The clinical features of multiple myeloma are variable. Findings that suggest the diagnosis include lytic bone lesions, anemia, azotemia, hypercalcemia, and recurrent infections. Approximately 30% of patients are free of symptoms and are diagnosed on routine physicals with abnormal laboratory studies, including elevation of serum protein.
Bone pain, especially from compression fractures of the vertebrae or ribs, is the most common symptom. At diagnosis, 70% of patients have lytic lesions, which are due to accelerated bone resorption. These changes are due to pathological imbalance between osteoblast (bone formation) and osteoclast (bone resorption) activity in the bone marrow microenvironment induced by the presence of myeloma cells. Factors inducing osteoclastic activity include interleukin (IL)-1beta, TNF-α, and IL-6 as well as newly identified factors such as osteoprotogerin, TNF-related activation-induced cytokine (TRANCE), macrophage inflammatory protein (MIP)-1 α, and receptor activator of nuclear factor kappa B (RANK) ligand.
Osteoblastic activity is inhibited due to production of a soluble factor Dickkopf homolog 1 (DKK-1) by multiple myeloma cells, and overexpression of Activin-A by bone marrow stromal cells.
Normocytic, normochromic anemia is present in 60% of patients at diagnosis. It is due primarily to the decreased production of red blood cells by marrow, infiltration with plasma cells, and the suppressive effect of various cytokines. Patients with renal failure may also have decreased levels of erythropoietin(Drug information on erythropoietin), which can worsen the degree of anemia.
Among newly diagnosed patients, up to 20% have hypercalcemia (corrected serum calcium level > 11.5 mg/dL) secondary to progressive bone destruction, which may be exacerbated by prolonged immobility, especially in the context of fracture. Hypercalcemia should be suspected in patients with myeloma who have nausea, fatigue, confusion, polyuria, or constipation. It may also suggest high tumor burden. It should be considered an oncologic emergency and requires prompt treatment with aggressive hydration, use of bisphosphonates, calcitonin, and antimyeloma therapy, including steroids.
Approximately 20% of patients present with renal insufficiency and at least another 20% to 40% develop this complication in later phases of the disease. Light-chain cast nephropathy is the most common cause of renal failure. Additional causes include hypercalcemia, dehydration, and hyperuricemia. Less commonly, amyloidosis, light-chain deposition disease, nonsteroidal anti-inflammatory agents taken for pain control, intravenous radiographic contrast administration, and calcium stones may contribute to renal failure. More recently, bisphosphonate therapy has been associated with azotemia, which is usually reversible with treatment cessation.
Many patients with myeloma develop bacterial infections that may be serious, and infectious complications remain the most common cause of death in myeloma patients. In the past, gram-positive organisms (eg, Streptococcus pneumoniae, Staphylococcus aureus) and Haemophilus influenzae were the most common pathogens. More recently, however, infections with gram-negative organisms, anaerobes, and fungi have become frequent. The increased susceptibility of patients with multiple myeloma to bacterial infections, specifically with encapsulated organisms, has been attributed to impairments of host-defense mechanisms, such as hypogammaglobulinemia, qualitative deficiency in immunoglobulin function, granulocytopenia, decreased cell-mediated immunity, and the prolonged use of steroids.
No screening measures for multiple myeloma have demonstrated any benefit to date.
The diagnosis usually requires the presence of bone marrow plasmacytosis and a monoclonal protein in the urine and/or serum (Table 2), along with end-organ damage. One immunoglobulin class is produced in excess, whereas the other classes are usually depressed, with all three heavy chains typically reduced in the presence of light chain disease.
The initial workup for patients suspected of having a plasma cell dyscrasia should include:
• CBC with differential count and platelet count
• Routine serum chemistry panel (to include calcium, blood urea(Drug information on urea) nitrogen, creatinine)
• Bone marrow aspirate and biopsy to assess clonal plasmacytosis
• Serum protein electrophoresis and immunofixation to quantitate and define protein type
• Serum beta-2-microglobulin, serum albumin
• Serum free light chain
• 24-Hour urine protein, electrophoresis, and immunofixation
• Quantitative serum immunoglobulin levels
• Skeletal survey (bone scans contribute little since isotope uptake is often low in purely lytic bone disease)
• Cytogenetics, including FISH (fluorescence in situ hybridization) on bone marrow plasma cells.
The recently available serum free light chain assay is useful especially in patients with light-chain–only disease, oligo- or nonsecretory myeloma, patients with renal failure, and amyloidosis.
MRI is an excellent tool for evaluation of spinal cord compression/impingement. In addition, MRI identifies generalized marrow signal abnormalities and focal lesions that can be monitored after therapy. Whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan is becoming more widely used, as it provides details of axial and appendicular skeletal involvement but also identifies extramedullary soft-tissue plasmacytomas presenting as macrofocal lesions. Both MRI and PET/CT are especially useful in staging oligo- or nonsecretory disease.
In addition, additional useful data may be obtained by analysis of such prognostic factors as plasma cell labeling index, ploidy, immunophenotyping, flow cytometry, C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels.