Multiple Myeloma

Multiple myeloma is a malignant neoplastic proliferation of plasma cells originating in the bone marrow. It is characterized by the infiltration of the bone marrow by neoplastic plasma cells, the production of a monoclonal immunoglobulin (M-component or paraprotein) detectable in serum or urine, and subsequent organ dysfunction. The disease is systemic, often leading to osteolytic bone lesions, hypercalcemia, renal failure, anemia, and increased susceptibility to infections. In veterinary medicine, multiple myeloma is most commonly diagnosed in dogs and, less frequently, in cats. It is considered an incurable but manageable condition, with treatment aimed at inducing remission and improving quality of life.

The exact etiology of multiple myeloma in animals is largely unknown, but several factors are implicated. Genetic mutations and chromosomal abnormalities, such as translocations involving the immunoglobulin heavy chain locus, are believed to play a central role in the pathogenesis. Chronic antigenic stimulation, viral infections (e.g., feline leukemia virus in cats), and exposure to environmental carcinogens (e.g., radiation, chemicals) have been suggested as potential triggers. In dogs, no specific infectious agent has been consistently identified, but a genetic predisposition is suspected in certain breeds. The neoplastic transformation of plasma cells is a multistep process involving dysregulation of oncogenes and tumor suppressor genes, leading to uncontrolled clonal expansion.

Multiple myeloma is a relatively uncommon neoplasm in dogs and cats, accounting for approximately 1-2% of all canine tumors and less than 1% of feline tumors. It typically affects middle-aged to older animals, with a median age of 8-10 years in dogs and 10-12 years in cats. No significant sex predilection is reported. In dogs, certain breeds appear to be overrepresented, including German Shepherds, Golden Retrievers, and Boxers, suggesting a possible genetic component. In cats, no breed predisposition is clearly established, but the disease may be associated with feline leukemia virus (FeLV) infection in some cases. Geographic variation is not well-documented, but the disease is seen worldwide.

The pathophysiology of multiple myeloma involves the clonal expansion of malignant plasma cells in the bone marrow, leading to disruption of normal hematopoiesis. The neoplastic cells produce a monoclonal immunoglobulin (usually IgG or IgA in dogs, and IgG or IgM in cats) that accumulates in the serum and can cause hyperviscosity syndrome. The M-component can also be excreted in urine as Bence Jones proteins (light chains), which are nephrotoxic. Bone marrow infiltration results in cytopenias, particularly anemia, thrombocytopenia, and leukopenia. Osteolytic bone lesions occur due to the activation of osteoclasts by cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) released by myeloma cells, leading to bone pain, pathologic fractures, and hypercalcemia. Renal dysfunction arises from light chain deposition, hypercalcemia, dehydration, and amyloidosis. Hyperviscosity syndrome can cause neurologic signs, bleeding diathesis, and retinopathy. Immunosuppression results from decreased normal immunoglobulin production and impaired neutrophil function, increasing susceptibility to infections.

Predisposing factors for multiple myeloma include advanced age, as the disease is more common in older animals. Genetic predisposition is suggested by breed overrepresentation in dogs. Chronic immune stimulation, such as recurrent infections or autoimmune diseases, may increase the risk. In cats, retroviral infections (FeLV and possibly FIV) are risk factors. Exposure to environmental toxins, including radiation and certain chemicals, may also contribute. Immunosuppressive conditions or therapies could potentially promote the development of the disease, although this is not well-documented in veterinary medicine.

Clinical signs of multiple myeloma are variable and often nonspecific. Common systemic signs include lethargy, weakness, anorexia, and weight loss. Bone pain may manifest as lameness, reluctance to move, or spinal pain. Osteolytic lesions can lead to pathologic fractures, especially in the vertebrae, ribs, and long bones. Hypercalcemia may cause polyuria, polydipsia, vomiting, and constipation. Renal failure can result in azotemia, isosthenuria, and proteinuria. Hyperviscosity syndrome may present with neurologic signs (seizures, ataxia, disorientation), bleeding tendencies (epistaxis, gingival bleeding), and retinal changes (dilated tortuous retinal vessels, retinal hemorrhages, detachment). Anemia can cause pale mucous membranes and exercise intolerance. Recurrent infections, particularly respiratory and urinary tract infections, are common due to immunosuppression. In some cases, extramedullary plasmacytomas may be palpable as soft tissue masses.

Differential diagnoses for multiple myeloma include other plasma cell tumors such as solitary plasmacytoma (which is localized and lacks systemic signs), and other round cell tumors like lymphoma (especially B-cell lymphoma with plasmacytoid differentiation). Other conditions causing monoclonal gammopathy include chronic infections (e.g., ehrlichiosis, leishmaniasis), autoimmune diseases, and idiopathic monoclonal gammopathy. Causes of osteolytic bone lesions include primary bone tumors (osteosarcoma), fungal osteomyelitis, and metastatic neoplasia. Hypercalcemia may be due to other malignancies (lymphoma, anal sac adenocarcinoma), primary hyperparathyroidism, or chronic renal failure. Renal failure from other causes (e.g., chronic interstitial nephritis, glomerulonephritis) should also be considered. Anemia and thrombocytopenia may be seen in immune-mediated diseases, bone marrow disorders, or chronic blood loss.

The diagnostic algorithm for multiple myeloma begins with a thorough history and physical examination, paying attention to signs of bone pain, bleeding, and neurologic deficits. Initial laboratory tests include a complete blood count (CBC), serum biochemistry profile, and urinalysis. Key findings include anemia, thrombocytopenia, elevated total protein with decreased albumin (due to the M-component), hypercalcemia, and azotemia. Serum protein electrophoresis is essential to confirm a monoclonal gammopathy. Urine protein electrophoresis can detect Bence Jones proteins. Bone marrow aspiration or biopsy is the gold standard for diagnosis, revealing a plasmacytosis of >10-20% of nucleated cells. Radiographs of the axial and appendicular skeleton may show osteolytic lesions. If hyperviscosity syndrome is suspected, serum viscosity can be measured. Additional tests include immunoelectrophoresis to identify the immunoglobulin class, and flow cytometry to assess plasma cell markers (CD38, CD138). In cats, FeLV and FIV testing is recommended. A staging workup may include abdominal ultrasound and thoracic radiographs to evaluate for extramedullary involvement.

Hematology: Non-regenerative anemia is common (normocytic, normochromic), due to bone marrow infiltration and chronic disease. Thrombocytopenia and leukopenia may occur. Rouleaux formation is often seen on blood smears. Serum biochemistry: Total protein is markedly elevated (often >9 g/dL) due to the M-component, while albumin is normal or decreased. Hypercalcemia (total calcium >12 mg/dL) is present in up to 20% of dogs and 50% of cats. Azotemia (elevated BUN and creatinine) indicates renal involvement. Liver enzymes may be mildly elevated. Urinalysis: Proteinuria may be present, and Bence Jones proteinuria can be detected with urine protein electrophoresis. Specific biomarkers: Serum protein electrophoresis shows a sharp monoclonal spike in the gamma or beta region. Immunoelectrophoresis identifies the immunoglobulin type (IgG, IgA, IgM). Serum viscosity may be increased. In some cases, beta-2 microglobulin levels are elevated. Blood gas analysis may reveal metabolic acidosis if renal failure is severe.

Radiography: Skeletal radiographs often reveal multiple, well-defined osteolytic lesions (punched-out lesions) in the vertebrae, ribs, pelvis, and long bones. Generalized osteopenia may be seen. Thoracic radiographs may show evidence of pneumonia or other infections. Abdominal radiographs may reveal hepatosplenomegaly. Ultrasonography: Abdominal ultrasound may show enlarged kidneys, hepatosplenomegaly, or extramedullary plasmacytomas. Echocardiography is not routinely indicated but may be performed if cardiac signs are present. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are more sensitive for detecting bone lesions and extramedullary involvement, especially in the spine and skull. These advanced imaging modalities are useful for surgical planning if pathologic fractures are present.

Bone marrow aspiration cytology typically reveals a hypercellular marrow with a marked increase in plasma cells, often forming sheets or clusters. The plasma cells may appear atypical with pleomorphism, binucleation, and prominent nucleoli. Histopathology of bone marrow core biopsy confirms the diagnosis, showing diffuse infiltration by neoplastic plasma cells. Extramedullary plasmacytomas, if present, can be aspirated or biopsied, showing similar cytologic features. Immunohistochemistry can be performed to confirm plasma cell origin (positive for CD138, MUM1, and lambda light chains).

The treatment of multiple myeloma aims to reduce the tumor burden, alleviate clinical signs, and improve quality of life. The mainstay of therapy is chemotherapy, with melphalan (an alkylating agent) and prednisone being the most commonly used protocol. Melphalan is administered orally at a dosage of 0.1 mg/kg once daily for 10 days, followed by a maintenance dose of 0.05 mg/kg every other day, or as a pulse dose of 7 mg/m² orally for 5 consecutive days every 3 weeks. Prednisone is given at 0.5-1 mg/kg orally every other day. Alternative protocols include cyclophosphamide (200-250 mg/m² IV or orally every 3 weeks) or chlorambucil (0.2 mg/kg orally every other day). For cats, melphalan is used at a lower dose (0.1 mg/kg orally every 48 hours) due to increased sensitivity. Supportive care includes fluid therapy for dehydration and hypercalcemia, analgesics for bone pain, and antibiotics for infections. Bisphosphonates (e.g., pamidronate) may be used to manage hypercalcemia and osteolysis. In cases of hyperviscosity syndrome, plasmapheresis may be considered. Radiation therapy can be used for painful bone lesions or spinal cord compression. Surgical stabilization may be needed for pathologic fractures.

The prognosis for multiple myeloma is guarded but variable. With treatment, median survival times in dogs are approximately 12-18 months, with some dogs living longer. Cats have a median survival of 6-12 months. Negative prognostic factors include hypercalcemia, severe azotemia, advanced stage, and poor response to initial therapy. Animals that achieve a complete or partial remission (reduction in M-component by >50%) have a better prognosis. The disease is ultimately fatal due to progressive bone marrow failure, renal failure, or infections.

Follow-up is essential to monitor response to therapy and detect complications. Re-evaluation should be performed every 2-4 weeks during initial chemotherapy, then every 1-3 months thereafter. Monitoring includes a CBC, serum biochemistry profile, and serum protein electrophoresis to assess the M-component level. Urinalysis should be performed to monitor for proteinuria and renal function. Blood pressure measurement is recommended to detect hypertension. Imaging (radiographs or CT) may be repeated if bone lesions are present. Dose adjustments of chemotherapeutic agents are based on hematologic toxicity (neutropenia, thrombocytopenia). Long-term management includes regular monitoring for signs of relapse, such as recurrence of hypercalcemia, azotemia, or increasing M-component.

Pearls: Always perform serum protein electrophoresis in any dog or cat with unexplained hyperproteinemia, especially if accompanied by anemia or bone lesions. A monoclonal spike is highly suggestive of multiple myeloma. Bone marrow aspiration is essential for definitive diagnosis. Hypercalcemia in multiple myeloma is often severe and requires aggressive fluid therapy and bisphosphonates. Monitor for hyperviscosity syndrome, which can cause neurologic signs and bleeding; early recognition and plasmapheresis can be life-saving. Pitfalls: Do not rely solely on total protein; albumin and globulin fractions must be evaluated. A normal total protein does not rule out multiple myeloma, as some cases may have low M-component. Avoid using corticosteroids alone, as they can cause a transient decrease in M-component but do not induce durable remission. Be cautious with melphalan dosing, as it can cause severe myelosuppression, especially in cats. Do not overlook the possibility of solitary plasmacytoma, which has a better prognosis and may be treated with surgery or radiation alone.

Melphalan: Dogs: 0.1 mg/kg PO q24h for 10 days, then 0.05 mg/kg PO q48h; or 7 mg/m² PO for 5 consecutive days every 3 weeks. Cats: 0.1 mg/kg PO q48h. Prednisone: Dogs: 0.5-1 mg/kg PO q48h; Cats: 1-2 mg/kg PO q48h. Cyclophosphamide: Dogs: 200-250 mg/m² IV or PO every 3 weeks; Cats: 200 mg/m² IV every 3 weeks (with careful monitoring). Chlorambucil: Dogs: 0.2 mg/kg PO q48h; Cats: 0.1-0.2 mg/kg PO q48h. Pamidronate: Dogs: 1-2 mg/kg IV diluted in saline, infused over 2-4 hours, every 3-4 weeks for hypercalcemia. Fluid therapy: 0.9% NaCl at maintenance (60-100 mL/kg/day) for hypercalcemia. Analgesics: For bone pain, use opioids (e.g., tramadol 2-5 mg/kg PO q8-12h) or NSAIDs (e.g., carprofen 2.2 mg/kg PO q12h) with caution. Antibiotics: For infections, choose based on culture and sensitivity; commonly used are amoxicillin-clavulanate (13.75 mg/kg PO q12h) or enrofloxacin (5-10 mg/kg PO q24h).

Multiple studies have evaluated the efficacy of melphalan and prednisone in canine multiple myeloma. A landmark study by Matus et al. (1986) reported a median survival of 540 days in dogs treated with this protocol. More recent studies have confirmed similar outcomes. The use of cyclophosphamide as an alternative or in combination has shown comparable results. In cats, melphalan-based protocols have been associated with median survival times of 6-12 months. The ACVIM consensus statement on the diagnosis and treatment of multiple myeloma in dogs and cats (2018) provides guidelines for staging and management. Hypercalcemia is a negative prognostic indicator, and aggressive management with bisphosphonates is recommended. The role of novel agents such as bortezomib is being explored, but data in veterinary medicine are limited.