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Multiple Myeloma

Multiple myelomas or plasma cell myeloma is a neoplasm of well-differentiated B cell lymphocytes typically originating from the bone marrow.

Neoplastic cells can metastasize widely, having a predilection for bone and resulting in osteolysis. The malignant transformation of a single B cell can secrete a homogenous immunoglobulin product known as paraprotein, which will mimic the structure of normal immunoglobulins. Overabundant production of paraprotein, consisting of any of the immunoglobulin classes, will appear as a sharp, well-defined peak or monoclonal gammopathy on serum electrophoresis.

The most frequently encountered multiple myelomas secrete IgG or IgA paraproteins; however, IgM myelomas (macroglobulinemia) have also been diagnosed in companion animals. Light chain disease is caused by plasma cell overproduction of the light chain segment of the immunoglobulin complex, consisting of either the lambda or kappa light chain. These proteins are referred to as Bence-Jones proteins and are the most commonly observed immunoglobulin fragments in the monoclonal gammopathies. There are rare instances where a malignant plasma cell neoplasm will be nonsecretory. These tumors occur in approximately 1% of all cases of multiple myeloma and are referred to as nonsecretory multiple myeloma. In this type of neoplasm, malignant plasma cells produce either fragments or intact monoclonal immunoglobulins but do not secrete them from the cell. In rare cases of nonsecretory multiple myeloma, recognizable immunoglobulins are not produced.

Multiple myelomas have been described most commonly in dogs, humans, and cats. They account for

< 1% of all malignant canine tumors, ~ 8% of all malignant hematopoietic tumors in dogs, and 3.6% of all primary and secondary bone tumors diagnosed by biopsy. There is no current evidence suggesting any age, sex, or breed predilection; however, older dogs are most commonly affected with a mean age of 8 to 9 years. Multiple myeloma is even less common in cats with a median age of 12 to 14 years and possible male predisposition. The cause of multiple myeloma in companion animals is largely unknown although genetics, viral infections, chronic immune stimulation, and exposure to carcinogens have been identified as possible contributing factors.

The clinical manifestations of multiple myeloma are highly variable and may affect multiple organ systems. The pathologic conditions associated with multiple myeloma are related to the effects of the circulating paraprotein as well as organ or bone marrow dysfunction due to neoplastic infiltration. The presentation of a patient with multiple myeloma will depend on the type of neoplastic cell, type of immunoglobulin produced, location of the tumor, and severity of growth and infiltration. Affected dogs can exhibit signs of lethargy, weakness, lameness, bone pain, hemorrhage (e.g, petechiae on mucous membranes, gingival bleeding, and epistaxis), polyuria / polydypsia, and/or neurologic deficits. Other presenting signs of disease may include hypertension, ophthalmic abnormalities (e.g., venous dialation with sacculation, retinal hemorrhages, and retinal detachment), neurologic dysfunction (including seizures), organomegaly, and suggestion of multiple organ failure.

Hyperviscosity syndrome.
Hyperviscosity syndrome is an increase in the viscosity of the blood secondary to the high concentrations of circulating paraprotein, clinically manifesting in neurologic signs, retinopathy, and cardiomyopathy. IgA and IgM are most often associated with hyperviscosity syndrome because of their structure and size (IgA dimers and IgM pentamers). Cardiomegaly and cardiac disease may result secondary to increased cardiac workload and myocardial hypoxia caused by hyperviscosity. In a study of cats with multiple myeloma, two-thirds of the cats had cardiomegaly on thoracic radiographs and nearly half had a heart murmur.

Bone lesions associated with multiple myeloma include discrete radiolucent lytic areas (punched-out appearance) or diffuse osteopenia and commonly affect the axial skeleton and long bones. These lesions may be associated with severe bone pain, spinal cord compression, pathologic fracture, and hypercalcemia. However, only 50% of dogs have radiographic evidence of bone disease. And although cats are reported to have skeletal lesions (8% to 67%), the true incidence of lytic lesions in cats is unknown.

Bone lesion detection improves with focused imaging on specific regions or bones vs. routine survey abdominal and thoracic radiographs. In people, conventional radiography remains the gold standard imaging technique. Computed tomography and magnetic resonance imaging may also be useful; however, nuclear scintigraphy is generally not recommended since myeloma patients have inadequate skeletal uptake of technetium-99 secondary to osteoblast dysfunction.

Hemorrhagic diathesis.
Patients with multiple myeloma can manifest unique hemostatic disorders that predispose them to hemorrhage. Mechanisms include paraprotein-induced thrombocytopath, in which protein coating of platelets leads to platelet dysfunction and paraprotein interference with clotting factors. Other potential causes of bleeding include abnormalities in the formation and polymerization of fibrin, tissue fragility associated with amyloidosis, hypervolemia secondary to hyperviscosity syndrome, and thrombocytopenia. About one-third of dogs and cats with multiple myeloma have clinical signs of bleeding, most commonly epistaxis, intraocular hemorrhage, and gingival bleeding. These patients may have prolonged prothrombin and partial thromboplastin times and about 50% of cats and 30% of dogs are thrombocytopenic.

Patients with multiple myeloma can develop anemia from a variety of causes including chronic disease, hemorrhage due to coagulopathy, myelophthisis, and red blood cell destruction. Normocytic, normochromic, and nonregenerative anemia is one of the most common findings on a complete blood count (CBC); two-thirds of dogs and cats are affected. Pancytopenia may be seen in patients with marked bone marrow infiltration with neoplastic cells.

Hypercalcemia in cases of multiple myeloma can result from osteoclastic bone resorption, hypercalcemia of malignancy, or hyperglobulinemia. Bone stores of calcium can be released by osteoclasts secondary to cytokine secretion by myeloma cells (e.g. lymphotoxin, tumor necrosis factor alpha, interleukins 1, 3, and 6). Myeloma cells can also secrete parathyroid hormone-related peptide, resulting in paraneoplastic hypercalcemia of malignancy. Hyperglobulinemia results in calcium binding by the paraprotein increasing the total calcium concentration while the ionized calcium concentration remains normal. Ionized calcium measurement is, therefore, needed to confirm true hypercalcemia in patients with multiple myeloma.

Renal disease.
Renal disease occurs in about one-third of dogs and cats with multiple myeloma. Renal insufficiency is most commonly associated with excessive light chain production or hypercalcemia. First, excessive light chain production overwhelms the catabolic capacity of the renal tubular cells and the free light chains complex with proteins to form tubular casts leading to renal tubular obstruction. Endocytosis of light chains by tubular cells also induces cytokine release and inflammation resulting in further renal damage. Second, hypercalcemia can lead to prerenal azotemia secondary to antidiuretic hormone inhibition and eventual renal mineralization. Other potential causes of renal disease include amyloidosis, pyelonephritis, and decreased renal perfusion secondary to hyperviscosity syndrome.

Bacterial infection.
Increased susceptibility to bacterial infection is common in patients with multiple myeloma and infections can be life-threatening if not addressed. Immunodeficiency can be secondary to myelophthisis (which results in leukopenia), decreased production of functional immunoglobulin, and compromised B cell function.

Clinical signs and symptoms may be present for up to 1 year before a definitive diagnosis of multiple myeloma is made. Patients can also present with recurrent infections, non-regenerative anemia, pathologic bone fractures, and/or seizures. Complications secondary to multiple myeloma may include renal failure, infections secondary to immunosuppression, clotting disorders, chronic anemia, cardiac insufficiency, and neurologic dysfunctions such as senility.

A diagnosis of multiple myeloma may be made if there is radiographic evidence of osteolysis, there is a population of greater than 20% plasma cells in bone marrow aspirates or biopsies, a monoclonal gammopathy on serum electrophoresis exists, and/or Bence-Jones protinuria is present. Recent studies suggest that in cats’ visceral organ infiltration be included in the diagnostic criteria. Further studies suggest a primary extramedullary origin for neoplastic transformation in cats with multiple myeloma vs. primary intramedullary neoplastic transformation as accepted in the dog myeloma model.

Multifocal radiolucent lesions within the bone may be seen in ~ 40% of dogs suffering from multiple myeloma. In contrast, osteolytic lesions rarely are seen in cats. The bones most commonly involved in canine multiple myeloma include the spine, pelvis, ribs, skull, and proximal extremities. Malignant plasma cell tumors present in the bone marrow are often osteolytic. The presence of these tumors directly induces bone resorption by production of osteoclastic-activating factor from neoplastic cells. Osteolysis is also induced secondary to paraprotein binding of ionized calcium, which initiates secretion of parathormone (PTH) from the parathyroid gland. PTH acts directly on the bone to increase serum calcium concentration.

Survey radiographs may reveal focal, multifocal, or diffuse osteoporosis-type lesions approximately 3-4 weeks after bone changes have occurred. Clinically, the patient may present with pathologic fractures, rear limb lameness or paresis, or bone pain. Myelograms are an effective means of visualizing the changes to vertebral bodies, especially when the patient presents with rear limb lameness or paresis. Most commonly, the myelogram will show extradural compression of spinal cord in the area of the lesion. Plasma cell tumors producing IgM often infiltrate the spleen, liver, and lymph tissue rather than bone. Whole body survey radiographs may detect enlargement of these organs and tissues.

Dogs and cats with multiple myeloma may experience moderate to severe pain, and eliminating it should be a priority. Pain may be relieved by treating the underlying cancer and providing various analgesic therapies and supportive care. Antibiotic therapy may be needed to treat concurrent infections, such as urinary tract infection or bacterial pyoderma, as these can progress to life-threatening infections if left untreated. Intravenous fluid therapy is often needed initially to correct dehydration, improve cardiovascular status, and manage hypercalcemia and azotemia. Treatment with isotonic saline solution is preferred over other crystalloid replacement fluids in the initial management of hypercalcemic patients. Bisphosphonates, such as pamidronate, may be useful in managing hypercalcemia as well as reducing bone pain and decreasing osteoclastic bone resorption. Evaluation of blood urea nitrogen and creatinine concentrations in conjunction with urine specific gravity should be performed before using this medication since it is potentially nephrotoxic. The recommended dose of pamidronate is 1 to 2 mg/kg given intravenously in dogs and, anecdotally, 1 mg/kg given intravenously in cats every 21 to 28 days. This medication should be diluted in saline solution and administered as a slow infusion over two hours to minimize renal toxicosis. Bisphosphonates are an essential component of therapy for multiple myeloma in people, and their use is associated with significantly reduced skeletal-related events and improved survival times. Plasmapheresis is the best immediate treatment for hyperviscosity syndrome. Although rarely performed in veterinary medicine, this procedure involves withdrawing anticoagulated blood, separating blood components, removing the plasma, and reinfusing the remaining components with crystalloid fluids. Packed red blood cells or platelet-rich plasma transfusions may be required if marked hemorrhage or thrombocytopenia is present, respectively. Neoplastic plasma cells are sensitive to irradiation, and radiation therapy is a highly effective palliative treatment for multiple myeloma since it can relieve discomfort and decrease the size of the mass or tumor burden. Indications for radiation therapy include painful bone lesions, spinal cord compression, pathologic fracture (after fracture stabilization), or a large soft tissue mass.

Although a cure is unlikely, multiple myeloma can be a rewarding disease to treat since chemotherapy can greatly extend the quality and duration of life. The chemotherapy drugs most often used are alkylating agents, usually melphalan, combined with prednisone. However, eventual relapse during therapy is anticipated. In dogs, the recommended treatment protocol is melphalan administered orally once daily at a dose of 0.1 mg/kg for 10 days and then 0.05 mg/kg once daily until the disease relapses or myelosuppression occurs. Prednisone is given concurrently at a dose of 0.5 mg/kg given orally once daily for 10 days and then 0.5 mg/kg every other day for 30 to 60 days, at which time prednisone is discontinued. Pulse-dose therapy with melphalan has also been described, in which melphalan, at a dose of 7 mg/m2, is given orally once daily for five consecutive days every 21 days. The most common side effects associated with melphalan therapy are myelosuppression and delayed thrombocytopenia. A CBC should be performed every two weeks for the first two months of treatment and then monthly.

Combined melphalan and prednisone therapy can also be used in cats; however, cats appear to be much more susceptible to myelosuppression. The recommended treatment protocol is 0.1 mg/kg (or 0.5 mg total dose) melphalan given orally once daily for 10 to 14 days and then every other day until clinical improvement or leukopenia develops. A maintenance dose of 0.5 mg given every seven days is then recommended. Prednisone or prednisolone is given concurrently at a dose of 0.5 mg/kg orally once daily. If leukopenia develops, melphalan therapy should be discontinued until white blood cell counts return to normal; then, maintenance therapy may be attempted at the same or a lower dose.

Other chemotherapy agents used to treat multiple myeloma include chlorambucil and cyclophosphamide either alone or in combination with melphalan. In sick myeoma patients, in which a faster response to treatment is needed, cyclophosphamide may be administered intravenously at a dosage of 200 mg/m2 once at the time that oral melphalan therapy is initiated. Lomustine (CCNU) has also been used in combination with prednisone to treat multiple myeloma in cats.

In dogs with relapsing multiple myeloma or resistance to alkylating agents, single agent doxorubicin or the VAD (vincristine, Adriamycin [doxorubicin], and dexamethasone) protocol can be considered. This protocol combines vincristine (0.7 mg/m2 intravenously on days 8 and 15), doxorubicin (30 mg/m2 intravenously every 21 days), and dexamethasone sodium phosphate (1 mg/kg intravenously on days 1, 8, and 15); however, the reported duration of response to this protocol is only a few months.

The overall response rate for dogs treated with melphalan and prednisone chemotherapy is 92%, with 43.2% of dogs achieving a complete response and 48.6% achieving a partial response. The median survival time of dogs treated with this drug combination is 540 days, which is significantly longer than the survival time of 220 days in dogs treated with prednisone alone. Negative prognostic factors in dogs include hypercalcemia, light chain proteinuria, and extensive lytic bone lesions.

Response to therapy and duration of response appear to be more variable in cats. Factors associated with a more aggressive form of the disease and poor prognosis include bone lesions with pathologic fracture, anemia, light chain proteinuria, azotemia, and poor response to treatment. When treated with melphalan and prednisone chemotherapy, four cats classified as having aggressive disease had a median survival time of five days, whereas the median survival time of five cats with less aggressive disease was 387 days. Other studies have shown overall less promising results with a shorter duration of response to treatment and a survival time of six months or less in treated cats. In cats with multiple myeloma and other related disorders, the degree of plasma cell differentiation is significantly correlated with survival. Cats with well-differentiated tumors (< 15% plasmablasts) have a median survival of 254 days, whereas cats with poorly differentiated tumors (≥ 50% plasmablasts) have a median survival of 14 days.

In summary, multiple myeloma is a rare neoplasm in both cats and dogs. Conditions associated with multiple myeloma include hyperviscosity syndrome, bone lesions, hypercalcemia, renal disease, cytopenias, hemorrhagic diathesis, and increased susceptibility to bacterial infection. Multiple myeloma does not appear to have the same biologic behavior in dogs and cats and is best viewed as a heterogeneous disease with a different prognosis, clinical course, and response to therapy both within and between species. Although a good clinical response may be achieved with chemotherapy, eventual relapse of disease is to be expected.