Multiple myeloma: Vague symptoms can challenge diagnostic skills

Multiple myeloma is a hematologic malignancy characterized by a clonal proliferation of plasma cells that secrete a monoclonal protein. Infiltration of malignant cells into the bone marrow results in bone destruction. Bone pain, fatigue, and recurrent infections are the most common manifestations.1 Other signs and symptoms at presentation include anemia, renal failure and hypercalcemia, polyneuropathy, and spinal cord compression. However, approximately 10% of patients are asymptomatic.2 The variety of manifestations can make diagnosing multiple myeloma a challenge. Although the disease remains incurable, several new treatments are effective in achieving remission. This article reviews the clinical characteristics, diagnosis, and treatment of multiple myeloma.

Multiple myeloma accounts for 10% of hematologic malignancies and 1% of all malignancies.3 Annual incidence in the United States is 4 cases for every 100,000 persons.4 In 2007, an estimated 19,900 new diagnoses of multiple myeloma were made in the United States.5 

Multiple myeloma primarily afflicts older persons. The average age at diagnosis is about 66 years, and the disease is rare in patients younger than 40 years.1 The incidence is higher in African-Americans by a ratio of 2:1.6 The incidence is also slightly higher in men than women.

The signs and symptoms of multiple myeloma are nonspecific. Patients can present in a variety of clinical settings, which may further delay diagnosis and result in additional disease-related complications. In one study of new myeloma diagnoses, 40% of patients had experienced symptoms for more than 6 months before the diagnosis was made.7 Delays occur because patients do not seek medical attention or because clinicians do not suspect the disease.

Bone pain, the most common presenting symptom, occurs in approximately two-thirds of patients.1,7 The pain is caused by lytic bone lesions that form most often in the back or ribs. The lesions are a result of excess osteoclast activation and suppression of osteoblasts mediated by the malignant cells.8 Bone marrow involvement can be focal or diffuse; bone damage manifests as lytic lesions or a loss of bone density. Patients with myeloma also have an increased risk of vertebral compression fractures. Spinal cord compression can result from a collapsed vertebrae or extramedullary tumor. 

At diagnosis, 15% to 30% of patients are found to have acute renal failure.3,9 Precipitating causes include the presence of excess myeloma protein, hypercalcemia as a result of excess osteoclast activity in the bones, dehydration, infection, and the use of NSAIDs for bone pain.2 Renal disease is more common in patients who produce excess light chains that get filtered through the glomeruli but then accumulate in the tubules. Renal function returns to normal after treatment in about 50% of patients.10

Anemia, often associated with fatigue and usually normocytic and normochromic, is present in nearly three-quarters of patients at diagnosis.1 Frequent infections are also common because immune function becomes suppressed. Although unusual, hyperviscosity of the blood can manifest as fatigue, headache, blurry vision, and confusion. Other less common manifestations include neuropathy and uremia. 

Some patients are asymptomatic at the time of diagnosis. In such cases, myeloma is often diagnosed from an incidental detection in an abnormal blood test result, such as an elevation in serum total protein. 

Patients with monoclonal protein in the blood or urine have either a premalignant condition termed monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma. Multiple myeloma is further categorized as smoldering or active, based on the presence or absence of end-organ damage11 (see Table 1).

MGUS is much more prevalent than multiple myeloma and is a common finding in the general population. In a recent study conducted in Olmstead County, Minnesota, 3.2% of persons older than 50 years and 5.3% of persons older than 70 years were found to have MGUS.12 Although patients with MGUS do not require treatment, continuous monitoring with routine blood and urine tests is necessary. The rate of conversion from MGUS to multiple myeloma is about 1% per year.12

The majority of patients with myeloma typically have excess IgG or IgA. The presence of IgM monoclonal protein is usually a sign of Waldenström's macroglobulinemia, a low-grade lymphoproliferative disorder. IgD and IgE myeloma are rare subtypes, accounting for just 2% of cases.1 About 20% of patients with multiple myeloma secrete monoclonal protein only in the form of light chains in the urine, commonly referred to as Bence Jones proteinuria. Approximately 3% of cases are nonsecretory myeloma, in which the malignant cells do not produce a measurable amount of monoclonal protein in the blood or urine.1 

Physical examination findings in a patient with newly diagnosed multiple myeloma often are unremarkable. Hepatomegaly is seen in 4% of patients, and splenomegaly is seen in 1% of patients.1 Palpable plasmacytomas are occasionally found on examination, particularly in the skull.

Laboratory studies recommended by the National Comprehensive Cancer Network include a CBC with differential, BUN, creatinine, albumin, serum electrolytes, quantitative immunoglobulins, serum protein electrophoresis and immunofixation, beta2-microglobulin, C-reactive protein, and lactate dehydrogenase. A 24-hour urine collection should be evaluated for total protein, protein electrophoresis, and immunofixation. The serum free light chain assay is a useful new test, but it cannot be used in place of 24-hour urine protein in most situations. 

A unilateral bone marrow biopsy and aspirate will determine the presence of plasmacytosis.13 Fluorescence in situ hybridization and cytogenetic studies of the aspirate are recommended. Deletion of chromosome 13 (del[13]) and translocation of chromosomes 4 and 14 (t[4;14]) are associated with a worse prognosis.14 The plasma cell labeling index measures proliferative activity of the malignant cells; this bone-marrow test also has prognostic significance.1 

A skeletal survey for the presence of lytic bone lesions is needed. MRI, particularly of the skull, spine, and pelvis, can show the degree of tumor burden and rule out spinal cord compression if vertebral fractures are present. Bone densitometry is used to determine the degree of bone density loss. Positron emission tomography/CT is used to assess tumor burden in patients in whom laboratory tests are not conclusive, such as those with nonsecretory myeloma.

Two staging systems are used in clinical practice. The Durie-Salmon Staging System provides information on the tumor burden but not on the patient's prognosis. The newer International Staging System is based on serum albumin and beta2-microglobulin test results (see Table 2). This system is a more accurate predictor of prognosis. The median survival times for patients with stages I, II, and III multiple myeloma are 62, 44, and 29 months, respectively.15 

Most patients with multiple myeloma are able to achieve remission with treatment; however, the disease remains incurable and relapse is inevitable. In the past, patients who relapsed after receiving conventional chemotherapy had few treatment options. At present, however, the number of available treatment options has increased and several novel agents offer hope of prolonged survival.

After a diagnosis of active multiple myeloma is confirmed, the clinician must determine if the patient is a candidate for high-dose chemotherapy and stem cell transplantation. High-dose melphalan supported by autologous stem cell transplantation is considered as standard therapy for patients younger than 65 years, as well as for those who are older and have few comorbidities and a good performance status.16 However, exposure to alkylating agents such as melphalan can impair the collection of stem cells; therefore most patients receive a corticosteroid-containing regimen as initial therapy in preparation for stem cell transplantation. For patients who are not candidates for stem cell transplantation, the standard frontline treatment is oral melphalan and prednisone in combination with thalidomide or bortezomib.17,18 

Patients who have a relapse of disease following initial therapy should receive additional treatment. Several trials have shown the survival advantages and efficacy of thalidomide, bortezomib, and lenalidomide. 

Thalidomide was used as an antiemetic and sleeping aid for pregnant women until it was removed from the market because of its teratogenicity. The efficacy of thalidomide in patients with refractory multiple myeloma was first demonstrated in 1999.19 A major dose-limiting toxicity of this drug is peripheral neuropathy, which occurs in 50% to 80% of patients.20 Other side effects include constipation, fatigue, and hypotension. The risk of thromboembolism is increased when thalidomide is taken in combination with corticosteroids; therefore patients should receive prophylactic antithrombotic therapy. 

Bortezomib is a proteasome inhibitor, the first drug in this class to receive FDA approval for the treatment of multiple myeloma relapse. Proteasome inhibition arrests the cell cycle and apoptosis, as well as other pathways needed for cancer cell growth and survival.21 Common side effects of this agent include thrombocytopenia, nausea, diarrhea, and peripheral neuropathy.21 

Lenalidomide is a thalidomide analogue that has shown significant antimyeloma activity. The effectiveness of this drug when combined with dexamethasone was demonstrated in two phase III clinical trials.22,23 Patients receiving the combination had an average remission of 11 months compared to 5 months in patients taking dexamethasone alone.22,23 Based on the results of these trials, the FDA approved lenalidomide for the treatment of myeloma relapse in June 2006. Lenalidomide is an oral drug whose side effects include neutropenia and thrombocytopenia. Like thalidomide, lenalidomide increases the risk of thromboembolic events when combined with corticosteroids.

Supportive care includes intravenous bisphosphonates, especially for patients with skeletal damage. The two drugs commonly used are pamidronate and zoledronic acid, typically administered in a monthly regimen. These agents inhibit osteoclast activity and have been shown to reduce the incidence of skeletal complications and improve quality of life.24 The primary side effects associated with long-term use of bisphosphonates are renal insufficiency, hypocalcemia, and osteonecrosis of the jaw (ONJ).3 Zoledronic acid is associated with a higher incidence of ONJ than pamidronate.25

The average survival of patients with myeloma used to be 3 years.3 Improved safety of autologous stem cell transplantation and the availability of novel drug therapies have increased median survival to more than 5 years. Patients eventually die from complications of the disease including renal failure, infection, and hemorrhage. 

The newer treatments for relapsed disease are still being studied in the frontline setting, and additional new therapies are in clinical trials. New technology such as gene expression profiling is also being studied. This technology may one day make it possible to tailor treatments to the specific genetic makeup of a patient's myeloma cells. 

CONCLUSION

Multiple myeloma is a hematologic malignancy that can affect several organ systems. Patients experience a variety of nonspecific symptoms and may present in a number of different clinical settings. PAs should include this disease in the differential diagnosis of patients presenting with bone pain, fatigue, recurrent infections, and other nonspecific signs and symptoms. Although the disease remains incurable, many treatment options are currently available and more are being developed. Several new drugs have improved survival rates, and ongoing research gives hope that a cure may someday be possible. JAAPA

Bortezomib (Velcade)

Dexamethasone (Decadron, Dexamethasone Intensol, Dexpak Taperpak)

Lenalidomide (Revlimid)

Melphalan (Alkeran)

Pamidronate (Aredia)

Prednisone (Prednisone Intensol, Sterapred)

Thalidomide (Thalomid)

Zoledronic acid (Zometa)

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