells are at least two to three times the size of peripheral lymphocytes and are round to oval, with one or more eccentrically placed nuclei (Fig. 98.3D). The nucleus, which contains either diffuse or clumped chromatin, is displaced from the center by an abundance of rough-surfaced endoplasmic reticulum, the site of specialized immunoglobulin synthesis. Intranuclear and cytoplasmic inclusions are not uncommon.135 There is a perinuclear clear zone that is the site of the Golgi apparatus, the machinery used for immunoglobulin packaging and glycosylation for secretion. Derangements of immunoglobulin secretion are responsible for an assortment of cytologic aberrations, including flaming cells, Mott cells, Russell bodies, and Gaucher-like cells. Flaming cells are plasma cells that have intensely eosinophilic cytoplasm with a magenta or
carmine coloring of their margins, which is due to plugging of peripheral secretory channels by precipitated immunoglobulin or immunoglobulin fragments. These cells are most commonly seen in IgA MM. Thesaurocytes are large flaming cells with a pyknotic nucleus that is pushed to the side. Mott cells (grape cells or morula forms) are plasma cells filled with dense spherical immunoglobulin inclusions; these inclusions are colorless, pink, or blue. Other inclusions are Russell bodies and their intranuclear counterparts (intranuclear dense bodies); these appear cherry red and can be as large as several microns in diameter. Gaucher-like cells are not uncommon in MM infiltrates; these cells are macrophages laden with sphingolipids released by the dying plasma cells.136 None of these interesting inclusions is specific for malignancy nor do they have prognostic value.
carmine coloring of their margins, which is due to plugging of peripheral secretory channels by precipitated immunoglobulin or immunoglobulin fragments. These cells are most commonly seen in IgA MM. Thesaurocytes are large flaming cells with a pyknotic nucleus that is pushed to the side. Mott cells (grape cells or morula forms) are plasma cells filled with dense spherical immunoglobulin inclusions; these inclusions are colorless, pink, or blue. Other inclusions are Russell bodies and their intranuclear counterparts (intranuclear dense bodies); these appear cherry red and can be as large as several microns in diameter. Gaucher-like cells are not uncommon in MM infiltrates; these cells are macrophages laden with sphingolipids released by the dying plasma cells.136 None of these interesting inclusions is specific for malignancy nor do they have prognostic value.
 FIGURE 98.3. Laboratory findings in patients with multiple myeloma. A: Rouleaux. B: Serum protein electrophoresis, illustrating a 3-g/dl monoclonal protein spike. C: Immunofixation electrophoresis, illustrating a monoclonal IgG lambdam monoclonal protein. D: Bone marrow: myeloma cells on aspirate specimen. |
In MM, there is often discordance between the nucleus and cytoplasm, the former appearing immature and the latter highly differentiated. About 20% of MM cases have plasmablastic morphology: a diffuse chromatin pattern, nucleus greater than 10 microns or nucleolus greater than 2 microns, relatively less abundant cytoplasm, and a concentrically placed nucleus with little or no hof.137, 138 Both diffuse and nodular infiltration patterns can be observed, although the former is more common. A minority of patients have plasma cells that have a lymphoplasmacytic appearance. MM cells are commonly present in cords around bone marrow microvessels. There is a high correlation between the extent of bone marrow angiogenesis, evaluated as microvessel area, and the proliferating fraction of marrow plasma cells in patients with MM.139, 140 Mild marrow fibrosis may be observed in as many as 27% of cases; extensive fibrosis is rare.141, 142 Less than 1% of cases have an extensive idiopathic granulomatous reaction.135
The immunophenotype of MM cells is complex. In general, MM cells are CD45 negative and CD38 and CD138 positive.143, 144 However, there is increasing evidence that a subset of MM cells is CD45 positive,144, 145 with an increasing proportion of CD45 positive MM cells in less advanced disease.146, 147 CD19 and CD20 are earlier B-cell antigens that are variably expressed on MM cells; surface immunoglobulin is seen in up to one third of patients. CD56 is strongly positive in about 55% to 78% of MM cases.144, 148, 149 CD56-negative MM cells tend to be present in more aggressive disease, such as end-stage MM or plasma cell leukemia.149, 150 Other surface antigens such as CD10 (CALLA), CD28, CD117 (c-KIT), CD13, CD33, and CD20 are present on a minority of patients’ MM cells.143, 144, 145, 151, 152 Co-stimulatory molecules involved in the activation of B- and T-lymphocytes (CD28 and CD40) are seen in 40% and 70% of patients, respectively.153, 154
No individual bone marrow finding, however, is pathognomonic for a malignant plasma cell process; the bone marrow diagnosis of MM relies on percentage of clonal bone marrow plasma cells, with 10% accepted as a cutoff. The clinical diagnosis, of course, is made from a synthesis of bone marrow findings and other clinical features.
Bone Disease
Approximately one third to two thirds of patients present with bone pain.124, 125, 126, 127 There is an uncoupling of the balance between osteoclastic and osteoblastic activity. Even before the development of bone lesions, enhanced osteoblastic recruitment with an increased generation of new osteoclasts is observed in early MM.155 Regardless of the initiating signal, whether IL-1β,
IL-6 and sIL-6R, tumor necrosis factor-α, MIP-1α, receptor activator of NF-kappaβ (RANK) ligand, or parathyroid hormone-related protein (PTHrP),156 the eventual outcome is bone destruction.157
IL-6 and sIL-6R, tumor necrosis factor-α, MIP-1α, receptor activator of NF-kappaβ (RANK) ligand, or parathyroid hormone-related protein (PTHrP),156 the eventual outcome is bone destruction.157
MM bone disease is a major source of morbidity and may present as an area of persistent pain or as a vague migratory bone pain, often in the lower back and pelvis. The type, location, and duration of the pain have no characteristic features. At times, pain and tenderness may be sudden in onset, especially when associated with a pathologic fracture, and are most commonly precipitated by movement. Persistent localized pain also may be associated with a pathologic fracture.
A myelomatous lesion may extend through the cortex of a vertebral body and cause either nerve root or spinal cord compression in less than 2% of patients.125 Alternatively, the MM can disturb the mechanical integrity of a vertebral body, resulting in compression fracture with retropulsion of either plasmacytoma or bony fragments into the spinal canal, again causing neurologic deficit. Approximately 75% of patients have punched-out lytic lesions, osteoporosis, or fractures on conventional radiography (Fig. 98.4A,B). The vertebrae, skull, ribs, sternum, proximal humeri, and femora are involved most frequently.124, 126, 127 A small subset of patients has de novo osteosclerotic lesions,158 and in a few patients osteosclerosis is seen after therapy and may serve as a marker of healing.
Because myelomatous bone lesions are characteristically lytic, conventional radiography is superior to technetium-99m bone scanning.159, 160 About twice as many myelomatous bone lesions are detected by radiograph as by bone scan; an exception to this general finding is at the lumbar spine and the rib cage, where the two methods are equally reliable.160 There have been reports supporting the use of technetium-99m sestamibi scans. These scans are almost as sensitive as plain radiographs for bone disease in untreated patients (i.e., patients with active disease).161 They may be able to distinguish active myelomatous bone lesions from inactive lesions161 and are quite sensitive for bone marrow involvement.162, 163, 164 There is a high concordance between scintigraphic findings and clinical status in patients undergoing chemotherapy or autologous stem cell transplantation (ASCT).165, 166 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) also shows promise in the staging of MM, with sensitivity and specificity rates of 84% to 92% and 83% to 100%, respectively167 (Fig. 98.4D,E).
 FIGURE 98.4. Myeloma bone disease. A: Plain radiograph of a skull with punched-out myeloma lesions. B: Plain radiograph of a compression fracture thoracic spine. C: Myelomatous marrow involvement of the lumbar spine by magnetic resonance imaging (MRI) with and without gadolinium. D: 18-Fluorodeoxyglucose positron emission tomography (FDG-PET), spine and rib involvement. E: Fusion image of CT/FDG-PET scan demonstrating lesion at rib and thoracic vertebra. |
Computed tomography and magnetic resonance imaging (MRI) are more sensitive than conventional radiography (Fig. 98.4C). Both reveal specific lesions in 40% of stage I MM patients.168 The presence of lacunae larger than 5 mm with trabecular disruption on computed tomography appears to be sensitive and specific for MM. This information may be useful in distinguishing between senile and myelomatous osteoporosis and compression fractures.169 Among asymptomatic MM patients with normal radiographs, 50% have tumor-related abnormalities on MRI of the lower spine.170 In patients with Durie-Salmon stage I MM, MRI can distinguish patients at higher and lower risks of progression.171 One third of patients with an apparently solitary plasmacytoma of bone have evidence of other plasma cell tumors on MRI.172
MRI is superior to radiographs for the detection of lesions in the pelvis and the spine, but overall it is inferior to radiographs for detecting bone involvement in MM (79% versus 87%, respectively).173 On MRI, vertebral fractures due to spinal infiltration or osteoporosis are seen in 48% of patients with symptomatic MM, and spinal canal narrowing with impingement occurs in 20%.170 Nanni et al.174 compared MRI to FDG-PET/CT in 28 newly diagnosed myeloma patients. In 25% of patients FDG-PET/CT
detected more lytic bone lesions, all of which were out of the field of view of MRI, and in 25% of patients MRI detected an infiltrative pattern in the spine that was not discerned on FDG-PET/CT. In subsequent studies, whole body MRI has been reported to have a higher sensitivity and specificity than FDG-PET/CT175 and than multidetector-row computed tomography.176 A major limitation, however, to MRI and PET/CT is that there are no uniformly accepted standard acquisition or interpretation protocols, limiting their generalizability. Detection of marrow infiltration on MRI does not translate into a deficit of cortical bone integrity. Also, given the expense of MRI, it cannot be recommended for routine clinical use in all patients.
detected more lytic bone lesions, all of which were out of the field of view of MRI, and in 25% of patients MRI detected an infiltrative pattern in the spine that was not discerned on FDG-PET/CT. In subsequent studies, whole body MRI has been reported to have a higher sensitivity and specificity than FDG-PET/CT175 and than multidetector-row computed tomography.176 A major limitation, however, to MRI and PET/CT is that there are no uniformly accepted standard acquisition or interpretation protocols, limiting their generalizability. Detection of marrow infiltration on MRI does not translate into a deficit of cortical bone integrity. Also, given the expense of MRI, it cannot be recommended for routine clinical use in all patients.
Hypercalcemia
Hypercalcemia occurs in 18% to 30% of patients. About 13% have concentrations greater than 11 mg/dl. Rates of hypercalcemia at presentation have been decreasing in the last few decades, perhaps because of the earlier diagnosis of patients.124, 125, 126, 127 Hypercalcemic patients may complain of fatigue, constipation, nausea, or confusion. Calcium can precipitate in the kidneys and aggravate renal insufficiency. Inorganic phosphate is rarely decreased, except in cases of acquired Fanconi syndrome.177
Renal Insufficiency
Approximately 25% of MM patients have a serum creatinine value greater than 2 mg/dl at diagnosis. Another 25% have mildly elevated creatinine values.124, 125, 126, 127, 178, 179, 180, 181 Patients with Bence Jones or IgD MM have the highest rates of renal insufficiency.179, 181 Free light chain proteinuria is a risk factor for renal failure.182 Contributing factors to the renal insufficiency associated with MM kidneys include hypercalcemia, dehydration, hyperuricemia, and the use of nephrotoxic drugs.183 If the renal insufficiency reverses with therapy, as it does in more than half of cases,183, 184 survival is fourfold to sevenfold higher than in those in whom it does not.178, 185 Factors predicting for renal function recovery include a serum creatinine less than 4 mg/dl, serum calcium value greater than 11.5 mg/dl, proteinuria less than 1 g/24 h, and adequate rehydration.178
The pathologic lesion of MM kidney consists of monoclonal light chains in the tubules in the form of dense, often laminated, tubular casts. These casts contain albumin and Tamm-Horsfall protein. Light chains are normally filtered by the glomeruli and reabsorbed and catabolized in the nephron’s proximal tubules. It is postulated that these systems become overwhelmed, and casts result. When other causes contributing to renal insufficiency are excluded, there is a good correlation between the extent of MM cast formation and the severity of renal insufficiency.186, 187 Tubular atrophy and degeneration correlate well with renal dysfunction.188 The most common findings on autopsy include tubular atrophy and fibrosis (77%), tubular hyaline casts (62%), tubular epithelial giant cell reaction (48%), and nephrocalcinosis (42%). Evidence of acute and chronic pyelonephritis were observed in 20% and 23% of cases, respectively. Plasma cell infiltrates and amyloid may be observed in 10% and 5% of cases, respectively.127 Rarely, MM may be associated with acquired Fanconi syndrome.177, 189
An important feature of myeloma kidney is that it is primarily a tubular, rather than a glomerular, disease.188 Glomerular function is preserved initially, and there is a predominance of immunoglobulin light chain protein in the urine instead of the nonspecific protein loss observed in glomerular disease. This feature helps predict the renal lesion: nonspecific protein loss (i.e., mostly albumin) is more compatible with primary systemic amyloidosis, light chain deposition disease of the kidney, or proteinuria unrelated to the PCD;186 a free light chain predominance is consistent with myeloma kidney.
Infection
Patients with MM are at high risk for bacterial infections and for dying of overwhelming bacteremia. Overall, the incidence of infection is from 0.8 to 1.4 per patient-year.190, 191, 192 During the first 2 months after initiating chemotherapy the infection incidence is as high as 4.68 infections per patient-year192 but decreases to 0.44 to 0.49 per patient-year in those reaching a plateau phase.191, 192 Risk factors for infection are serum creatinine values greater than or equal to 2 mg/dl190, 192 and decreased levels of polyclonal serum immunoglobulins.191, 192 Since the 1960s, Gram-negative bacilli have become more common pathogens than Streptococcus pneumoniae in patients with MM.193 At disease onset, infections with encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae are most common.193 After diagnosis, the proportion of infections due to Gram-negative bacilli and Staphyloccocus aureus increases markedly, and are responsible for more than 90% of deaths from infection.193
Hemostasis in Multiple Myeloma
MM can be associated with hemostatic abnormalities, more often bleeding than thrombosis. Bleeding as a complication of MM may be present in as many as one third of patients194 and is related to thrombocytopenia, uremia, hyperviscosity, and interference with the function of coagulation factors. Rarely, MM proteins may also interact with coagulation proteins.192, 193
The association with thrombosis is less clear because of co-existing factors such as old age and immobility that confound the interpretation of available data, however, the risk of thrombosis may be increased in MM patients.194, 195 Individual cases of aberrance have been reported. Monoclonal proteins have been shown to be responsible for lupus anticoagulants,196, 197 acquired protein S deficiency,198, 199 acquired activated protein C resistance,200 and inhibition of tissue plasminogen activator.201
Fewer than 7% of MM patients have a viscosity greater than 4.124, 126 Symptoms of hyperviscosity include bleeding (particularly of the oronasal areas), purpura, decrease in visual acuity, retinopathy, neurologic symptoms, dyspnea, expanded plasma volume, and congestive heart failure. Most patients become symptomatic when the serum viscosity is 6 or 7 centipoise (normal is less than or equal to 1.8 centipoise).
“Acute Terminal Phase of Plasma Cell Myeloma” and Cause of Death
Bergsagel and Pruzanski202 described the “acute terminal phase” of patients with MM, which they observed in about one third of their preterminal patients. They defined the syndrome as rapidly progressive disease with an unexplained fever and pancytopenia and a hypercellular marrow. Extramedullary plasmacytomas are also not uncommon preterminally.203 As the disease progresses, and at autopsy, cutaneous, visceral, and even meningeal involvement is possible.203 Besides “progressive disease,” the most frequent causes of death are infection in 24% to 52% and renal failure in about 20%.127, 183, 202, 203 Acute leukemia, myelodysplastic syndromes, and hemorrhage are the causes of death in a minority of patients.127, 202, 203 In one autopsy series, 85% of patients had evidence of either bacterial or fungal infection, and myelomatous involvement was found in the spleen, liver, lymph nodes, and kidneys in 45%, 28%, 27%, and 10% of patients, respectively. Other less frequent areas of myelomatous involvement were the lung, pleura, adrenal glands, pancreas, and testis.127
DIAGNOSIS
The diagnosis of MM has not been subject to static norms. In 1973, the Chronic Leukemia-Myeloma Task Force204 set forth guidelines for the diagnosis of MM (Table 98.1). These criteria,
which by today’s standards are not stringent enough, have been replaced by a more modern definition.205 In the last 3 decades, the terms and definitions of MGUS, smoldering MM, indolent MM, and symptomatic MM124, 206, 207, 208 have evolved and are now to be replaced by the following designations: MGUS, inactive (smoldering) MM, and active (or symptomatic) MM.205
which by today’s standards are not stringent enough, have been replaced by a more modern definition.205 In the last 3 decades, the terms and definitions of MGUS, smoldering MM, indolent MM, and symptomatic MM124, 206, 207, 208 have evolved and are now to be replaced by the following designations: MGUS, inactive (smoldering) MM, and active (or symptomatic) MM.205
TABLE 98.1 CRITERIA FOR DIAGNOSIS OF MGUS, SMM, AND MM | ||||||||||||||||||
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Because MM includes a spectrum of biologic features, physicians should not feel compelled to start treatment as a result of a single threshold value. The diagnosis of active MM is not a straightforward pathologic one; rather, it is a clinical diagnosis that requires thoughtful synthesis of multiple variables. Patients with Durie-Salmon stage I disease, who also meet the criteria for smoldering or asymptomatic MM, should be managed expectantly. Median progression-free survival in asymptomatic stage I patients, observed without any therapy, is 12 to more than 48 months;209, 210, 211, 212 for similar stage II patients, progression-free survival is 12 months.209 Until recently,213 no survival advantage had been demonstrated by treating asymptomatic MM patients.208, 210, 211, 214
SYSTEMIC THERAPY FOR MULTIPLE MYELOMA
Before starting therapy for MM, a distinction must be made between smoldering (asymptomatic) MM and active MM (Table 98.1). Approximately 20% of patients with MM are recognized by chance without significant symptoms; such patients can be carefully monitored without instituting therapy (see Chapter 97). Once the decision has been made to treat for symptomatic disease, a long-term plan for managing the disease should be formulated before instituting therapy. Because high-dose therapy with autologous hematopoietic stem cell transplantation (ASCT) has been accepted as an important treatment modality for patients younger than age 70, only a limited amount of alkylator-based therapy should used prior to the collection of hematopoietic stem cells in patients considered candidates for high-dose therapy.
Historically, the bifunctional alkylating agents, including melphalan and cyclophosphamide, had been the foundation of therapy for MM. MM cells tend to proliferate slowly, and alkylators, whose effectiveness does not rely heavily on cell division and DNA replication, are useful therapeutic agents. Prior to 1999, the bifunctional alkylators, nitrosoureas, doxorubicin, and glucocorticoids were the primary agents shown to have single-agent activity against MM in vivo.215 These drugs along with vincristine, either singly or in combination, had been the mainstay of chemotherapy for MM from the early 1960s to the present (Fig. 98.1). Until recently, the higher response rates seen with regimens that combine multiple active agents as part of initial therapy, had not resulted in improved OS rates.216 IFN-α had been incorporated into induction and maintenance protocols with minimal benefit.34, 217, 218, 219 Both autologous and allogeneic stem cell transplantation (AlloSCT) have become important therapeutic options since McElwain and Powles’ description in 1983220 of the benefit of dose intensification of melphalan in patients with MM. With the recognition of thalidomide’s activity against MM in 199937 and the subsequent development of bortezomib,38 lenalidomide,39 and carfilzomib221 there is hope that the next 4 decades of MM treatment will be even more promising than the last.
Before discussing induction, transplantation, maintenance, and salvage therapies, two general concepts are reviewed: interpretation of study response data and the efficacy of single
chemotherapeutic agents commonly used to treat MM. Figure 98.5 is one potential algorithm for treating patients with newly diagnosed MM.
chemotherapeutic agents commonly used to treat MM. Figure 98.5 is one potential algorithm for treating patients with newly diagnosed MM.
 FIGURE 98.5. Mayo stratification for myeloma and risk-adapted therapy (mSMART).357, 358 Possible treatment algorithm for patients with newly diagnosed myeloma for patients not being treated on a clinical trial.CR, complete response; CyBorD, cyclophosphamide, bortezomib, and dexamethasone; MPT, melphalan, prednisone, and thalidomide; Tx, transplantation; VRd, bortezomib, lenalidomide, and dexamethasone, VGPR, very good partial response. aNote that a subset of patients with these factors will be classified as high-risk by GEP. bBortezomib containing regimens preferred in renal failure or if rapid response needed. cIf age >65 or > 4 cycles of Rd Consider G-CSF plus cytoxan or plerixafor. dContinuing Rd is option for patients responding to Rd and with low toxicities; Dex is usually discontinued after first year. eConsider allogeneic stem cell transplantation in suitable patients. |
Interpreting Study Response and Survival Data
Four points are emphasized regarding the interpretation and comparisons of the MM treatment literature. First, historically definitions of response have varied (Table 98.2). Second, definitions of evaluable patients may be different. Third, concurrent corticosteroid therapy, either as part of the regimen or for other indications, may confound interpretation of efficacy. Finally, patient population risk and prognosis may differ substantially. Lead-time bias and treatment of MGUS or smoldering MM can significantly distort survival figures, as can effective salvage regimens.
The measurement of MM disease burden is complex, and investigators have used different methods to define response (Table 98.2). The four most common response criteria that had been used until acceptance of the Uniform Response Criteria (URC) in 2006222 were the Chronic Leukemia-Myeloma Task Force (CLMTF),204 Southwest Oncology Group (SWOG),223, 224 Eastern Cooperative Oncology Group ECOG),225 and Autologous Blood and Marrow Transplant Registry and the International Bone Marrow Transplant Registry (IBMTR/ABMTR).226 Although all address calcium, bone changes, and bone marrow plasmacytosis, the main distinction among them is their consideration of the serum and urine M components. With the exception of the old SWOG criteria,223, 224 a partial response (PR) has been considered to be a 50% reduction in serum M component and a greater than 50% to 90% reduction in urine M component. Until about 1990, a SWOG objective response was defined as a 75% reduction in the tumor mass index (NOT serum M protein) and improvement was defined as a 50% to 74% reduction in the tumor mass index.224 A subsequent iteration of the SWOG response criteria used the M component (rather than the tumor mass index) as the primary measurement of the plasma cell burden.
In the earliest literature, response included such factors as increasing hemoglobin concentration or performance status, or decreasing blood urea nitrogen levels. Neither the CLMTF or SWOG originally had a complete response (CR) category, because it was unusual for the M protein to disappear completely. It was not until the advent of high-dose melphalan that investigators227, 228 began to define a complete remission category. Earliest definitions of CR only included disappearance of M protein as determined by electrophoresis, which is less sensitive than immunoelectrophoresis or immunofixation. Subsequent definitions have required immunofixation negativity to qualify as complete remission.226 The first iteration of an international consensus definition of MM response was the IBMTR/ABMTR response criteria.226 After nearly 8 years of use, several deficiencies were noted, and the International Myeloma Working Group issued a new consensus definition called the International Uniform Response Criteria (URC) which includes the Intergroupe Français du Myélome (IFM) very good partial response category,229 the ability to measure response using the serum immunoglobulin free light chain, and a new category of “stringent complete response,” which requires documentation of the absence of clonality in the bone marrow and by including a normal serum immunoglobulin free light chain ratio in the definition.222
TABLE 98.2 RESPONSE CRITERIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Efficacy of Single Chemotherapeutic Agents
Single agents are not commonly used as upfront therapy, but they are used in the relapsed setting, and understanding each drug’s activity provides insight into how much they may be contributing to combination therapy.
Melphalan
Bergsagel et al.31 demonstrated the benefit of melphalan in 14 of 24 patients with MM. Others (Table 98.3) have substantiated that melphalan as a single agent results in response rates of 20% to 34% and median OS duration of 15 to 27 months.32, 230, 231, 232, 233 Since early reports by Blokhin et al.30 and Bergsagel et al.,31 various schedules of melphalan have been tried, including continuous daily dose, 6 to 10 mg/day for 2 to 3 weeks, followed by maintenance therapy of 0.01 to 0.03 mg/kg per day; intermittent total doses of 0.25 mg/day given for 4 days every 4 to 8 weeks; or 0.15 mg/kg per day for 7 days every 6 weeks.232, 234 Several studies suggest that the intermittent schedule is superior to continuous daily dosing.232, 234
Cyclophosphamide
Korst et al. were the first to report on the activity of oral cyclophosphamide.33 A partial response (50% M-protein reduction) was achieved by 24% of MM patients, and 48% had objective improvement. Median survival was 24.5 months in all 207 patients and 32 months in the group that received at least 2 months of cyclophosphamide therapy. The single-agent activity of cyclophosphamide (Table 98.3) has been demonstrated in a placebo-controlled trial,231 in multiple studies of previously untreated patients,235, 236 and in those who relapsed or had refractory disease.237
Despite documented equivalency for low-dose oral regimens of cyclophosphamide and melphalan,235 induction therapies of MP have historically been preferred over those of cyclophosphamide and prednisone. Cyclophosphamide has most commonly been used in multidrug combinations for induction, for therapy in relapse, and for stem cell mobilization rather than as a single agent for induction, as has melphalan. In newly diagnosed MM, oral daily dosing of cyclophosphamide (150 mg/d)235, 238, 239 or intravenous doses of 600 mg/m2 every 3 weeks236 with or without prednisone resulted in a response rate of approximately 25% and median survival of 24 months.
Glucocorticoids
In 1950, Thorn et al.27 reported the first observations on the beneficial effects of adrenocorticotropic hormone in MM. Adams and Skoog28 observed a marked decrease in the MM serum protein in 18 of 26 patients treated with corticosteroids. Surprisingly, Mass240 failed to show a difference between the survival of 55 patients randomly assigned to prednisone therapy or placebo despite clinical improvement in the former group. Subsequently, high-dose corticosteroids have been shown to produce response rates of 40% to 50% in previously untreated patients, and 25%
in refractory or relapsed patients;29, 241, 242, 243, 244, 245, 246, 247 median survival of responding patients is 16 to 22 months.243, 244, 245 In reviewing their experience with single-agent dexamethasone and VAD, Alexanian et al.244 noted that in patients with refractory disease, response rates with single-agent dexamethasone were comparable to those with VAD (27% vs. 32%). In contrast, in relapsed disease, response rates achieved with single-agent dexamethasone were inferior to those with VAD. These data were not randomized but rather serial observations. On occasion, patients who do not respond to high-dose dexamethasone can be salvaged with intermittent high-dose methylprednisolone.245
in refractory or relapsed patients;29, 241, 242, 243, 244, 245, 246, 247 median survival of responding patients is 16 to 22 months.243, 244, 245 In reviewing their experience with single-agent dexamethasone and VAD, Alexanian et al.244 noted that in patients with refractory disease, response rates with single-agent dexamethasone were comparable to those with VAD (27% vs. 32%). In contrast, in relapsed disease, response rates achieved with single-agent dexamethasone were inferior to those with VAD. These data were not randomized but rather serial observations. On occasion, patients who do not respond to high-dose dexamethasone can be salvaged with intermittent high-dose methylprednisolone.245
TABLE 98.3 EARLY (1969 TO 1982), ALKYLATOR-BASED RANDOMIZED TRIALS FOR NEWLY DIAGNOSED MYELOMA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Despite their contribution to quicker and more abundant responses, there are conflicting data as to whether corticosteroids prolong survival.230, 232, 248 As initial therapy for elderly patients, single-agent dexamethasone is responsible for both higher treatment-related morbidity and mortality as compared to melphalan-containing regimens.249 The mechanism of action of this drug class is complex. Corticosteroids suppress the production of cytokines important in MM growth, such as IL-6 and IL-1β, and reduce nuclear factor κB activity, resulting in enhanced apoptosis.250, 251, 252, 253
Vincristine
Although never evaluated as a single agent in newly diagnosed MM, vincristine has little activity as a single agent in refractory disease. There were 21 patients treated with a 0.5 mg bolus of vincristine followed by 0.25 to 0.5 mg/m2 per day as a continuous infusion over 5 days on a 3-week schedule. Two patients had transient responses (1.2 and 2.2 months).254 Finally, the activity credited to vincristine as a maintenance therapy is also ambiguous. Although a superior survival (35 vs. 27 months, P = 0.003) was reported in patients treated with single-agent melphalan and maintained on bimonthly vincristine (1 mg/m2) and prednisone (0.6 mg/kg for 7 days), the benefit could easily be attributed to prednisone alone.255
Alexanian et al.256, 257 suggested that regimens which included vincristine resulted in better patient outcome than protocols not including this agent. The theory behind its posited utility was that after an initial kill of MM cells by alkylating agents, the subsequent increase in the mitotic index made MM cells more sensitive to vincristine.258 Reports by Lee , Salmon, and Case have been cited as confirmatory evidence for activity of vincristine in MM.259, 260, 261 However, several randomized controlled trials do not support this premise.262, 263, 264, 265 The most compelling of these is the MRC IV Trial in Myelomatosis, which randomized 530 newly diagnosed MM patients to monthly MP, with or without monthly vincristine. Median survival in both arms was 26 months.264 Even though vincristine has not been shown to have significant single-agent in vivo activity or to improve OS,254, 264, 265, 266 it has been included in multiple therapeutic regimens.
Anthracyclines
Doxorubicin is the most commonly used anthracycline in the treatment of MM, but it has not been studied as a single agent in newly diagnosed MM patients. Its activity as a single agent in relapsed or refractory disease is modest, with response rates of about 10%.35, 267 The pegylated form has been used in a number of MM regimens since the 1990s.268, 269 A phase II trial of mitoxantrone as a single agent (12 mg/m2 every 3 weeks) yielded a partial response rate of 3% (1 of 35). An additional 4 patients showed clinical improvement lasting 4 to 7 months.270 Idarubicin is another anthracycline that has been studied in MM. Response rates of 0% to 27% have been observed in relapsed and refractory patients with single-agent oral regimens (30 mg/week in three divided doses given 3 of 5 weeks or 40 mg/m2 every 3 weeks).271, 272
Etoposide
In relapsed and refractory disease, single-agent etoposide (200 to 250 mg/m2 over 5 days) has minimal activity; in 85 patients the response rate was < 5%.273 Barlogie et al.274 treated 14 patients with 200 mg/m2 by continuous infusion, and 2 responded. In addition, there are two anecdotal reports of activity of low-dose (25 to 50 mg/day) oral etoposide.275, 276
Nitrosoureas
The nitrosoureas have single-agent activity in MM. In a randomized trial of 361 previously untreated patients, objective response frequency with carmustine (BCNU; 40%) and lomustine (CCNU; 42%) was lower than that of melphalan (59%), although the survivals for all groups were not significantly different.262
Interferon
Despite the encouraging reports that daily human leukocyte IFN (3 to 9 MU/day) could induce responses in as many as 60% of MM patients34, 217 subsequent studies with recombinant IFN yielded rates of 10% to 20%.219, 277, 278, 279, 280 Toxicity was not inconsequential.280 In vitro activity had good predictive value for in vivo clinical response in 26 patients studied.278 However, IFN has a stimulatory effect in about one third of MM samples tested in vitro.278 This drug has been used most commonly in the maintenance setting as discussed below.
Bendamustine
Bendamustine is a multifunctional alkylating agent with a purinelike ring system and a novel mechanism of action. Bendamustine appears to be more efficient in inducing DNA double-strand breaks compared with other more commonly used alkylating agents such as cyclophosphamide or phenylalanine mustard.
In a phase I study of bendamustine, Knoop et al. enrolled 31 patients with MM that had progressed after high-dose chemotherapy. Bendamustine 100 mg/m2 on days 1 and 2 per cycle was found to be the maximal tolerated dose. The overall response rate was 55% with a median progression-free survival of 26 (0 to 61) weeks. Toxicity was mild and mainly hematologic.281, 282 In this retrospective analysis of a single institution experience, 39 patients with relapsed or refractory MM received bendamustine as salvage therapy.283 Bendamustine used at 80 to 150 mg on day 1 + 2 of a monthly cycle with or without steroids resulted in 3% VGPR, 33% PR, 18% MR, 26% SD, and 20% PD. The median EFSand OS were 7 and 17 months, respectively.
Thalidomide
Thalidomide is the first in the class of drugs called immune modulatory drugs (IMiDs). Recognition of the role of increased angiogenesis in the pathogenesis and progression of MM,139 and evidence of thalidomide’s antiangiogenic properties,284, 285 led to clinical trials in MM.37, 286 The observed responses in patients without high-grade angiogenesis suggest that thalidomide may act via other mechanisms as well.287 In vitro data suggest that the drug and its metabolites may inhibit angiogenesis, but in addition may modulate adhesion molecules of MM cells and their surrounding stroma, modulate cytokines, and affect natural killer cells. There is evidence that thalidomide and its analogues induce apoptosis and G1 growth arrest in MM cells.287
The first report of the utility of thalidomide in patients with relapsed MM37 who were treated with escalating doses of thalidomide was published in 1999. Patients were started on 200 mg each evening; the dose was escalated every 2 weeks, if tolerated, to a final maximal dose of 800 mg daily. A total of 25% of patients had at least a 50% reduction in their serum paraprotein. Preliminary evidence of response was apparent within 2 months in more than three quarters of the patients who did respond. Other investigators have confirmed a partial response rate of 25% to 58%, with an additional 6% to 26% achieving a minimal response, median response duration of 9 to 12 months, 2-year progression-free survival of 10% to 20%, and 2-year OS of 48%.286, 288, 289, 290, 291, 292, 293, 294, 295, 296 As a single agent in previously untreated patients, response rates of 25% may be achieved.297, 298, 299 The role of dose intensity in thalidomide effectiveness is unclear.293, 300 In the original reports, the highest dose tolerated was administered.37 In high-risk patients there was a suggestion that response rates were higher and survival longer in patients receiving high doses of thalidomide (greater than or equal to 600 mg/day).301 However, in some patients, responses may be seen with doses as low as 50 to 100 mg/day.300
Toxicities associated with thalidomide include fetal malformations, constipation, weakness or fatigue, somnolence, skin problems, and sensory neuropathy in more than one third of patients. There is also an increased risk of thrombosis in patients treated with thalidomide, which appears to be exacerbated by the use of concurrent combination chemotherapy, with rates as high as 28%.302, 303, 304 Other life-threatening complications have included Stevens-Johnson syndrome and hepatitis.305, 306
Thalidomide received US Food and Drug Administration approval for use in conjunction with dexamethasone for newly diagnosed MM in 2006.
Lenalidomide (CC-5013; RevlimidTM)
This drug is a small molecule derivative of thalidomide and a member of the immunomodulatory (IMiD) class. Lenalidomide is more potent than thalidomide in mediating direct cytokine-related and immunomodulatory effects against human MM cell lines and patient-derived cells in vitro. It induces apoptosis of MM cells; overcomes cytokine and bone marrow stromal cell-mediated drug resistance; has antiangiogenic effects; and stimulates host anti-MM T and natural killer cell immunity.39, 307 In the original phase I study, 30% of patients responded to the single-agent drug, with a median duration of response of 6 months.39 At 50 mg per day the dose limiting toxicity was myelosuppression. In the randomized phase II trial, two schedules were evaluated: 25 mg daily and 15 mg twice daily. In both arms, drug was given only 21 out of 28 days. Overall approximately 17% of relapsed or refractory patients achieved a partial response, including a 4% complete response rate, with a median progression-free survival (PFS) of 4.6 months for the patients receiving once-daily dosing.39, 307 Aside from myelosuppression, other grade 3 to 4 toxicities included neuropathy and fatigue in 3% and 7% of patients. In the open label phase II tral, including 222 patients, there was 25% partial response rate, with a time to progression of 5.1 months.308 newly diagnosed MM, single agent lenalidomide induces responses in fewer than one-third of patients.309 The FDA approved the drug in combination with dexamethasone as second line therapy for patients with MM in 2006.
Pomalidomide (CC-4047; ActimidTM)
Pomalidomide is another IMiD with activity310 that is currently undergoing clinical trials in relapsed MM.311, 312 Preclinical studies have shown changes that suggest a significant immunomodulatory effect of the drug, with decrease in CD8+/CD45RA+ cells and CD4+/CD45RA+ initially following therapy, which was also accompanied by a corresponding increase in CD8+/CD45RO+ cells and CD4+/CD45RO+, suggesting a switch from naïve cells to activated effector T-cells.310 It also has an effect on the inflammatory pathways via transcriptional inhibition of cyclooxygenase-2 (COX-2) production, which is associated with increased prostaglandins in human lipopolysaccharide (LPS)-stimulated monocytes.313 In addition to the direct anti-MM activity and the immunomodulatory functions, pomalidomide also alters the tumor microenvironment. In vitro studies also have shown potent inhibitory effect on osteoclast differentiation as well as bone marrow angiogenesis.314, 315 A total of 54% of previously treated patients respond to the single-agent drug. Median PFS was 9 months. Additional studies have been done as are described in the section of relapsed/refractory disease. As of this writing, the drug is not available except in clinical trials.
Bortezomib (VelcadeTM, PS-341)
Bortezomib is the first drug in its class of proteasome inhibitors. It is a boronic acid dipeptide that reversibly and selectively inhibits the proteasome, an intracellular complex that degrades primarily ubiquitinated proteins. The proteasome has a key role in protein degradation, cell-cycle regulation, and gene expression. Tumor cells, including MM, are heavily dependent on proteasomeregulated proteins for their growth and interaction with stromal cells. Inhibition of the proteasome has emerged as an important antitumor target, and bortezomib has been shown in vitro and in vivo to cause growth arrest, to induce apoptosis, and to inhibit angiogenesis.
Of newly diagnosed MM patients, 38% to 48% will respond to single-agent bortezomib.316, 317, 318 The addition of dexamethasone results in an overall response rate of 67% to 88%.317, 319 Single-agent response rates in relapsed/refractory MM range from 28% to 38% with a median duration of response of 8 months.308, 320, 321, 322 The most common adverse events associated with bortezomib are: gastrointestinal disturbances, fatigue, peripheral neuropathy, and myelosuppression. There were 75% of patients who had serious (grade 3 to 4) adverse events, the most common of which were thrombocytopenia, neutropenia, anemia, gastrointestinal disturbances, fatigue, and peripheral neuropathy (sensory, motor, and pain).321, 323 In a review of 256 patients treated on two phase II studies, over 80% of paitents had baseline peripheral neuropathy. Treatment-emergent neuropathy was reported in 35% of patients. Grade 1-2, 3, and 4 neuropathy occurred in 22%, 13%, and 0.4% of patients, respectively. Grade 3 neuropathy was more likely to occur in patients with a baseline neuropathy. A total of 71% of patients with neuropathy greater than or equal to grade 3 and/or requiring discontinuation who had resolution to baseline or improvement. Subcutaneous administration and/or weekly administration of bortezomib reduces the incidence of severe peripheral neuropathy by nearly 40%.324
The FDA approved bortezomib for patients with refractory MM in 2003, patients who failed one prior regimen in 2005, and as initial therapy in 2008. Because of toxicity, two important modifications to bortezomib administration have been made over the past decade. The first was introduction of weekly bortezomib rather than twice weekly followed by a 10-day rest; the second was the subcutaneous administration rather than the intravenous route of administration. This latter change was approved by the FDA in 2012 based on a randomized control trial that demonstrated comparable efficacy but significantly lower toxicity.324 Overall response rate for both arms was 42% to 43%, but grade 3 or higher peripheral neuropathy was 6% versus 16% and any neuropathy was 38% versus 53%, favoring the subcutaneous administration.
Carfilzomib (PX-171, KyprolisTM)
Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. It differs from bortezomib in that it does not contain a boronic acid residue, and irreversibly binds to the proteasome subunit. It was FDA approved for the indication of relapsed or refractory MM among patients who have had prior exposure to an IMiD and bortezomib. Two schedules had been tested in hematologic malignancies,325, 326 and best tolerance was seen with an IV infusion on days 1, 2, 8, 9, 15, and 16 every 28 days. In bortezomib-naïve patients,221 reponse rates were seen in 25% of patients treated at the 20 mg/m2 level and in 52% of patients treated with first cycle 20 mg/m2, but subsequent cycles at 27 mg/m2. An additional 17% and 12% of patients had a minimal response (i.e., a 25% reduction in their serum M-protein) in the 20 mg/m2 cohort and the 20/27 mg/m2 cohorts, respectively. Median duration of response is 13 months among patients achieving a a PR or better. The most common side effects of drug are fatigue, nausea, anemia, dyspnea, cough, and pyrexia occurring in 34% to 62% of patients. The most common grade 3 or higher AEs were hematologic (13% to 16%) and pneumonia (12%). Treatment-emergent peripheral neuropathy was rare with only 1 patient in 129 developing a grade 3 PN. Because fever, chills, shortness of breath, and/or rigors may occur during cycle 1 and sometimes cycle 2, dexamethasone 4 mg daily can be given before each dose in cycle 1 and before the first dose of the cycle 2 if dose escalation is planned.
Other Agents
Barlogie et al.274 explored the utility of cisplatin therapy for patients with MM. A total of 14 patients were treated with 10 mg/m2 for 7 days by continuous infusion, and 2 responded. The drug has been incorporated into other regimens for relapsed disease274, 327, 328 and induction therapy.329
Cytosine arabinoside,330 tenoposide,331 topotecan,332 deoxycoformycin,333, 334 arsenic trioxide,335, 336 and paclitaxel337, 338 have been reported to produce response rates of 7%, 28%, 16%, 0% to 15%, 7.1%, and 15% to 29%, respectively. Topotecan induces significant toxicity including greater than or equal to grade 3 granulocytopenia and thrombocytopenia in 93% and 53% of patients, respectively.332 Patients treated with paclitaxel were premedicated with 40 mg of dexamethasone every 21 days,337, 338 bringing into question whether the observed responses were attributable to dexamethasone or paclitaxel.
Agents that do not appear to have any activity in MM include drugs that are interesting from an historical perspective and drugs that have known activity in other diseases. Agents in the former category include diamidines, such as stilbamidine; 1-aminocyclopentanecarboxylic acid; amsacrine,339, 340 aclarubin,341 chlorozotocin,342 hexamethylmelamine343 and azaserine.32 Other agents without activity against MM include: methotrexate, 6-mercaptopurine, 6-thioguanine, 5-fluorouracil, fluorodeoxyuridine, hydroxyurea, mitomycin C,32 vinblastine, vindesine,243 carboplatin,344 bleomycin,267 ATRA (all trans-retinoic acid), fludarabine,345 2-chlorodeoxyadenosine,346 flavopiridol,347 and imatinib.348 Although Durie et al.349 reported a 57% response rate with clarithromycin, subsequent reports did not corroborate this response rate, and the activity observed in the original report was attributed to concurrent corticosteroid therapy.350, 351, 352
Combination Chemotherapy for Induction
Combining multiple active agents in an effort to achieve synergy is a logical corollary. The last 3 decades of the 20th century were spent combining alkylators, anthracyclines, corticosteroids, and IFN. Thirty years of study indicate that the higher response rates
afforded by these combinations as initial therapy did not translate into longer OS rates than standard MP therapy216 (Fig. 98.6), and the data are conflicting as to whether patients with more advanced disease benefited from combination alkylator chemotherapy.210, 216, 233, 258, 353, 354, 355 Once IMiDs and proteasome inhibitors were shown to have activity, clinical investigators began using these drugs in combination. Table 98.4 serves as a reference for commonly cited regimens. For expediency, the section on induction regimens is separated into three larger categories: those commonly used in all types of MM patients, those specifically for transplant-ineligible patients, and those for transplant-eligible patients.
afforded by these combinations as initial therapy did not translate into longer OS rates than standard MP therapy216 (Fig. 98.6), and the data are conflicting as to whether patients with more advanced disease benefited from combination alkylator chemotherapy.210, 216, 233, 258, 353, 354, 355 Once IMiDs and proteasome inhibitors were shown to have activity, clinical investigators began using these drugs in combination. Table 98.4 serves as a reference for commonly cited regimens. For expediency, the section on induction regimens is separated into three larger categories: those commonly used in all types of MM patients, those specifically for transplant-ineligible patients, and those for transplant-eligible patients.
 FIGURE 98.6. Melphalan and prednisone (MP) versus combined chemotherapy (CCT) as induction. Results from 6,633 patients from 27 randomized trials. A: Overall survival. B: Response duration. (From the Myeloma Trialists’ Collaborative Group.216 By permission of the American Society of Clinical Oncology.) |
Clinical research in MM began to move at breakneck speed starting in the first decade of the 21st century. Because of the abundance of induction data and the absence of definitive “best options,” the Mayo Clinic group has published a treatment algorithm for patients with newly diagnosed MM called mSMART. 357, 358 This is an online algorithm that is updated as new data emerge (Fig. 98.5; http://www.msmart.org/index.html). As a general rule, patients who are being considered for stem cell collection and transplantation receive nonalkylator-containing induction regimens, or if alkylator-containing regimens are used, the number of cycles is restiricted to four prior to stem cell mobilization.
Commonly Used Regimens for Any Newly Diagnosed Multiple Myeloma Patient
Three of the most commonly used induction regimens in the United States—lenalidomide/dexamethasone (Rd), bortezomib/lenalidomide/dexamethasone (VRD), and cyclophosphamide/bortezomib/dexamethasone (CyBorD)—are regimens that can be used for patients regardless of their transplant eligibility. Surpisingly, these three regimens have the least published phase III data to support their use. The mSMART method of prioritizing their use is shown in Figure 98.5.357, 358 Table 98.5 also lists these regimens, as well as other phase II regimens of interest that are discussed later in this chapter.
Lenalidomide/Dexamethasone (Rd)
In previously untreated patients with active MM, the combination of lenalidomide and dexamethasone with or without clarithromycin yields overall response rates of 91% to 95%, with complete response/very good response rates of 32% to 38%.359, 360 Rajkumar et al.359 treated 34 patients with lenalidomide 25 mg orally days 1 to 21 and dexamethasone 40 mg days 1 to 4, 9 to 12, and 17 to 20, both repeated every 28 days. Aspirin was given as DVT prophylaxis. The overall response rate was 91%, with 6% achieving complete response and 32% very good partial response. Grade 3 to 4 neutropenia occurred in 12% of patients. A total of 47% of patients experienced grade 3 or higher nonhematologic toxicity, most commonly fatigue (15%). The 2-year progression-free survival rates for patients proceeding to SCT and patients remaining on Rev-Dex were 83% and 59%, respectively; the OS rates were 92% and 90% at 2 years and 92% and 85% at 3 years, respectively. The 3-year OS rate for the whole cohort was 88%.361
Niesvizky et al.360 treated 72 patients with clarithromycin, lenalidomide, and dexamethasone (BiRD). The rationale for the clarithromycin use is that it alters the hepatic metabolism of both drugs, resulting in higher effective doses. The lenalidomide schedule was as above, but dexamethasone was administered only once weekly. Clarithromycin was given 500 mg twice daily. Aspirin was given as DVT prophylaxis. The overall response rate was 90%, including 39% CR and 35% VGPR. Twenty patients went on to receive ASCT. Two-year EFS for the nontransplant group was 75%. The most common grade 3 or higher nonhematologic AEs were myopathy (11%) and thromboembolic events (12.5%). Grade 3 or higher hematologic toxicies were neutropenia in 19.4%, anemia in 13.8%, and thrombocytopenia in 22.2%.
A randomized controlled trial comparing lenalidomide with standard dexamethasone (12 days/month schedule)—RD—to lenalidomide with reduced intensity dexamethasone (weekly dexamethasone) —Rd.362 After 4 months of therapy, 79% of the RD patients and 68% of the Rd patients had achieved a partial response or better; however, at 1 year, OS was superior in the Rd arm as compared to the RD arm (92% vs. 87%, P = 0.0002). Among those aged less than 65, the 1-year OS was 91% with RD and 98% with Rd; among those older than 65, the 1-year OS was 83% with RD and 94% with Rd. The trial was stopped due to this safety concern, and patients receiving high-intensity dexamethasone (RD) were crossed over to the low-intensity arm (Rd). Grade 3 to 4 AEs and early deaths were higher in the RD group (52% vs. 35%, P = 0.0001 and 5.4% vs. 0.5%, P = 0.003), respectively. The most common grade 3 or higher toxicities were DVT (26% vs. 12%, P = 0.0003), infections (16% vs. 9%, P = 0.04), and fatigue (15% vs. 9%, P = 0.08).
Because of the ease of administration and low early death rate, many consider Rd an excellent first-line therapeutic option. Others express concern that a 68% response rate and a VGPR or better rate of 40% is insufficient, and therefore favor the use of triplets, especially in younger patients. To date, there are no
completed randomized trials demonstrating survival advantage of any of the triplets over the Rd. Several clinical trials are ongoing that compare a triplet (MPT, VRD) to Rd. In the absence of prospective data, a retrospective comparison of three consecutive clinical trials [RD (lenalidomide-dexamethasone, n = 34), CLD (cyclophosphamide-lenalidomide- dexamethasone, n = 53), and CyBorD (cyclophosphamide/bortezomib/dexamethasone, n = 63)], has been reported.363 Overall response rates were comparable at 94%, 85%, and 90%, but complete response/near complete response rates were highest in the CyBorD arm, 35%, 15%, and 41%, P = 0.006. Despite this difference, however, PFS and OS were no different among the groups. Respective median PFS rates were: 3.2, 2.3, and 2.7 years, P = 0.11, and respective 3-year OS rates were 88%, 79%, and 88%. Poor cytogenetic risk was not overcome by any of these regimens. A notable finding of this study was that 80% of patients were alive at 4 years.
completed randomized trials demonstrating survival advantage of any of the triplets over the Rd. Several clinical trials are ongoing that compare a triplet (MPT, VRD) to Rd. In the absence of prospective data, a retrospective comparison of three consecutive clinical trials [RD (lenalidomide-dexamethasone, n = 34), CLD (cyclophosphamide-lenalidomide- dexamethasone, n = 53), and CyBorD (cyclophosphamide/bortezomib/dexamethasone, n = 63)], has been reported.363 Overall response rates were comparable at 94%, 85%, and 90%, but complete response/near complete response rates were highest in the CyBorD arm, 35%, 15%, and 41%, P = 0.006. Despite this difference, however, PFS and OS were no different among the groups. Respective median PFS rates were: 3.2, 2.3, and 2.7 years, P = 0.11, and respective 3-year OS rates were 88%, 79%, and 88%. Poor cytogenetic risk was not overcome by any of these regimens. A notable finding of this study was that 80% of patients were alive at 4 years.
TABLE 98.4 COMMONLY CITED REGIMENS AND THEIR DOSAGE SCHEDULES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Despite the concern of an increased rate of secondary malignancies when using lenalidomide as maintenance after ASCT and in conjunction with MP, the use of Rd appears to impart a lower rate of acute myeloid leukemia and myelodysplastic syndrome than MPT with respective rates of 0.15 per 100 person-years (95% CI 0.05 to 0.47) versus 1.04 per 100 person-years (95% CI 0.56 to 1.94),
respectively. Rates of other secondary primary malignancies were comparable in both arms and within the expected range for an elderly population.364
respectively. Rates of other secondary primary malignancies were comparable in both arms and within the expected range for an elderly population.364
TABLE 98.5 SELECTED PHASE 2 INDUCTION REGIMENS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD or VCD)
The combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD or VCD) has been explored both in the relapsed setting and in patients with newly diagnosed MM. The first resport was that of a four 28-day cycles of bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, cyclophosphamide 300 mg/m2 orally on days 1, 8, 15, and 22, and dexamethasone 40 mg orally on days 1 to 4, 9 to 12, and 17 to 20 on a 28-day cycle for four cycles.365 Among the 33 pateints enrolled, responses were rapid. The overall response rate was 88%, with 39% achieving complete/near complete response. Peripheral neuropathy rate was 66%, with 7% grade 3. A modified extension of that trial included another 30 patients to maximize dose delivery and reduce toxicity.366 Patients received the same weekly cyclophosphamide schedule, but bortezomib was increased to 1.5 mg/m2 IV on days 1, 8, 15, and 22 and dexamethasone was modified to 40 mg once weekly after cycle 2. Response rates were comparable and toxicity was less; grade 3/4 AEs dropped from 60% to 40% of patients, and no patient had grade 3 PN.
Bensinger reported results from a phase II study of two sequential three-drug combinations: three 21-day cycles of bortezomib, cyclophosphamide, and dexamethasone (VCD) followed by three 21-day cycles of bortezomib, thalidomide, and dexamethasone (VTD).367 Among the 42 evaluable patients, overall response rate was 95%, including 19% stringent complete response (sCR). Adverse cyctogenetics did not appear to affect response. With a median follow-up of 21 months, 1-year EFS and are OS were 81% and 91%, respectively. The most common nonhematological grade 3/4 AE was periphaeral neuropathy, which occurred in 11% of patients. Four patients had cardiovascular events all during the VTD cycles.
A randomized phase II study comparing bortezomib, dexamethasone, cyclophosphamide, and lenalidomide (VDCR); bortezomib, dexamethasone, and lenalidomide (VRD); and two formulations of VCD in 140 previously untreated patients has
been reported.368 A maximum of eight 21-day cycles followed by maintenance bortezomib (1.3 mg/m2 every other week for 24 weeks) was administered. The bortezomib was administered as 1.3 mg/m2 days 1, 4, 8, and 11 and the dexamethasone was administered as 40 mg days 1, 8, and 15 for all patients. The VRD patients received lenalidomide 25 mg days 1 to 14, whereas the VDCR patients received lenalidomide 15 mg days 1 to 14 and cyclophosphamide 500 mg/m2 days 1 and 8. The VCD paitents received cyclophophamamide 500 mg/m2 days 1 and 8, whereas, the VCD-mod patients received cyclophophamamide 500 mg/m2 days 1, 8, and 15. Nearly all patients responded and the VGPR or better (CR) rates were 58% (25%), 51% (24%), 41% (22%), and 53% (47%) for patients on VDCR, VDR, VCD, and VCD-mod, respectively. The corresponding 1-year progression-free survival was 86%, 83%, 93%, and 100%. Grade 3 or higher AEs were seen in 76% to 88% of patients, with the highest rate of AE resulting in discontinuation in the VDCR arm. The highest rate of grade 3/4 hematologic AEs was in the VDCR and VCD arms. Grade 3/4 peripheral neuropathy rates ranged from 9% to 18%. The two regimens recommended by the authors were VCD-mod and VRD.
been reported.368 A maximum of eight 21-day cycles followed by maintenance bortezomib (1.3 mg/m2 every other week for 24 weeks) was administered. The bortezomib was administered as 1.3 mg/m2 days 1, 4, 8, and 11 and the dexamethasone was administered as 40 mg days 1, 8, and 15 for all patients. The VRD patients received lenalidomide 25 mg days 1 to 14, whereas the VDCR patients received lenalidomide 15 mg days 1 to 14 and cyclophosphamide 500 mg/m2 days 1 and 8. The VCD paitents received cyclophophamamide 500 mg/m2 days 1 and 8, whereas, the VCD-mod patients received cyclophophamamide 500 mg/m2 days 1, 8, and 15. Nearly all patients responded and the VGPR or better (CR) rates were 58% (25%), 51% (24%), 41% (22%), and 53% (47%) for patients on VDCR, VDR, VCD, and VCD-mod, respectively. The corresponding 1-year progression-free survival was 86%, 83%, 93%, and 100%. Grade 3 or higher AEs were seen in 76% to 88% of patients, with the highest rate of AE resulting in discontinuation in the VDCR arm. The highest rate of grade 3/4 hematologic AEs was in the VDCR and VCD arms. Grade 3/4 peripheral neuropathy rates ranged from 9% to 18%. The two regimens recommended by the authors were VCD-mod and VRD.
Kropff et al. reported phase I results of a variant of CyBorD. Thirty patients were treated with three 21-day cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, 11 plus dexamethasone 40 mg on the day of bortezomib injection and the day after plus cyclophosphamide at 900, 1,200, or 1,500 mg/m2 on day 1.369 The maximum tolerated dose of cyclophosphamide was defined as 900 mg/m2. Overall response rate across all levels was 77%, with a 10% CR rate.
Bortezomib, Lenalidomide, Dexamethasone (VRD)
Richardson and colleagues reported on 66 patients treated on a phase I/II study using the combination of bortezomib, lenalidomide, and dexamethasone for previously untreated MM patients.370 Patients receved eight 3-week cycles and either proceeded to transplantation or maintenance. All patients responded, and 67% achieved a VGPR or better. A total of 42% proceeded to ASCT. With median follow-up of 21 months, estimated 18-month PFS and OS for the combination treatment with/without transplantation were 75% and 97%, respectively. Sensory neuropathy occurred in 80% of patients and 32% reported neuropathic pain (grade 2/3 in 14%). Grade 3 to 4 neutropenia and thrombocytopenia occurred in 9% and 6% of patients respectively.
Summary statement: Based on complete response rates, the triplets are superior. Based on toxicity, lenalidomide and dexamethasone are superior. There are no compelling OS data to support one option over another.
Transplant Ineligible Patients
Transplant Ineligible Patients: Phase III Trials of Induction Regimens Including IMiDs and/or Proteasome Inhibitors (Table 98.6)
The combination of melphalan and prednisone (MP) was the standard for all patients with MM for nearly 40 years. The combination of MP has been studied extensively.223, 230 Response rates are 40% to 60% and anticipated median survivals are 18 to 42 months.210, 216, 223, 230, 232, 236, 257, 263, 264, 354, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386 Because of the variable gastrointestinal tract absorption of melphalan, intravenous regimens of 15 to 25 mg/m2 every 4 weeks along with oral prednisone or dexamethasone have been tried and resulted in response rates of 50% to 82%.386, 387 An important phase III trial (IFM 95-01) directed at the elderly (age 65 to 75 years) was a fourarm study comparing MP to melphalan-dexamethasone (MD), dexamethasone, or dexamethasone-IFN.249 A total of 488 patients was randomized, and follow-up was 83 months. Response rates were significantly higher among patients receiving MD, and PFS was significantly better among patients receiving melphalan (22 vs. 13 months), but there was no difference in OS among the four treatment groups. The median survival for the whole series was 35 months. The morbidity associated with dexamethasone-based regimens was significantly higher than with MP.
With the advent of ASCT, MP was relegated to those not eligible for ASCT. As drugs outside the alkylator, anthracycline, and corticosteroid classes began to show activity around 2000, combining these drugs with alkylator and prednisone became the obvious path for study.388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400 Such regimens have become part of the standard for treating elderly patients with MM (Table 98.6) in addition to a few combinations that have not been directly compared to MP, but have shown promise in either phase II or III trials.362, 365, 366, 370 A major limitation of several of the trials that compare a doublet to a triplet is that it is often unclear what percentage of the doublet patients got access to the third drug at the time of relapse or progression.
There have been seven randomized controlled trials comparing MP to MP and a novel agent.388, 389, 390, 391, 392, 393, 394, 395, 396 In terms of the six MPT studies, all have favored MPT with regard to higher CR rates. Four of six have been positive with regard to PFS, again in favor of three drugs over two drugs, but only three of six have been positive with regard to OS. An individual patient meta-analysis has recently been reported.401 In aggregate, MPT was superior to MP in terms of overall response rate (59% vs 37%), median PFS (20 versus. 15 months), and median OS (39 vs. 33 months). Although this meta-analysis is an extraordinarily important study, there was no effort to examine what percentage of the relapsing MP patients received thalidomide as salvage. In a side meta-analysis examining serious adverse events of individual patient data of these same six trials,402 a higher cumulative incidence of grade 3 to 4 nonhematologic (39% vs. 17%, HR 2.78, 95%CI 2.21 to 3.50) and hematologic (28% vs. 22%, HR 1.32, 95%CI 1.05 to 1.66) toxicities was documented with MPT. Nonhematologic toxicities were more likely to occur in patients with a baseline poorer performance status (HR 1.18, 95%CI 1.06 to 1.32). The specific serious adverse events that were more common in patients receiving MPT were peripheral neuropathy, neurologic other than peripheral neuropathy, thrombosis, and dermatologic toxicity. The experience of a nonhematologic grade 3 to 4 AE had a negative impact on both PFS (HR 1.24, 95%CI 1.07 to 1.45, P = 0.006) and OS (HR 1.23, 95%CI 1.03 to 1.47, P = 0.006).
The first positive MP versus MPT trial (Table 98.6) is the the IFM 99-06 study,388 in which 447 patients were randomized to twelve 6-week cycles of either of MP (melphalan 0.25 mg/kg per day and prednisone 2 mg/kg/day days 1 to 4 every 6 weeks) or MPT (MP plus 200 to 400 mg of thalidomide daily) or to two sequential miniautologous peripheral blood stem cell transplants (MEL100). The thalidomide was not continued past the twelfth cycle of therapy. Higher response rates and longer PFS were seen with the MPT as compared to either the MP or MEL100 groups, with respective PFS times of 28, 18, and 19.0 months. With a median follow-up of 51 months, there was a significant survival advantage for the patients on the MPT arm, with respective OS times not reached at 52 months, 33 months, and 38 months.388
The IFM01-01391 included 129 patients over the age of 75. They were randomized to twelve 6-week cycles of either of MP (melphalan 0.2 mg/kg per day and prednisone 2 mg/kg/day days 1 to 4 every 6 weeks) or MPT (MP plus 50 to 100 mg of thalidomide daily). With a median follow-up of 47.5 months, in the MPT arm both median OS (44 vs. 29 months, P = 0.03) and PFS (24 vs. 19 months, P = 0.001) were longer. Grade 2 to 4 peripheral neuropathy (20% vs. 5%, P = 0.001) and neutropenia (23% vs. 9%, P = 0.003) were more frequent in the MPT arm.
In the GIMEMA MP versus MPT trial, patients were randomized to either standard dose oral MP for 6 months or to MP for 6 months with concurrent thalidomide, which was continued indefinitely.389, 390 Overall response rates were significantly higher with the MPT than the MP as were the complete response rates and the median PFS rates (22 vs. 14 months, P = 0.004). In the initial
report, there was a trend toward an improved 3-year OS in favor of MPT, but a second report with 38 months follow-up showed no difference in OS. This trial addressed a maintenance question as much as an induction question.
report, there was a trend toward an improved 3-year OS in favor of MPT, but a second report with 38 months follow-up showed no difference in OS. This trial addressed a maintenance question as much as an induction question.
TABLE 98.6 RANDOMIZED TRIALS OF INDUCTION REGIMENS FOR ELDERLY PATIENTS/PATIENTS NOT DESTINED FOR AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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In the Dutch-Belgium Hemato-Oncology Cooperative Group (HOVON) 49 trial, patients were randomized to either eight cycles of MP (melphalan 0.25 mg/kg per day and prednisone 2 mg/kg/day days 1 to 5 every 4 weeks) or MPT (MP plus 200 mg/day thalidomide). The median EFS was 9 months with MP and 13 months with MPT, and 2-year PFS was 33% versus 21%, P < 0.05. OS of those treated with MPT was also superior (40 vs. 31 months, P < 0.05). In a partner health-related quality-of-life study,403 the higher frequency of adverse events associated with the MPT arm did not translate into a negative effect on the health-related quality of life. Only the score for paresthesia worsened in the MPT arm, but subscales rating emotional function and future perspectives favored the MPT arm.
In the Nordic study,392 357 patients were randomized to MP (4 days of melphalan 0.25 mg/kg per day and prednisone 100 mg/day every 6 weeks) or MPT (MP plus 200 to 400 mg/day thalidomide). Treatment was continued to plateau and the thalidomide was continued until relapse. Although there were superior CR and PR rates in the MPT arm, there was no difference in PFS or OS between the two groups. In fact, there was a higher mortality rate in the first 6 months among the MPT patients over age 75. In a partner health-related quality-of-life study, patients in the
MPT arm had higher rates of constipation and lower rates of diarrhea, physical function, and social function.
MPT arm had higher rates of constipation and lower rates of diarrhea, physical function, and social function.
The final MP versus MPT study was conducted in Turkey where 114 patients were randomized to 12 months of MP (melphalan 9 mg/m2/day and prednisone 60 mg/m2/day for 4 days every 6 weeks) or MPT (MP plus thalidomide 100 mg/day continuously). Although response rates were higher in the MPT patients than the MP patients, PFS and OS did not differ.
CTDa (cyclophosphamide, thalidomide, and dexamethasone) is a variation on the theme of MPT. The MRC IX trial399 randomized elderly patients to either MP or CTDa (Table 98.4) to maximum response, with a minimum of six cycles to a maximum of nine cycles (Table 98.6). There was a secondary randomization to thalidomide or no thalidomide maintenance.404 Median follow-up is 44 months, and PFS was marginally better in the CTDa arm, but OS was not different between the two arms. Patients in the CTDa group had higher rates of sensory and motor neuropathy, thromboembolic events, constipation, infection, rash, and elevated alkaline phosphatase levels than did those in the MP group, but lower incidence of cytopenias.
The combination of thalidomide and dexamethasone (TD) has also been compared to MP.405 In these 282 elderly patients although there were higher response rates using TD (68% vs. 52%, P = 0.002), there was also higher rates AEs: neuropathy (72% vs. 33%), psychological toxicity (36% vs. 18%, P < 0.001), constipation (33% vs. 13%, P < 0.001), and a trend toward more DVTs (10% vs. 4%). The only toxicity more commonly seen in the MP arm was myelosuppression. With a median follow-up of 28 months, there was no difference in PFS, but there was a trend toward shorter OS among TD-treated patients which was more notable in patients older than 75 years. MP has also been compared to the combination of melphalan, prednisone, and lenalidomide in a three-arm phase III trial398: MP versus MP with lenalidomide (MPR) versus MPR with lenalidomide maintenance (MPR-R). A total of 459 patients was randomized to either MP (nine 4-week cycles of melphalan 0.18 mg/kg/day and prednisone 2 mg/mg/kg/day days 1 to 4), MPR (nine 4-week cycles of MP plus lenalidomide 10 mg days 1 to 21), or nine cycles of MPR with indefinite lenalidomide maintenance (10 mg days 1 to 21 every 4 weeks). Overall response rates were lowest in the MP (50%) arm with progressively better rates for MPR (68%) and MPR-R (77%). With a median follow-up period of 30 months, however, neither PFS nor OS was better among patients treated with MPR as compared to MP. MPR-R patients had better PFS (31 months vs. 14 and 13 months) but not 3-year OS (70%) as compared to the other two groups (62% vs. 66%). Toxicity was substantially higher in the lenalidomide arms.
The VISTA trial395 is the one large trial comparing MP to bortezomib and MP (VMP). Patients received nine 6-week cycles of either melphalan (at a dose of 9 mg/m2) and prednisone (60 mg/m2) on days 1 to 4, alone or in combination with bortezomib (1.3 mg/m2) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. All response and survival outcomes were superior with the VMP, most notably CR rates of 30% versus 4%. Median PFS was 24 months as compared to 17 months, and 3-year OS was 68% as compared to 54%.396 Time to response was also quicker with VMP 1.4 months versus 4.2 months. Grade 3 to 4 adverse events, however, were more frequent in patients receiving VMP (46% vs. 36%). A total of 33% of patients discontinued bortezomib due to toxicity. Peripheral sensory neuropathy occurred in 44% of patients with grade 3 to 4 in 13%. Neuralgia was also reported in 36% of patients.
There are three phase III trials for the elderly that compare VMP to other regimens.400, 406 A major finding of two of these trials was the feasibility and efficacy of changing the bortezomib scheduled from days 1, 4, 8, 11 every 21 days to a once-weekly schedule. This alteration dramatically reduced rates of peripheral neuropathy.
With median follow-up of 32 months, the VMP vs. VTP trial was negative.400 Response rates, PFS, and OS were comparable but grade 3 to 4 AEs were significantly higher in the VTP arm. More patients in the VTP arm discontinued therapy prematurely, and they had higher rates of cardiac events (8% vs. 0%) but lower rates of infection (1% vs. 7%). An analysis based on cytogenetic risk was done, comparing outcomes based on hyperdiploidy versus nonhyperdiploidy. The 3-year OS in the VMP-treated patients was no different based on cytogenetic risk category implying that this regimen may abrogate the risk of nonhyperdiploid cytogenetics; this difference was not observed in the VTP-treated patients. There was a secondary randomization in this trial to maintenance with either bortezomib and thalidomide (VT) or bortezomib with prednisone (VP).
Palumbo and colleagues randomized patients to receive either nine 5-week cycles of VMP (Table 98.6) or nine 5-week cycles of VMPT, which also added thalidomide 50 mg continuously, and continued with maintenance thalidomide along with alternate week bortezomib. Median follow-up at the time of the publication was 23 months. Response rates and PFS were higher in the four-drug combination with maintenance as compared to the three-drug with no maintenance, but OS was not different. Toxicity was significantly higher using the four-drug regimen: grade 3 to 4 neutropenia (38% vs. 28%; P < 0.02), cardiologic events (10% vs. 5%; P < 0.04), and thromboembolic events (5% vs. 2%, P < 0.08). The most important observation of this trial was that the bortezomib schedule could be changed from days 1, 4, 8, 11, 22, 25, 29, and 32 to days 1, 8, 15, and 22 without reducing efficacy (or actual dose of drug delivered) but significantly reducing adverse events. Severe sensory peripheral neuropathy was reduced from 16% to 3%.
The multicenter, phase IIIb UPFRONT study compares the efficacy and safety in newly diagnosed MM patients ineligible for HDT-SCT of three bortezomib-based induction regimens followed by weekly bortezomib maintenance: VcD (bortezomib-dexamethasone); VTD; and VMP.406 Although this has only been presented in abstract and oral presentation, the findings are important. Despite the highest rates of VGPR or better in the VTD arm (51% vs. 37% and 40%), with a median follow-up of 26 months, there was no difference in PFS or OS among the groups, but the mean global health status score (QOL) worsened for all groups during induction. During maintenance, QOL trended back toward baseline for the VcD and the VMP arms, but remained much lower than baseline for the VTD cohort.
Two trials address the combination of thalidomide-dexamethasone (TD) versus dexamethasone alone.407, 408 The smaller trial is discussed in a later section and is reviewed in Table 98.7 inasmuch as the majority of patients proceeded to ASCT.407 The larger trial is summarized in Table 98.6 and includes patients not destined for ASCT. In the TD arm, time to progression was significantly better (17.4 months, 95% CI: 8.1 months not reached versus 6.4 months, 95% CI: 5.6 to 7.4 months), but grade 3 to 4 adverse events were also higher: DVT/PE 15.4 versus 4.3%; cerebral ischemia 3.4% versus 1.3%; myocardial infarction 4.7% versus 1.3%, and peripheral neuropathy 3.8% versus 0.4%.407
In E4A03, the subset of patients aged 70 or older who were treated with lenalidomide with high-intensity dexamethasone (RD) or low-intensity dexamethasone (Rd) are considered.362, 409 Although in this trial there is no comparator to MP, it is still relevant because many judge it to be an effective and well-tolerated option for elderly patients. The major findings are shown in Table 98.6. Patients treated on the high-intensity dexamethasone arm had slightly higher response rates, comparable PFS, and inferior OS as compared the low-intensity dexamethasone arm. Rates of nonhematologic toxicity in the RD and Rd arms were 68% and 61%, respectively, with treatment-related deaths in 13% versus 4% of patients. The 2-year OS survival rate of 90% for patients treated with Rd in this randomized trial prompted a large trial
comparing Rd to MPT, which has completed accrual (MM-020), but has not yet been reported.
comparing Rd to MPT, which has completed accrual (MM-020), but has not yet been reported.
TABLE 98.7 OUTCOMES FOR INDUCTION REGIMENS AMONG PATIENTS DESTINED FOR AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT), RANDOMIZED CONTROLLED TRIALS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Transplant-Ineligible Patients: Induction Chemotherapy for Patients Ineligible for ASCT Prior to the 21st Century
The 1970s and 1980s were a testing ground for various combinations of alkylators, corticosteroids, and doxorubicin. Melphalan-cyclophosphamide-prednisone,256 carmustine-cyclophosphamide-prednisone,371, 372 melphalancyclophosphamide-carmustine-prednisone (MCBP),256, 353 and vincristine-melphalan-cyclophosphamide-prednisone (VMCP)256 resulted in response rates of 47%, 37% to 50%, 49% to 68%, and 62%, respectively. Median survivals with these regimens were 25 to 36 months.256, 353, 371, 372 Lee and Case260 introduced the five-drug regimen of vincristine-carmustine-melphalan-cyclophosphamideprednisone (VBMCP or the M-2 regimen), which included the same four drugs as MCBP plus vincristine; dose intensities, however, were different in these two regimens. The response rate for VBMCP was about 85% in previously untreated patients with a median survival of 38 months.260, 410 The success of the VBMCP regimen supported the value of vincristine. However, the MRC IV trial, which randomized 530 previously untreated patients with MM to MP versus melphalan-vincristine-prednisone, revealed no difference in either response rate or OS between the two arms.264 VMCP has not produced any response or survival advantage over MP.383, 411
Although subsequent randomized trials have substantiated the superior response rates of VBMCP over standard MP,
they have not demonstrated superior survival.263, 376, 385, 412 In fact, the meta-analysis performed by the Myeloma Trialists’ Collaborative Group216 involving 6,633 patients in 27 randomized trials, revealed a superior response rate (60.2% vs. 53.2%, P < 0.000001, two-tailed) but no survival benefit for combination chemotherapy over standard MP (Fig. 98.6). A prior meta-analysis of 18 published trials (3,814 patients) also demonstrated no benefit for combination chemotherapy in terms of survival. There was a suggestion of a survival advantage in the subgroup of patients with more aggressive disease,355 but this was not substantiated in the larger meta-analysis.216
they have not demonstrated superior survival.263, 376, 385, 412 In fact, the meta-analysis performed by the Myeloma Trialists’ Collaborative Group216 involving 6,633 patients in 27 randomized trials, revealed a superior response rate (60.2% vs. 53.2%, P < 0.000001, two-tailed) but no survival benefit for combination chemotherapy over standard MP (Fig. 98.6). A prior meta-analysis of 18 published trials (3,814 patients) also demonstrated no benefit for combination chemotherapy in terms of survival. There was a suggestion of a survival advantage in the subgroup of patients with more aggressive disease,355 but this was not substantiated in the larger meta-analysis.216
The use of alkylator-doxorubicin-based combination chemotherapy was stimulated by a report on the benefits of a combination of doxorubicin and BCNU in patients who had become resistant to melphalan.413 Regimens such as MAP (melphalan-doxorubicin-prednisone), CAP (cyclophosphamidedoxorubicin-prednisone), VCAP (vincristine and CAP), and VBAP (vincristine-BCNU-doxorubicin-prednisone) were tried; by SWOG response criteria, objective response rates were 41%, 46%, 64%, and 61%, respectively.256, 414 Median survival ranged from 30 to 32 months; subsequent analysis demonstrated a superior median survival for the VBAP arm of 37 months.415 Enthusiasm for alternating VMCP and VBAP (or VCAP) was generated by the SWOG study of 237 patients randomized to MP or the above regimens.380, 381 Response rates and OS were superior in the alternating combination chemotherapy arms compared to the MP arm,414, 415 but the survival benefits of this initial study were not reproducible by others.257, 377, 378, 382, 384, 416, 417 The V MRC myelomatosis trial randomized patients to ABCM (VBAP-VMCP without the vincristine or prednisone) or melphalan as a single agent on the basis of findings emanating from the IV MRC trial, which demonstrated a lack of benefit attributable to the addition of vincristine. Median survival in the ABCM group was superior to that of the melphalan-only arm (32 vs. 24 months, P = 0.0003).233, 266
Combination Chemotherapy with Interferon-α for Induction
IFN and dexamethasone have been combined as an induction regimen in patients with newly diagnosed myeloma and a low tumor mass. A retrospective comparison showed that the response rate of this regimen (57%) was similar to the response rate (48%) previously observed with dexamethasone alone.418 A randomized trial comparing MP, melphalan-dexamethasone, dexamethasone, and dexamethasone-IFN did not demonstrate any added benefit by incorportating IFN into the treatment regimen.249 Ahre et al.419 randomized 55 patients to MP or IFN (3 to 6 MU daily); response rates in the MP arm were significantly higher than in the IFN arm (44% vs. 14%, P < 0.001). These results spawned a multitude of trials adding IFN to MP420, 421, 422, 423, 424, 425, 426, 427, 428 and numerous alkylator-corticosteroid combinations with or without anthracycline422, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438 as part of an induction regimen. Results have been mixed. Two meta-analyses have been performed in an attempt to reconcile these conflicting results.439, 440 The first, reported in 2000,439 used published data and included 17 induction trials420, 421, 422, 423, 424, 425, 426, 427, 428, 430, 431, 432, 433, 434, 435, 437, 438 with 2,333 evaluable patients;439 the second, reported by The Myeloma Trialists’ Collaborative Group in 2001,440 used primary data from 12 induction trials420, 421, 422, 423, 424, 425, 426, 427, 428, 430, 432, 433, 434, 436, 437, 438, 441 involving 2,469 patients.440 Overall, the results were similar. In the first meta-analysis, the benefits attributable to the addition of IFN to the induction regimen included a 6.6% higher response rate (P < 0.002) and a 4.8-month and 3.1-month prolongation of relapse-free (P < 0.01) and OS (P < 0.01).439 In the second meta-analysis, patients receiving IFN had a slightly better response rate (57.5% vs. 53.1%, P = 0.01) and PFS (30% vs. 25% at 3 years, P < 0.0003), with a superior median time to progression of about 6 months. The survival advantage of 2 months, however, was not significant (P = 0.1).440 These meta-analyses suggest that incorporation of IFN into induction provides a modest prolongation of response and possibly of survival. Wisloff et al.442 evaluated the quality of life of 583 patients randomized to either MP or MP plus IFN as induction. During the first year of treatment with IFN, the patients reported significantly more fever, chills, dry skin, fatigue, pain, nausea, vomiting, and appetite loss than the control patients. After the first year, however, the only symptom reported more often was dizziness. Although patients receiving IFN had a 5- to 6-month prolongation of the response and plateau phase, there was no late quality-of-life benefit observed to compensate for the early impairment. The authors questioned the clinical value of the plateau phase prolongation and reported that only 60% of patients continued to receive IFN after 24 months, suggesting that their data might underestimate the potential toxicity of the drug.
Transplant Eligible Patients
VAD-like regimens—incorporating different corticosteroids,243, 246, 443 and C-VAMP (cyclophosphamide-vincristinedoxorubicin-methylprednisolone)245 had commonly been used as induction therapy before stem cell collection and transplantation, but have been largely replaced by regimens incorporating IMiDs and/or proteasome inhibitors. These VAD-like regimens had initially been piloted with salutary effect in relapsed disease, and were subsequently applied in previously untreated patients with response rates of 50% to 84%.444, 445, 446, 447, 448, 449, 450, 451, 452, 453 Median survival for patients treated initially with VAD and no transplant was about 36 months.454 The complete response rate of C-VAMP was higher than that of VAMP alone, but survival was not different.447 Response rates of 80% have also been achieved using the CAD (cyclophosphamide-doxorubicin-dexamethasone) regimen.455 The addition of etoposide to C-VAD appears to contribute only toxicity.456
By the late 1990s and early 2000s, single-agent high-dose dexamethasone was used by some experts in lieu of VAD for induction in those patients destined for stem cell collection based on a nearly comparable response rate of single-agent high-dose dexamethasone of 43%242 and the advantage of an oral noninfusional therapy. This strategy was used successfully, resulting in adequate collections of peripheral blood stem cells without any apparent adverse effects on complete remission rates or progression-free survival in several single-arm studys.457, 458 With the advent of additional therapies, single-agent dexamethasone is no longer a standard induction option.
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