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Multiple Myeloma: An Overview in 1996

Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA

Correspondence: R.A. Kyle, M.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

	ABSTRACT

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Multiple myeloma (MM) has an incidence of approximately four per 100,000 per year. Ninety-nine percent of patients with MM have a monoclonal (M-) protein in the serum or urine during the course of their disease. MM must be differentiated from smoldering multiple myeloma (SMM), which has an M-protein value of more than 30 g/l and more than 10% plasma cells in the bone marrow, but no other features of MM. The plasma cell labeling index (PCLI) and the presence of circulating plasma cells in the peripheral blood help to differentiate monoclonal gammopathy of undetermined significance and SMM from MM. The current median duration of survival with chemotherapy is about three years. Patients with low PCLI and low ß₂-microglobulin values have a median duration of survival of approximately six years. Melphalan and prednisone produce an objective response in 50% to 60% of patients. Combinations of chemotherapy produce a higher response rate, but the survival rate is not different. Allogeneic bone marrow transplantation is associated with a mortality rate of 25% within six months and an actuarial survival rate of 28% at seven years. Autologous peripheral stem cell transplantation is applicable to more patients and is reported to produce a higher response rate and longer survival than chemotherapy, but most patients will eventually have relapse.

Key Words. Differential diagnosis • Multiple myeloma • Allogeneic transplantation • Autologous transplantation • Treatment

	INTRODUCTION

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Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. The plasma cell proliferation usually results in extensive skeletal destruction with osteolytic lesions, hypercalcemia, anemia, and, occasionally, plasma cell infiltration in different organs [1,2]. The excessive production of a monoclonal (M-) protein can lead to renal failure, hyperviscosity syndrome or recurrent bacterial infections. Although MM was described in 1844 by Solly and subsequently in 1850 by MacIntyre, it was rarely recognized until 1889, when Kahler reported the case of Dr. Loos. Kahler recognized the unique protein in the patient’s urine, which had been described by Henry Bence Jones almost a half century earlier [3].

	ETIOLOGY AND EPIDEMIOLOGY

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The cause of MM is unknown. Radiation may be a factor in some cases. An increased incidence of MM has been reported in atomic bomb survivors exposed to more than 50 cGy of radiation and in radiologists who had relatively large doses of long-term radiation. Exposure to asbestos, benzene, or industrial and agricultural toxins, a genetic element, and viruses have all been considered possible causes, but proof is meager. A relationship between MM and pre-existing chronic inflammatory diseases has been suggested, but a recent case-control study provided no support for the role of chronic antigenic stimulation [4]. MM has been reported in familial clusters of two or more first-degree relatives and in identical twins. Thus, a genetic element may exist in some patients.

MM accounts for about 1% of all types of malignant disease and slightly more than 10% of hematologic malignancies. The incidence of MM is approximately four per 100,000 per year [5]. The apparent increase of rates in recent years is probably related to increased availability and utilization of medical facilities and improved diagnostic techniques, particularly in the older population. The incidence in African-Americans is twice that in Caucasians and is slightly higher in men than in women. The median age at diagnosis is approximately 65 years. Less than 3% of patients are younger than 40 years [6].

	BIOLOGIC AND MOLECULAR ASPECTS

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Myeloma cells express CD38 and PCA-1 and are CIg-positive. Most myeloma cells express interleukin 1ß (IL-1ß) and CD56. Only a minority express CD10, HLA-DR and CD20. However, the nature of the clonogenic cell in MM is still unknown. It is likely that plasma cell precursors of myeloma circulate in the peripheral blood. These circulating clonogenic pre-myeloma cells may home to the bone marrow by means of adhesion molecules, where they find an appropriate microenvironment in which to differentiate and proliferate. T cells may play an important role. Expansion of T cell subsets has been recognized in MM. Resting B cells enter into DNA synthesis stimulated by IL-4, proliferate with IL-5, and differentiate into plasma cells with IL-6. IL-6 is an important growth factor for myeloma cells. Elevated IL-6 levels have been found in many patients with progressive, terminal MM and in those with plasma cell leukemia, in contrast to patients with monoclonal gammopathy of undetermined significance (MGUS).

Increased expression of C-myc, N-ras, K-ras and BCL-2 has been found in myeloma; ras mutations have been reported in about 40% of patients with MM. Shorter survival has been noted in patients with a mutation in the K-ras gene. Point mutations of the tumor suppressor gene p53 occur in about 15% of patients. Thus, C-myc, N-ras, K-ras and p53 genes may be involved in the pathogenesis of myeloma. Flow cytometric analysis has led to the demonstration of an aneuploid myeloma cell population in approximately 80% of patients. Hyperdiploidy occurs in 70% and hypodiploidy in about 10%. Cytogenetic studies have been hindered because of the low proliferative activity of plasma cells. Cytogenetic abnormalities have been detected in about half of patients; no specific abnormality has been demonstrated. Partial or complete deletions of chromosome 13 or abnormalities involving 11q have been associated with a poor prognosis [7].

	CLINICAL MANIFESTATIONS

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Bone pain, particularly in the back or chest and less often in the extremities, is present at diagnosis in more than two-thirds of patients. The pain is usually induced by movement and does not occur at night except with change of position. The patient’s height may be reduced several inches because of vertebral collapse. Weakness and fatigue are common and are often associated with anemia. Fever from the disease itself is rare; most patients with MM and fever have an infection. Epistaxis or purpura may occur. Symptoms from hypercalcemia, renal insufficiency, acute infection, or amyloidosis (AL) may be the initial manifestations.

Pallor is the most common physical finding. The liver is palpable in about 20% of patients and the spleen in 5%. Extramedullary plasmacytomas are not common and usually occur late in the course of the disease as large, vascular, subcutaneous masses with a purplish hue. Table 1 presents the findings at diagnosis of MM patients.

Skeletal Involvement
Conventional radiographs show abnormalities consisting of punched-out lytic lesions, osteoporosis or fractures in 75% of patients at diagnosis. Technetium-99m-labeled bone scans are inferior to conventional radiographs for the detection of lytic lesions. Computed tomography and magnetic resonance imaging are more sensitive and may be useful when skeletal pain is atypical and radiographs show no abnormalities.

Other Organs
Radiculopathy is the single most frequent neurologic complication. It results from compression of the nerve by epidural extension from a vertebral lesion or by the collapsed bone itself and is usually in the thoracic or lumbosacral area. Compression of the spinal cord occurs in 5% to 10% of patients. Peripheral neuropathy is uncommon in MM, and when present it is usually due to AL. Leptomeningeal myelomatosis is rare but is being recognized more frequently.

The incidence of infection is increased in MM. Diplococcus pneumoniae and Staphylococcus aureus were the most frequent pathogens, but more recently gram-negative organisms are more common. Impaired antibody response, deficient normal immunoglobulins, impaired serum opsonic activity and neutropenia all contribute to the increased incidence of infections. Treatment with glucocorticoids, particularly high-dose dexamethasone, is an important cause of infection. Herpes zoster is common.

	LABORATORY FINDINGS

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Normocytic, normochromic anemia is present at diagnosis in about two-thirds of patients. The leukocyte count is usually normal, but leukopenia may occur. Thrombocytopenia is present in approximately 15% of patients at diagnosis.

The serum protein electrophoretic pattern shows a peak or localized band in 80% of patients; hypogammaglobulinemia or a normal pattern is found in the remainder. An M-protein is found in the serum in about 90% of patients at diagnosis. More than 15% of patients have a free or M-protein (Bence Jones proteinemia) (Fig. 1). Immunoelectrophoresis or immunofixation of the urine reveals an M-protein in 75%. About two-thirds are . An M-protein is found in the serum or urine in 99% of patients during the course of their disease.

View larger version (27K): [in this window] [in a new window]   Figure 1. Type of serum monoclonal protein in 984 cases of multiple myeloma at Mayo Clinic from 1982 to 1994.

	DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

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As illustrated in Table 2, minimal criteria for the diagnosis of MM are bone marrow containing more than 10% plasma cells or a plasmacytoma plus at least one of the following: A) M-protein in the serum (usually more than 30 g/l), B) M-protein in the urine, or C) lytic bone lesions. The patient must have the usual clinical features of MM (Table 1). The main conditions to consider in the differential diagnoses are MGUS, smoldering multiple myeloma (SMM), AL, lymphoma and metastatic carcinoma. An M-protein value less than 30 g/l, less than 10% bone marrow plasma cells, absence of lytic lesions, anemia, hypercalcemia, or renal insufficiency in an asymptomatic patient are characteristic of MGUS. An M-protein value more than 30 g/l and more than 10% bone marrow plasma cells fulfill the diagnostic criteria for SMM in asymptomatic patients [8]. In these patients, the diagnosis must be recognized and no treatment given because they may remain stable for months to years.

In summary, no single factor can differentiate a patient with MGUS from one in whom MM or other malignant disease will subsequently develop. The serum and urinary M-protein values should be periodically measured, and clinical and other laboratory features should be re-evaluated to determine whether MM, AL, macroglobulinemia or other lymphoproliferative disorders have developed.

Patients with MGUS should have a repeat serum protein electrophoresis in six months. If there is no progression, electrophoresis and a clinical evaluation should be performed annually thereafter. Patients should be told that the risk of development of a serious disease is only 25% even after follow-up for more than 20 years. However, they should be aware that evolution from MGUS to MM may occur quickly, and they should be advised to be examined promptly if clinical symptoms occur.

The differentiation of AL from MM is arbitrary because both are plasma cell proliferative disorders. In AL, the proportion of bone marrow plasma cells is usually less than 20%, there are no osteolytic lesions and the amount of Bence Jones protein in the urine is modest. In AL, a nephrotic urinary protein pattern is common, and the monoclonal light-chain band is small and overshadowed by albumin. It is obvious that AL and MM have overlapping features in the spectrum of the plasma cell proliferative disorders. The most likely diagnosis is metastatic carcinoma with an unrelated MGUS in a patient with constitutional symptoms, osteolytic lesions, a modest M-component and fewer than 10% bone marrow plasma cells. The plasma cells will also be polyclonal in this setting.

	PROGNOSIS

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MM has a progressive course; the median duration of survival is six months when no treatment is given (Table 3). The current median duration of survival with chemotherapy is about three years. Approximately 20% to 25% of patients survive five or more years, but only 2% to 4% live longer than 10 years. The bone marrow PCLI and ß₂-microglobulin levels are the most important prognostic factors in previously untreated myeloma [11,12]. In our experience, patients younger than 65 years who have a low PCLI and a low ß₂-microglobulin level have a median duration of survival of approximately six years. In addition, elevated soluble IL-6 receptor, lactate dehydrogenase, and C-reactive protein levels, presence of plasmablastic morphology, older age, presence of circulating plasma cells in the peripheral blood, increased colony growth, low numbers of CD4 T cells, increased thymidine kinase level and increased levels of IL-6 are all associated with a poorer prognosis.

Except for a few rare cases in which cure is achieved with conventional chemotherapy, all patients with myeloma will eventually have relapse and become refractory to chemotherapy. The most important feature of relapse is an increase in the M-protein level, in addition to clinical and laboratory characteristics of progressive disease. Occasionally, relapse consists of only an increase in Bence Jones proteinuria or osteolytic lesions without an increase in the serum M-protein level. In the acute or aggressive terminal phase characterized by rapid tumor growth, pancytopenia and, often, rapidly enlarging soft tissue masses, decreasing levels of M-protein or fever may occur [14]. In this case, patients do not respond satisfactorily to chemotherapy, and usually they survive for only a few months.

	TREATMENT

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Not all patients who fulfill the minimal criteria for the diagnosis of MM should be treated. Patients with SMM or MGUS should not be treated. The symptoms, physical findings and all laboratory data must be considered. If there is doubt in the physician’s mind, it is usually better to withhold therapy and to re-evaluate the patient in two or three months.

Chemotherapy
Chemotherapy is the preferred initial treatment for overt, symptomatic MM. In most instances, analgesics, together with chemotherapy, can control the pain. This combination is preferred to focal radiation because the bone marrow reserve of many patients is limited and focal irradiation does not benefit systemic disease. Palliative radiation, at doses of 20 Gy to 30 Gy, should be limited to patients with severe and persistent pain from a localized lesion that does not respond to chemotherapy.

The oral administration of melphalan and prednisone produces objective response in 50% to 60% of patients. We prefer to give melphalan orally in a daily dosage of 0.15 mg/kg for seven days (8 to 10 mg/day) and 20 mg of prednisone three times daily for the same period. The melphalan must be given while the patient is fasting because food reduces absorption. If renal failure is present, the initial dosage of oral melphalan should be reduced by 25%. Leukocyte and platelet levels should be determined every three weeks after beginning each cycle of chemotherapy, and the melphalan and prednisone therapy should be repeated every six weeks. The dosage of melphalan must be adjusted until mid-cycle cytopenia occurs because absorption of the agent is variable.

Because of the obvious shortcomings of melphalan and prednisone, various combinations of therapeutic agents have been tried. One of the best-known combinations is the M2 protocol, which includes vincristine, carmustine (BCNU), melphalan, cyclophosphamide and prednisone (VBMCP). This regimen produces an objective response in about 70% of patients. In a recent Eastern Cooperative Oncology Group study, the addition of interferon 2a (IFN-2a) to VBMCP produced a higher percentage of complete responses, but the overall duration of survival of 43 months was the same as that with VBMCP. Complete responses were more common with the IFN-2a regimen (17%) than with VBMCP alone (10%) (p < 0.03) [15]. In a large series from the Medical Research Council, treatment with doxorubicin (Adriamycin), BCNU, cyclophosphamide, and melphalan (ABCM regimen) increased both the proportion of patients reaching the plateau phase and the survival in comparison with melphalan alone [16]. In a meta-analysis of 18 published trials, no difference in efficacy was shown between melphalan-prednisone and combination chemotherapy [17]. However, there was an implication that melphalan-prednisone was superior for patients with a good prognosis and inferior to combination chemotherapy for those with a poor prognosis.

Chemotherapy should be continued for at least one year or until the patient is in a plateau state. This is defined as stable serum and urine M-protein levels and no evidence of progression. Continued chemotherapy may lead to the development of a myelodysplastic syndrome or acute leukemia [18]. IFN-2a appears to prolong the duration of the plateau state but does not significantly influence survival [19]. Patients should be followed closely during the plateau state, and the same chemotherapy should be reinstituted when relapse occurs. The treatment of MM has recently been reviewed [20].

Allogeneic or Syngeneic Bone Marrow Transplantation
Bone marrow transplantation from an identical twin donor (syngeneic) has been associated with occasional prolonged survival, but most patients die of their MM. Allogeneic bone marrow transplantation is advantageous in that the graft contains no tumor cells that can subsequently lead to a relapse [21–23].

The European Group for Bone Marrow Transplantation reported 162 patients who received an allogeneic bone marrow transplant from 1983 to 1993. The median age was 43 years (range: 23 to 59 years) [24]. Forty-four percent of all patients obtained a complete remission. The stage of the disease at diagnosis, number of regimens of prior treatment, and status at the time of conditioning were important prognostic factors for obtaining a complete remission. Patients with IgA or Bence Jones myeloma and females had a better response, as did patients with a ß₂-microglobulin value less than 339 nmol/l (4 mg/l). The actuarial survival rate was 32% at four years and 28% at seven years. Survival was related to response. Of the 72 patients who had a complete remission, only five were in complete remission more than four years after transplantation. Six patients received marrow from non-sibling donors—three were unrelated donors. Five of the six patients died within 2.5 months [24].

However, only 5% to 8% of patients with MM are eligible for allogeneic transplantation because an HLA-compatible donor is available in only one-third of patients, 80% are older than 50 years, and renal insufficiency (creatinine value more than 177 µmol/l) occurs in 20%. In addition, a significant mortality rate of 25% within six months, the risk of graft-versus-host disease and eventual relapse in most patients make allogeneic bone marrow transplantation currently of limited use.

Autologous Peripheral Blood Stem Cell Transplantation
Autologous bone marrow transplantation has been virtually replaced by autologous peripheral blood stem cell transplantation because there is less contamination with myeloma cells and engraftment is more rapid. Autologous peripheral blood stem cell or bone marrow transplantation is applicable to more patients than allogeneic transplantation because the age limit is higher (65 to 70 years) and a matched donor is unnecessary. However, two major problems exist: A) eradication of MM from the patient usually does not occur, even with large doses of chemotherapy and irradiation; and B) reinfusing autologous peripheral blood stem cells or bone marrow contaminated by myeloma cells or their precursors is a major concern.

Attal et al. [25] of the French Myeloma Group described 200 patients with previously untreated MM who were randomized to receive autologous bone marrow transplantation or chemotherapy. Chemotherapy consisted of alternating cycles of vincristine, melphalan, cyclophosphamide and prednisone (VMCP) and BCNU, vincristine, doxorubicin (Adriamycin), and prednisone (BVAP) given at three-week intervals for 12 months. IFN-2a was given three times weekly from cycle 9 until relapse. After four cycles of VMCP and BVAP, bone marrow was collected and transplantation was done if the performance status was grade 1 or 2, the serum creatinine value was less than 150 µmol/l and more than 200,000,000 nucleated cells/kg had been collected. Seventy-four patients underwent transplantation. Thirty-eight percent of the patients in the transplant group had complete or very good partial responses, compared with 14% for the chemotherapy group. The overall survival probability at five years was 52% in the transplant group and 12% in the chemotherapy group (p = 0.03). With multivariate analysis, the serum ß₂-microglobulin value and the treatment regimen were significant prognostic factors. Overall survival was related only to the level of ß₂-microglobulin (p = 0.001). The results with chemotherapy were inferior to those expected.

In a recent study of 608 evaluable patients treated with chemotherapy, the actuarial survival at five years was 30% [15]. However, Bladé et al. [26] reported that 77 of 487 patients treated with chemotherapy could have been candidates for autologous stem cell transplantation. They were younger than 65 years, had stage II or III myeloma, had a performance status of grade 1 or 2, and had objective or partial response to initial chemotherapy. The median survival in these patients treated with chemotherapy was 60 months, which is comparable to the French transplant experience.

Sixty-three patients with MM received an autologous bone marrow or peripheral blood stem cell transplant after treatment with busulfan and cyclophosphamide and total body radiation. Two-thirds of the patients had resistant disease and 69% had received chemotherapy for more than six months previously. Twenty-five percent died within 100 days, and 40% obtained a complete remission. The probability of survival at three years was 43%. ß₂-microglobulin levels more than 212 nmol/l (2.5 mg/dl), more than two regimens of prior therapy at the time of transplantation, longer than three years from diagnosis, and prior radiation were associated with adverse outcomes [27].

Prior treatment with alkylating agents reduces the number of granulocyte-macrophage colony-forming units per kilogram and results in delayed engraftment. Prince et al. [28] showed that more than 200 mg/m² of melphalan produced delayed engraftment.

Selection of CD34⁺Lin^-Thy⁺ stem cells may be a useful approach [29]. CD34 cells can be selected from cryopreserved material, expanded ex vivo, and then reinfused [30]. Gazitt et al. [31] showed that the highest proportions of hematopoietic progenitor cells were obtained during the first two days of leukapheresis, whereas increased numbers of myeloma cells were present on days 5 and 6. Purging of the marrow in vitro with a combination of monoclonal antibodies [32] or cytotoxic agents is not effective for routine clinical use.

It is essential to develop more sensitive techniques for detection of residual myeloma with the advent of more aggressive therapy with autologous and allogeneic transplantation. When the M-protein is not detected in the serum and urine with immunofixation and the bone marrow contains no identifiable myeloma cells with immunofluorescence, the patient still frequently has relapse with myeloma of the same isotype that was present initially. Oligonucleotide primers to amplify regions of rearranged heavy-chain alleles with polymerase chain reaction can detect one myeloma cell in 100,000 cells [33].

	TREATMENT FOR REFRACTORY MULTIPLE MYELOMA

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Almost all patients with MM who respond to chemotherapy eventually have relapse. The highest response rates for patients resistant to alkylating agents have been with VAD (vincristine, doxorubicin [Adriamycin] and dexamethasone). Most of the activity of VAD is from dexamethasone. Intravenous methylprednisolone (2 g three times weekly intravenously for a minimum of four weeks) is helpful for patients with pancytopenia, and we find fewer side effects than from dexamethasone. If there is a response, administration of methylprednisolone is reduced to once or twice weekly [34]. VBAP (vincristine, carmustine [BCNU], and doxorubicin [Adriamycin] on day 1 and prednisone daily for five days every 3 to 4 weeks) benefits 30% of patients. IFN-2a produces an objective response in 10% to 20% of patients with myeloma refractory to alkylating agents. Cyclophosphamide (600 mg/m² intravenously daily for four days) plus prednisone followed by granulocyte-colony-stimulating factor has been helpful in refractory patients with advanced disease.

Other Therapeutic Approaches
Paclitaxel (Taxol®) has been disappointing in that it produces an objective response in about 25% of patients, but it is associated with considerable neutropenia. Topotecan has also produced some objective responses. Of 17 patients with refractory myeloma, six experienced some tumor response from IL-2: two had an objective reduction in tumor mass, and four remained stable during treatment [35].

The reversal of resistance to chemotherapeutic agents is an important area of research. The use of verapamil or quinine to reverse the resistance to doxorubicin (Adriamycin) has been disappointing. PSC 833, an analog of cyclosporin, is being investigated in an effort to reduce multidrug resistance to vinca alkaloids and anthracyclines. It appears to be a much more effective inhibitor of multidrug resistance than cyclosporin A.

The use of a high-affinity monoclonal antibody against CD38 with a complementarity-determining region-grafted humanized IgG1 is of interest [36]. Immunization with the autologous monoclonal immunoglobulin produced an amplified anti-idiotype T cell response in three of five patients and may be of future benefit [37].

The use of monoclonal antibodies to IL-6, a potent growth factor for plasma cells, inhibited C-reactive protein synthesis, lowered IL-6 production, and reduced the labeling index in some patients with advanced myeloma and plasma cell leukemia. However, the use of this murine antibody is not yet practical for therapy [38]. New agents for the treatment of MM are needed.

Management of Complications
Hypercalcemia must be suspected if the patient has anorexia, nausea, vomiting, polyuria, increased constipation, weakness, confusion, stupor or coma. Treatment is urgent because renal insufficiency commonly develops. Hydration, preferably with isotonic saline, is essential. In addition, oral prednisone in an initial dosage of 25 mg four times daily should be given, but the dosage must be reduced and use of the drug discontinued as soon as possible. If these measures fail to control the hypercalcemia, pamidronate (Aredia), etidronate (Didronel) or gallium nitrate is useful.

Maintenance of a high fluid intake (3 l of urine/24 h) is important for preventing renal failure. Allopurinol is necessary if hyperuricemia is present. Patients with acute renal failure should be treated promptly with fluid and electrolyte correction and then with hemodialysis if necessary. Peritoneal dialysis is useful in patients with hypotension from hemodialysis. Plasma exchange may be helpful for regaining renal function, but patients with severe myeloma cast formation or other irreversible renal changes are not likely to benefit from plasmapheresis. Renal transplantation for myeloma kidney has been followed by prolonged survival.

Prompt and appropriate treatment of bacterial infections is necessary. Pneumococcal and influenza vaccines should be given to all patients despite their suboptimal antibody response. Intravenously administered gamma globulin may be helpful for patients with recurrent infections, but it is very expensive for long-term therapy. Prophylactic daily oral penicillin often benefits patients with recurrent pneumococcal pneumonia infections. Patients should be encouraged to be as active as possible, because confinement to bed increases demineralization of the skeleton. Trauma must be avoided because even mild stress may result in a fracture. Fixation of long-bone fractures or impending fractures with an intramedullary rod and methyl methacrylate has given excellent results. Bisphosphonates such as pamidronate may be of benefit for reduction of skeletal complications [39]. Erythropoietin is helpful for many patients with symptomatic anemia when the plateau state has been reached [40,41].

Symptoms of hyperviscosity include oronasal bleeding, blurred vision, neurologic symptoms and congestive heart failure. Hyperviscosity is more common in IgA myeloma than in IgG myeloma. Plasmapheresis promptly relieves the symptoms of hyperviscosity. If spinal cord compression is suspected, magnetic resonance imaging, computed tomography or myelography must be done immediately to determine whether an extradural mass is causing the symptoms. Radiation therapy to the lesion is usually beneficial.

	ACKNOWLEDGMENT

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This work was supported in part by NIH Grant CA 62242 from the National Cancer Institute.

	REFERENCES

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