INCIDENCE AND ETIOLOGY

Multiple myeloma (MM) is an uncommon disease in cats, accounting for less than 1 per cent of all malignant neoplasms in two large compilations of feline neoplasms.^1,2 Similarly, in one recent report of feline MM, the disease represented less than 1 per cent of all feline neoplasms diagnosed at the Veterinary Hospital of the University of Pennsylvania from 1996 to 2004.³ Related plasma cell disorders, such as MGUS, Waldenström macroglobulinemia, and plasma cell leukemia, are rare, with only a few case reports existing in the feline literature. MM is a disease of older cats (median age ≈12 years), with no breed or gender predilection. A slight increase in incidence in male cats has been suggested; however, the total number of cases reported is low, making this predilection difficult to verify.^3,4

The etiology of the disease is unknown. Although the development of B lymphoid neoplasms has been associated with the prevalence of retroviruses in several domestic species, there is no association with FeLV or FIV in cats with MM.^4,5 There also is no association with feline coronavirus.⁴ In human beings, exposure to ionizing radiation (including occupational exposure), as well as exposure to metals, benzenes, petroleum products, and silicon, have been considered potential risk factors. Familial associations have been reported in human patients and inbred mice, supporting the role of hereditary and genetic factors.⁶ A potential familial association was suggested in one report of a pair of sibling cats with MM.⁷ Chronic immune stimulation has been suggested as a predisposing factor in human beings and mice. In a case series of 24 cats with “myeloma-related disorders,” Mellor et al examined medical records for antecedent inflammatory disease. One cat had a history of severe, recurrent dental disease, and one cat had unilateral uveitis of unknown origin. No other evidence of chronic antigenic stimulation or inflammation preceding the development of the disease was found.⁸ In a case report of a cat with an intraocular plasmacytoma, previous trauma had occurred to the involved eye, and the authors hypothesized that chronic inflammation played a role in the development of the plasmacytoma.⁹ Although it is uncommon, solitary extramedullary plasmacytomas can precede MM in several species, and a cutaneous EMP has been reported to precede MM in a cat.¹⁰ This also has been reported occasionally in dogs and human beings.^11,12

PATHOLOGY AND PATHOGENESIS

MM is derived from a clonal proliferation of malignant plasma cells (immunoglobulin-secreting B lymphocytes). It is a systemic disease arising typically from the bone marrow. The malignant plasma cells range from well differentiated to atypical on cytological and histological preparations. In a recent retrospective study, atypical cytological changes were noted in plasma cells in the majority of cats with MM. These changes included increased size, multiple nuclei, clefted nuclei, anisocytosis, anisokaryosis, variable N : C ratios, decreased chromatin density, and variably sized nucleoli.³ Flame cells, characterized by peripheral eosinophilic cytoplasmic projections, or Mott cells, characterized by Russell bodies representing globules of immunoglobulin, may be present (Figure 65-1).

Figure 65-1 A, A cytological sample from a hepatic plasmacytoma in a cat with multiple myeloma. Note the pleomorphic cells with eccentrically placed nuclei and a perinuclear clear zone (representing the Golgi body). A mitotic figure also is present. (Wright-Giemsa, 100×.) B, A cytological sample of a skeletal lytic lesion in a cat with multiple myeloma. Note the Mott cell in the center (cell containing Russell bodies representing globules of immunoglobulin within a plasma cell). (Wright-Giemsa, 100×.) C, A bone marrow aspirate of a cat with multiple myeloma. (Wright-Giemsa, 100×.)

MM is characterized by the presence of a monoclonal gammopathy (M protein, M component, paraprotein) signifying the production of a single immunoglobulin from the neoplastic cells (Figure 65-2). In cats, this is represented most commonly by IgG gammopathy. The second most common M protein is IgA.^3,13 Biclonal spikes also occur in cats, and this may be due to two independent secretory tumor cell lines each secreting a unique M protein, one tumor cell line producing two separate M proteins, or a spurious biclonal spike secondary to an increase in the dimeric protein IgA. A monoclonal increase in the pentamer IgM (Waldenström macroglobulinemia) has been reported in one cat.¹⁴ Waldenström macroglobulinemia in human beings is characterized by the absence of skeletal lytic lesions and the involvement of liver, spleen, and/or lymph nodes; more recently, it has been classified as a lymphoplasmacytic lymphoma in human beings.⁶ Production of the entire immunoglobulin is most common in cats; however, light chain myeloma has been reported in two cats, as well as in a dog.^15–17

Figure 65-2 A, Serum protein electrophoresis from a cat with a nonspecific polyclonal gammopathy (stained cellulose acetate electrophoretic strip with accompanying densitogram). B, Serum protein electrophoresis from a cat with multiple myeloma. Note the large M component spike in the gamma region (interpreted as a monoclonal gammopathy). C, Serum protein electrophoresis representing a biclonal gammopathy.

Light chain myeloma is characterized by the presence of light chains (L chains) in urine without a concurrent monoclonal gammopathy. Nonsecretory disease, characterized by marrow plasmacytosis and skeletal lytic lesions, occurs in dogs and human beings,¹⁸ although it has not been reported in cats. This manifestation typically carries a poor prognosis in human beings.⁶ In heavy chain disease, which is rare in human patients and has been reported in one dog, the M protein is characterized by an incomplete heavy chain, lacking a light chain.¹⁹ Cryoglobulinemia has been reported in one cat.²⁰ This is characterized by the oversecretion of an M protein that is insoluble at low temperatures. Clinical signs associated with cryoglobulinemia result from precipitation of the cryoglobulin in small-diameter blood vessels and include purpura, cold intolerance, and ulceration and necrosis of the skin of distal extremities. To evaluate for cryoglobulins, blood must be collected and serum separated at 37° C to avoid precipitation of the protein in the clot. Plasma cell leukemia can be diagnosed as either primary, without a previous diagnosis of MM, or secondary, with concurrent myeloma or plasmacytoma. This is a rare disease that has been reported in one cat with a cutaneous extramedullary plasmacytoma that progressed to MM with secondary plasma cell leukemia.^3,10

CLINICAL SIGNS AND MANIFESTATIONS

In the three most recent compilations of feline MM cases, the most common presenting clinical signs are nonspecific and consist of lethargy, decreased appetite, and weight loss.^3,7,8 Other clinical signs and physical examination abnormalities include polyuria/polydipsia, vomiting, diarrhea, lameness or paresis/paralysis, central nervous system signs, fundic changes (retinal hemorrhages, retinal detachment), palpable hepatosplenomegaly, other evidence of bleeding (epistaxis, oral bleeding), and concurrent skin masses.

The clinical manifestations associated with MM include bony involvement, extramedullary involvement, hyperviscosity syndrome, cardiac disease, bleeding diathesis, chronic kidney disease, hypercalcemia, and possible increased susceptibility to infections. The resulting manifestations often occur due to high levels of circulating M protein or organ/bone infiltration by neoplastic plasma cells.

Bone lesions are characterized by lysis and are classically described as “punched-out” lesions (Figure 65-3). They can be single or multiple or represented by diffuse osteopenia or pathological fractures. Reported sites of skeletal lytic lesions are the pelvis, ribs, vertebrae, and long bones. Reports of the frequency of bone lesions in cats with MM are conflicting, ranging from 8 to 60 per cent.^3,7,8

Figure 65-3 Lateral (A) and anteroposterior (B) radiographic views of the elbow of a cat with multiple myeloma. This cat had concurrent cutaneous plasma cell tumors, in conjunction with systemic evidence of multiple myeloma.

Extramedullary infiltration by neoplastic plasma cells is a common finding in feline MM. By contrast, extramedullary involvement is uncommon in human beings and dogs with MM.^4,6 A recent report examining cats diagnosed with MM reported that approximately 40 per cent had cytologically or histologically confirmed plasma cell neoplasia in the spleen, liver, and abdominal lymph nodes, with splenic infiltration being the most common (Figure 65-4).³ Additionally, in a report evaluating the spectrum of myeloma-related disorders in cats, 50 per cent of cats with plasma cell infiltration in the bone marrow had concurrent involvement of abdominal organs. Several cats in this report had abdominal organ involvement without concurrent bone marrow infiltration. However, all of these cats had concurrent monoclonal gammopathy.⁸

Figure 65-4 A, A liver biopsy from a cat with multiple myeloma. The biopsy consists of hepatocytes with intermixed plasma cells arranged in sheets. The neoplastic cells are round to oval with eccentrically placed nuclei. (H&E, 40×.) B, Fine-needle aspirate cytological sample of the liver of the same cat. Note the binucleate plasma cells and the cluster of hepatocytes in right upper corner.

Hyperviscosity syndrome (HVS) results from elevations in circulating M protein leading to increased serum viscosity. Incidence is highest with IgM due to the high molecular weight of IgM, a pentamer, followed by IgA, a dimer that can polymerize, and IgG. HVS also may be more common with cryoglobulinemia. High serum viscosity can lead to central nervous system abnormalities, such as mentation changes and seizures. It also can lead to increased cardiac workload and cardiac failure, retinal hemorrhages, and coagulation abnormalities. These complications are thought to occur secondary to sludging of blood in small vessels and ineffective delivery of oxygen to tissues.^21,22 HVS was present in 40 per cent (four of nine) of cats in one study; however, serum viscosity is not measured routinely at most institutions.⁷

Bleeding diathesis or coagulation defects can result from several mechanisms, including M protein interfering with clotting factors and platelets, the Fab fragment of the M protein binding to fibrin preventing its aggregation, or adsorption of minor clotting proteins. Additionally, bone marrow infiltration (myelophthisis) may lead to thrombocytopenia.^4,6 Evidence of bleeding diathesis or bleeding abnormalities was noted in approximately 30 per cent of cats in recent reports.^3,7,8

Chronic kidney disease may be present for a variety of reasons in cats with MM. In three recent reports of MM in cats, 25 to 40 per cent of cats were azotemic.^3,7,8 Light chain proteinuria occurs due to an unbalanced production of kappa (κ) or lambda (λ) light chains. These excessive light chains are filtered freely by the glomerulus leading to their presence in urine. Filtered light chains can form protein precipitates that lead to tubular damage and resulting azotemia. Other possible mechanisms of kidney disease include hypercalcemia, amyloidosis, renal infiltration by neoplastic plasma cells, decreased renal perfusion secondary to HVS, or pyelonephritis.^4,6 Light chain proteinuria was reported in 40 to 50 per cent of cats with MM in recent reports.^3,7 Amyloidosis, the systemic deposition of light-chain (AL) amyloid in organs (including the kidney), is rare in cats with MM.

Hypercalcemia may result from direct tumor lysis of infiltrated bone or osteoclast activation. Osteoblast inhibition also is cited as a mechanism of hypercalcemia in affected human beings. In human patients, osteoclast activation occurs secondary to aberrant production of interleukin (IL)-1β (previously called osteoclast activating factor), tumor necrosis factor (TNF)-β, and IL-6. Receptor activator of nuclear factor-κB ligand (RANKL) also is elicited by parathyroid hormone (PTH), PTHrp, and IL-1β, and likely plays a role in hypercalcemia associated with MM. RANK (the receptor for RANKL) is located on osteoclasts and becomes activated with the binding of RANKL on stromal cells, osteoblasts, and possibly tumor cells (Figure 65-5).^6,23 Hypercalcemia is reported to occur in 20 to 40 per cent of cats in recent reports.^3,7

Figure 65-5 Graphic depiction of neoplastic mechanisms of hypercalcemia. Receptor activator of nuclear factor-κB ligand (RANKL) is located on osteoblasts or stromal cells while RANK is located on osteoclasts or osteoclast progenitors. The numbers indicate hypothesized mechanisms of bisphosphonates (BPS) on cancer cells.

(From Milner RJ, Farese J, Henry CJ, et al: Bisphosphonates and cancer, J Vet Intern Med 18:597, 2004.)

A number of factors contribute to the increased risk of infection in MM patients. In human beings with MM, there are documented decreases in the levels of uninvolved immunoglobulins, which increases patients’ risk for bacterial infections. Additionally, B-cell and T-cell function may be dysregulated secondary to immunosuppressive cytokines (e.g., TGF-β), and neutropenia may result from myelophthisis.⁶ One recent report includes three cats (approximately 20 per cent of the study group) with concurrent infectious processes, including upper respiratory infection, severe dental disease, and terminal bacteremia³; however, overwhelming infection is not reported commonly in feline MM patients.

Cytopenias were relatively common in recent reports, with approximately 55 to 75 per cent of cats being anemic, 30 per cent being neutropenic, and 50 per cent being thrombocytopenic. Anemia in cats with MM typically is nonregenerative, normochromic, and normocytic.^3,6

Clinical signs and clinicopathological abnormalities in cats with MM reported since 2000 are summarized in Tables 65-3 and 65-4.

Table 65-3 Clinical Signs in Cats with Multiple Myeloma*

N = 52.

* References 3, 7, 8, 10, 13, 19, 23.

† Mellor et al included cats with “myeloma-related disorders.” Five cats with solitary cutaneous plasma cell tumors with no systemic involvement were excluded from this summary.

Table 65-4 Clinicopathological Abnormalities in Cats with Multiple Myeloma*

N = 28.

* References 3, 7, 10, 13, 19, 23.