An overview of multiple myeloma in dogs and cats

Plasma cell neoplasms originate from terminally differentiated B lymphocytes that have undergone malignant transformation. These neoplasms incorporate a wide range of clinical syndromes including multiple myeloma, macroglobulinemia, solitary osseous plasmacytoma, and extramedullary plasmacytoma. In this article, we focus on multiple myeloma, which refers to diffuse disease and, clinically, is the most important plasma cell neoplasm. See the next article in this issue for a discussion of plasmacytomas, which involve soft tissue or bone.

SIGNALMENT AND CAUSE

Multiple myeloma is an uncommon lymphoproliferative disease in animals, accounting for less than 8% of all hematopoietic tumors in dogs. No breed or sex predilections exist, and older dogs are most commonly affected, with a mean age of 8 to 9 years.1-3 Multiple myeloma is even less common in cats, with a median age of 12 to 14 years and possible male predisposition.2,4-7

The cause of multiple myeloma in companion animals is largely unknown. In people, plasma cell diseases are associated with working in the agricultural industry, exposure to petroleum products, and chronic exposure to an antigen stimulus.8-11 At a molecular level, multiple myeloma has been associated with altered expression of the c-myc oncogene (people) and the cell cycle protein cyclin D (people and dogs).12-14 One case report involving feline siblings with multiple myeloma suggests that a genetic predisposition may exist.5 In contrast to other hematopoietic diseases such as lymphoma, there is no evidence that feline immunodeficiency virus, feline leukemia virus, or feline infectious peritonitis virus infections are related to multiple myeloma development in cats.7

PATHOLOGY

Multiple myeloma is a B cell malignancy characterized by the infiltration and growth of plasma cells in the bone marrow (Figure 1). Normal B cells are transformed into malignant plasma cells in a multistep process that includes cumulative mutational damage and multiple genetic abnormalities. Myeloma cells are clonal expansions of a neoplastic plasma cell, and they produce an identical immunoglobulin protein, called the paraprotein or monoclonal (M) protein, in large quantities. These paraproteins can often be identified as a monoclonal spike on a serum or urine protein electrophoretogram; protein electrophoresis is performed at many commercial laboratories (e.g. Colorado State University's College of Veterinary Medicine & Biomedical Sciences Veterinary Diagnostic Laboratories, Texas A&M University's Texas Veterinary Medical Diagnostic Laboratory).

Figure 1. A photomicrograph of a bone marrow aspirate from a dog with multiple myeloma. Plasma cells (black arrows) are characterized by an eccentric nucleus, basophilic cytoplasm, and perinuclear clear zone/Golgi. Mitotic figures are present (white arrow) (Wright's stain; 500X).

The paraprotein may represent a complete immunoglobulin or a portion of the immunoglobulin (light or heavy chain). Immunoglobulin G (IgG) and immunoglobulin A (IgA) gammopathies are the most common in people, dogs, and cats; immunoglobulin M (IgM) gammopathy (macroglobulinemia) is rare. While IgG and IgA gammopathies are equally common in dogs, cats are reported to develop 80% IgG and 20% IgA gammopathies.1,4 Biclonal gammopathies, occasionally reported in veterinary patients, may be attributable to the development of two independent neoplastic clones, isotype switching of some clones, or spurious electrophoretic biclonal peaks due to splitting of dimeric or multimeric paraproteins (e.g. IgA).4,7,15 Pure light chain (kappa or lambda type) production, referred to as light chain myeloma or Bence Jones myeloma, has rarely been reported in cats and dogs.3,16

Pathologic effects

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. High serum paraprotein concentrations may result in hyperviscosity syndrome. Other conditions include osteolysis, hemorrhagic diathesis, cytopenias, hypercalcemia, renal disease, and increased susceptibility to bacterial infection.

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.7 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.4

Osteolysis. 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 (Figures 2 & 3). These lesions may be associated with severe bone pain, spinal cord compression, pathologic fracture, and hypercalcemia.1,3-5,17

Figure 2. A lateral thoracic spinal radiograph of a dog with multiple myeloma. This patient has multiple osteolytic lesions in the dorsal spinous processes, as demonstrated by the white arrow. (Radiograph courtesy of Dr. Laura Garrett.)

In people, the destructive bone loss associated with myeloma bone disease is a result of increased osteoclastic bone resorption and decreased osteoblastic bone formation, resulting from dysregulated cytokine production (e.g. interleukin-3, macrophage inflammatory protein-1alpha, vascular endothelial growth factor, and transforming growth factor-beta) and an altered ratio of receptor activator of nuclear factor kappa B and osteoprotegerin.18,19 Although not proven, a similar mechanism of bone loss is thought to occur in dogs. 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.1,4,5,7

Figure 3. A lateral stifle radiograph of a dog with multiple myeloma. A lytic punched-out bone lesion (white arrow) is present in the proximal tibia. (Radiograph courtesy of Dr. Laura Garrett.)

Bone lesion detection improves with focused imaging on specific regions or bones vs. routine survey abdominal and thoracic radiographs.5 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.17,20

Hemorrhagic diathesis. Patients with multiple myeloma can manifest unique hemostatic disorders that predispose them to hemorrhage. Mechanisms include paraprotein-induced thrombocytopathy, in which protein coating of platelets leads to platelet dysfunction, and paraprotein interference with clotting factors.1,4,21 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.21 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.1,4,5

Cytopenias. 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, nonregenerative anemia is one of the most common findings on a complete blood count (CBC); two-thirds of dogs and cats are affected.1,4,5,7 Erythrophagocytic multiple myeloma has been reported in a cat, dogs, and people, so it may be a source of anemia as well.22-24 Pancytopenia may be seen in patients with marked bone marrow infiltration with neoplastic cells.

Hypercalcemia. 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).18 Myeloma cells can also secrete parathyroid hormone-related peptide, resulting in paraneoplastic hypercalcemia of malignancy.2 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.22

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.25 Second, hypercalcemia can lead to prerenal azotemia secondary to antidiuretic hormone inhibition and eventual renal mineralization.26 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.4

CLINICAL SIGNS

Clinical signs associated with multiple myeloma, which are often nonspecific and insidious in onset, include lethargy, weakness, and anorexia. Polyuria and polydipsia can occur secondary to hypercalcemia or myeloma-related renal disease. Lameness, paresis or paralysis, and pain occur secondary to osteolysis or spinal cord compression. Bleeding diatheses, including epistaxis, gingival bleeding, intraocular hemorrhage, and, less frequently, melena or hematuria, are common.1,4,5 Retinal abnormalities occur frequently secondary to serum hyperviscosity and include retinal hemorrhage or venous dilatation with tortuous vessels.1,27 Central nervous system deficits, including dementia with midbrain or brainstem deficits, and seizures may also be present secondary to hyperviscosity syndrome or severe hypercalcemia.1,5,7 The median duration of clinical signs before presentation is 30 days in dogs.1

DIAGNOSIS

Diagnosing multiple myeloma is adapted from human medicine and requires confirming at least two of the criteria listed in Table 1. Recent studies suggest that these criteria should be re-evaluated in cats. In a study of 16 cats with multiple myeloma, noncutaneous extramedullary tumors (internal organ involvement) (see the next article in this issue: "Extramedullary and solitary osseous plasmacytomas in dogs and cats") were detected in all seven cats in which this was assessed. Affected sites included the spleen, liver, and lymph nodes.4 In this report, it was suggested that visceral organ infiltration be included in the diagnostic criteria for cats. Also in a recent review of 24 cats with myeloma-related disorders, plasma cell neoplasia of an abdominal organ (primarily the liver or spleen) accounted for 50% of cats at initial presentation. More than 40% of cats with internal organ involvement had bone marrow infiltration by neoplastic cells.7 In people, extramedullary involvement is rare (about 5% of cases) at initial presentation for myeloma-related disorders. Further studies suggest a primary extramedullary origin for neoplastic transformation in cats with multiple myeloma vs. primary intramedullary neoplastic transformation as accepted in the human myeloma model.6

Table 1. Diagnostic Criteria for Multiple Myeloma*

Staging

Recommended primary staging tests include a CBC, serum chemistry profile, and urinalysis, although advanced diagnostic modalities may be required (Table 2). Nonregenerative anemia is the most common finding on a CBC, reported in 55% to 68% of cases.1,4,5 Key findings on a serum chemistry profile include azotemia and hypercalcemia; other common abnormalities include hypoalbuminemia with hyperglobulinemia and hypocholesterolemia. Urine bacterial culture is also recommended since these animals may be immunologically compromised and prone to urinary tract infection.

Table 2. Approximate Frequency of Clinicopathologic and Imaging Abnormalities in Patients with Multiple Myeloma*

Serum and urine samples can be submitted for parallel protein electrophoresis. Serum protein electrophoresis generally reveals a monoclonal gammopathy with a peak in the beta or gamma globulin region or, less commonly, a biclonal gammopathy.4,7,15 Test urine samples for light chain proteinuria by using either the Bence Jones heat precipitation method or immunoelectrophoresis. Evaulation by using a urine dipstick is not an adequate screening test for light chain proteinuria because dipsticks primarily detect albuminurina.4 Bence Jones proteins in the urine without a corresponding monoclonal gammopathy on serum electrophoresis is diagnostic for pure light chain disease.3

To evaluate for hyperviscosity syndrome, serum viscosity, relative to water, can be assessed with laboratory viscometers (e.g. Wells-Brookfield Cone/Plate Viscometer/Rheometer—Can-Am Instruments).4

Abdominal imaging (radiography or ultrasonography) is useful to evaluate commonly affected organs such as the liver and spleen. In cats with multiple myeloma, 85% of abdominal organs with an imaging abnormality had cytologically confirmed plasma cell infiltration within that tissue.7 Limb and spinal radiographs can help detect bone lesions.

Multiple myeloma is usually definitively diagnosed with cytologic examination of a bone marrow aspirate; plasma cells are unevenly distributed among normal marrow elements.4 Optimal samples may be obtained by performing a bone marrow aspirate from the site of lytic lesions; however, multiple aspirates or a core biopsy may be necessary for definitive diagnosis.

Differential diagnoses

Other conditions can induce monoclonal gammopathies in companion animals, including monoclonal gammopathy of undetermined significance (MGUS), chronic infection (e.g. feline infectious peritonitis, ehrlichiosis, leishmaniasis, pyoderma), and other lymphoreticular neoplasms (e.g. B cell lymphoma, acute and chronic lymphocytic leukemia).28-30

MGUS has been reported in a cat in which paraproteinemia was detected several years before multiple myeloma was diagnosed. MGUS was diagnosed based on a lack of evidence for multiple myeloma, including the absence of abnormal physical findings or clinical signs and the lack of marrow plasmacytosis, radiographic changes, or light chain proteinuria.4 MGUS is considered a pre-myeloma condition in people; about 25% of people with MGUS ultimately develop multiple myeloma or related diseases.31

TREATMENT

When treating patients with multiple myeloma, it is necessary not only to treat the underlying neoplasia but also the secondary conditions associated with the disease.

Fluid therapy

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.

Antibiotics

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.

Palliative radiation

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.3,17,32 Indications for radiation therapy include painful bone lesions, spinal cord compression, pathologic fracture (after fracture stabilization), or a large soft tissue mass.33

Bisphosphonates

Bisphosphonates, such as pamidronate, may be useful in managing hypercalcemia as well as reducing bone pain and decreasing osteoclastic bone resorption. Evaluate blood urea nitrogen and creatinine concentrations in conjunction with urine specific gravity before using this medication since it is potentially nephrotoxic.34

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.35 This medication should be diluted in saline solution (amount varies based on the size of the patient) 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 in some studies.36

Analgesics

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.37,38

Plasmapheresis and other transfusions

Plasmapheresis, an extracorporeal blood purification technique, is the best immediate treatment for hyperviscosity syndrome.39 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.1,39 Packed red blood cells or platelet-rich plasma transfusions may be required if marked hemorrhage or thrombocytopenia is present, respectively.

Chemotherapy

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.

Melphalan. 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.1 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.1 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.2 The most common side effects associated with melphalan therapy are myelosuppression and delayed thrombocytopenia. Perform a CBC 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.5 Prednisone or prednisolone is given concurrently at a dose of 0.5 mg/kg orally once daily.4,5 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.5

Other chemotherapeutics. Other chemotherapy agents used to treat multiple myeloma include chlorambucil and cyclophosphamide, either alone or in combination with melphalan.1,7 In sick myeloma 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.2 Lomustine (CCNU) has also been used in combination with prednisone to treat multiple myeloma in a cat; a partial response was obtained.40

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.2

PROGNOSTIC FACTORS

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.1 Negative prognostic factors in dogs include hypercalcemia, light chain proteinuria, and extensive lytic bone lesions.1

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.5 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.5 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.4 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.6

MONITORING RESPONSE TO TREATMENT

Clinical response to treatment is assessed based on improvement or resolution of clinical signs and laboratory and imaging abnormalities.

In patients that respond to treatment, improvement in clinical signs and laboratory findings (CBC, serum chemistry profile, and protein electrophoresis) are expected within the first four to eight weeks of treatment.5 When assessing serum immunoglobulin, complete remission is defined as normal globulin concentrations or undetectable monoclonal immunoglobulin. Partial remission is defined as a 50% decrease in globulin concentrations.1 Repeated CBCs to evaluate for resolution of cytopenias as well as serum chemistry profiles to check for resolution of azotemia and hypercalcemia are important.

Repeated assessments of bone marrow aspirates, serum viscosity, and light chain proteinuria are less useful in gauging response to treatment. A bone marrow aspirate is indicated in patients with persistent cytopenias to identify persistent bone marrow involvement vs. myelosuppression secondary to chemotherapy.

Additionally, ultrasonography with or without fine-needle aspiration may be used to evaluate resolution of visceral organ infiltration. Although serial radiographs can be used to assess for improvement of bony changes, radiographic changes may not adequately reflect current disease progression or remission.

NOVEL TREATMENTS FOR MULTIPLE MYELOMA

In people, multiple myeloma remains incurable despite conventional high-dose chemotherapy with stem cell support. Novel treatments for multiple myeloma in people target the interaction between the neoplastic plasma cells and components of the bone marrow microenvironment. Bortezomib, a proteasome inhibitor, has shown therapeutic efficacy in treating both relapsed and previously untreated myeloma patients.41,42 Bortezomib is a potent inhibitor of myeloma cell growth and survival and also inhibits osteoclast formation and bone resorption, which is important in the development of myeloma bone disease.18 Thalidomide, an immunomodulatory and antiangiogenic agent, has also shown striking antimyeloma activity as first-line therapy in people or in those with relapsed disease.43

These novel therapeutic agents have been largely unexplored in treating veterinary patients with multiple myeloma. In dogs, oral toceranib phosphate (Palladia—Pfizer Animal Health), a receptor tyrosine kinase inhibitor, has been used to treat two dogs with multiple myeloma.44 One dog showed a partial response to treatment; the other dog did not respond to treatment.

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.

Rachel Sternberg, DVM

Jackie Wypig, DVM DACVIM (oncology)

Department of Veterinary Clinical Medicine

College of Veterinary Medicine

University of Illinois

Urbana, IL 61802

Anne M. Barger, DVM, DACVP

Department of Pathology

College of Veterinary Medicine

University of Illinois

Urbana, IL 61802

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