Feline Multiple Myeloma

Shirin Modaresi, DVM, and Melinda Camus, DVM

Class of 2010 (Modaresi) and Clinical Pathology Resident (Camus)
College of Veterinary Medicine, The University of Georgia
Athens, GA 30602

Introduction

Feline myeloma-related disorders (MRD) are a group of rare plasma cell neoplasms.⁵ Neoplastic plasma cells are a clonally expanded population of terminally differentiated B lymphocytes that typically secrete immunoglobulin. The incidence of plasma cell neoplasia is low, accounting for 0.0012-0.0025% of all reported feline malignancies.² Mellor, et al. (2008) have recently classified this group of disorders into 7 different categories:

• myeloma (intramedullary with or without extramedullary involvement);
• cutaneous extramedullary plasmacytoma (CEMP);
• noncutaneous extramedullary plasmacytoma (NCEMP);
• solitary plasmacytoma of bone (SPB);
• IgM (Waldenstrom's) macroglobulinemia;
• immunoglobulin secreting lymphoma (IgSL);
• myeloma cell leukemia

Multiple myeloma (MM) is the classic MRD disease and has numerous diagnostic criteria that must be present for a definitive diagnosis. These criteria are more fitting for MRDs that afflict humans and dogs and are less applicable to cats. The current diagnostic criteria that must be met in dogs includes the presence of at least three of the following criteria:

• monoclonal gammopathy on serum protein electrophoresis;
• radiographic evidence of osteolytic bone lesions^1,3;
• greater than 20% plasma cells in the bone marrow;
• immunoglobulin light chain proteinuria (Bence-Jones proteinuria)

As a few infectious diseases (e.g. Ehrlichiosis) can result in a similar clinical picture, negative tick titers are also recommended prior to diagnosis multiple myeloma. Since this condition is the most common of the myeloma related disorders in cats, this discussion will focus on that manifestation of MRD.

Signalment and etiology

Multiple myeloma is most often reported in domestic shorthaired cats with a possible overrepresentation in male cats.⁵ The median ages of reported cases ranges are between 11.7 years¹ to 14 years of age⁴. There is no known association between MM and coronavirus, feline leukemia, or feline immunodeficiency virus infection.⁵ Genetic predisposition has been supported by cases reported in siblings.¹

Clinical signs

Common presenting complaints of cats diagnosed with MM include:

• lethargy
• inappetence
• weight loss
• vomiting⁴

See Table 1 for frequencies of clinical signs in cats.

Other possible clinical signs include:

• epistaxis
• gingival bleeding
• blindness
• CNS signs
• bone pain
• organomegaly
• ataxia/hindlimb paresis
• history of chronic respiratory infections
• fever⁵

Pathophysiology

Clinical signs of multiple myeloma are often the result of high levels of circulating immunoglobulin, produced by the malignant plasma cells either within the bone marrow (intramedullary) or within soft tissues or the skeleton (extramedullary). Most of the gammaglobulinemias appear to be monoclonal, although there are known cases of biclonal gammopathies and two reported cases of non-secretory MM.^4,5

Potential complications of MM include:

• pathologic fractures
• hyperviscosity syndrome (HVS)
• coagulopathies
• renal disease
• hypercalcemia
• various cytopenias
• cardiac failure⁵

Pathologic fractures resulting from lytic bone lesions are more common in dogs and humans but can been seen in cats.⁵

Hyperviscosity syndrome, a disorder caused by the thickening of blood due to increased serum immunoglobulins, has been reported more commonly in dogs than cats, although Hannah (2005) found 4 out of 9 cats with MM to have a higher serum viscosity than normal. Sequelae of HVS include dementia, depression, seizures, retinal hemorrhage, retinal detachment, and development of a cardiomyopathy due to increased workload for the heart.

Approximately 25% of cats diagnosed with MM have clinical evidence of hemorrhage.^4,5 This could be due, in part, to thromobocytopenias due to decreased platelet production, with plasma cell infiltration in the bone marrow. It could also result from clotting factor and endothelial alterations secondary to hyperproteinemia.

Of the cats diagnosed with MM, 33% of them have azotemia.^4,5 Renal failure can develop secondary to HVS, tumor infiltration into the kidneys, Bence Jones proteinuria, or hypercalcemia.⁵

Hypercalcemia is reported in 25% of cats suffering from MM, due to tumor production of PTHrP (parathyroid hormone related protein).^4,5

In cats with cytopenias, approximately 66% are anemic, 50% are thrombocytopenic, and 33% are neutropenic.^4,5 Along with a component of anemia of chronic disease, decreased production in the bone marrow is likely due to the infiltration of neoplastic plasma cells into the viable marrow space.

A cardiac murmur is reported in approximately 50% of cats with MM with no evidence for primary cardiac disease.⁴ Cardiac failure is usually due to increased workload of the heart or secondary myocardial hypoxia due to HVS.

The ultimate cause of death in cats with MM is immunodeficiency with increased susceptibility to infection, as neoplastic plasma cells fail to produce fully functional immunoglobulins, crippling the affected patient's humoral immune system.⁵

Diagnostic tests for multiple myeloma

General recommendations for diagnosing feline multiple myeloma⁵ :

• Complete blood count
• Serum biochemistry profile
• Urinalysis
• Serum  protein electrophoresis
• Heat precipitation of urine  for evaluation of Bence-Jones proteins*
• Bone marrow aspiration/bone marrow core biopsy
• Radiographs
• Ultrasonography

*This test is currently unavailable in the United States for veterinary patients.

The diagnosis of MM in dogs is usually accomplished by finding greater than 20% plasma cells in the bone marrow, the presence of osteolytic lesions of the skeleton , and evidence of proteinemia or proteinuria. Cats often have less severe bone marrow infiltration and it has been suggested that the finding of increased plasma cells in the visceral organs of cats be accepted in place of intramedullary plasmacytosis.⁴

When interpreting the CBC, chemistry panel, and urinalysis, particular attention should be given to the renal function (blood urea nitrogen, creatinine, and urine specific gravity), as well as the serum calcium levels.⁵

On cytologic and histologic examination of the bone marrow of affected cats, plasma cells can vary in appearance. In felines, neoplastic plasma cells often appear immature and exhibit moderate to marked atypia, characterized by increased size, anisocytosis, anisokaryosis, variable nucleus-to-cytoplasm ratios, and often one or more prominent nucleoli. Approximately 25% of neoplastic plasma cells in cats have a "flame edge" morphology (peripheral eosinophilic cytoplasm), indicating active immunoglobulin secretion, typically of IgA.^4,5 (See figure 1)

Figure 1: Bone marrow with numerous plasma cells, including an irregular mitotic figure, several binucleated plasma cells, and many plasma cells with a hypereosinophilic periphery ("flame edge" plasma cells)

Serum protein electrophoresis is performed to demonstrate a monoclonal spike in the gamma globulin region, which can be due to any part of the antibody produced by the malignant plasma cell population.  While the most common immunoglobulin produced by neoplastic plasma cells in canine MM is IgG or IgA (approximately 50% of each), the most common in feline MM is IgG, with only 20% of these neoplasms producing IgA.⁵

Radiographs of the thorax and abdomen are recommended for clinical staging.  Splenomegaly, hepatomegaly, and renomegaly are common findings in cats with MM. Abdominal ultrasonography is also recommended, particularly in cats, as they can have abdominal masses as an extramedullary component of MM.⁴

Other diagnostic tools, such as splenic aspirates, biopsies of osteolytic bone lesions, and PCR of the immunoglobulin heavy-chain variable region gene have been used for diagnosis in rare, complicated cases.⁵

Key differences between humans, dogs, and cats

• Cats have more extramedullary involvement than humans or dogs.
• Cats are less likely to have osteolytic lesions than humans or dogs.
• Multiple myeloma is much less frequent in cats than in dogs.⁵

Treatment

Treatment includes the use of the chemotherapeutic agent melphalan (trade name is Alkeran(R)), an alkylating agent, in combination with prednisone or prednisolone.²   Patients are monitored weekly for the first month, with subsequent monthly rechecks.  At these visits, complete blood counts and serum protein levels are checked.  The most common side effect of melphalan is myelosuppression, which seems to be more severe in cats than in dogs.⁵   Alternative chemotherapeutic agents have been used in dogs, including cyclophosphamide and chlorambucil.  In cats, CCNU (Lomustine) has been used with partial success.⁵   Consultation with a veterinary oncologist is strongly recommended prior to institution of a chemotherapeutic regimen.

Clinical signs typically improve within the first 3-4 weeks of treatment. Initial response to therapy is often based on subjective assessments by owners, who report less lethargy and pain. Laboratory abnormalities often improve within 3-6 weeks of initiating chemotherapy.⁵ Hannah (2005) reported that the melphalan/prednisone treatment of cats with MM showed some amount of clinical improvement in 4 weeks and radiographic improvement of bony lesions in 8 weeks.¹ While MM is not expected to resolve completely, a reduction in the production of immunoglobulin by at least half is considered a good response to therapy.⁵

Adjunctive treatment of any of the sequelae of multiple myeloma must also be employed for the health and welfare of the animal, including aggressive fluid therapy for renal disease, plasmapheresis for HVS, blood transfusions for thrombocytopenia, bisphosphonate drugs for orthopedic problems, prophylactic antibiotics for immunosuppression, and treatment of hypercalcemia with fluid diuresis, prednisone, or calcitonin.⁵

Prognosis

The prognosis for cats with MM is less favorable than it is for dogs. Approximately 60% of cats initially respond to chemotherapy, but the responses usually only partial and not long-lasting. Mean survival time for cats with MM is 4 months post diagnosis.^1,4,5 There are reports of cats who have survived longer than 1 year.^1,4 Survival times vary in part due to the severity of the disease at the time of diagnosis (see Table 2).

Negative prognostic indicators include hypercalcemia, Bence Jones proteinuria, and extensive osteolysis.⁵

References

1. Hannah F. Multiple myeloma in cats. J Feline Med Surg. 2005 Oct;7(5):275-87.

2. Mellor PJ, Haugland S, Smith KC, et al. Histopathologic, immunohistochemical, and cytologic analysis of feline myeloma-related disorders: further evidence for primary extramedullary development in the cat. Vet Pathol. 2008 Mar; 45(2):159-73.

3. Mellor PJ, Haugland S, Murphy S, et al. Myeloma-related disorders in cats commonly present as extramedullary neoplasms in contrast to myeloma in human patients: 24 cases with clinical follow-up. J Vet Intern Med. 2006 Nov-Dec; 20(6):1376-83

4. Patel RT, Caceres A, French AF, McManus PM. Multiple myeloma in 16 cats: a retrospective study. Vet Clin Pathol. 2005 Dec; 34(4):341-52.

5. Withrow SJ, MacEwen EG. Small Animal Clinical Oncology, 4th ed. Plasma Cell Neoplasms. Ed. David Vail, DM. Saunders: St. Louis, MO, 2007. 769-784.

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