**4. Clinical signs**

in dogs. Further, the largest retrospective study to date (60 dogs) included 30 males and 30

The mean age of diagnosis in cats ranges between 12.5 and 14 years, and most of the cats with MM are older than 7 year-old [28,29,4,30,31,32,33,9]. According to the literature, the youngest cat with MM was 1.5 year-old [31]. A myeloma-related disorder has been described for a 19-month-old cat [34]. Males accounted for about 55-56%. The age and gender in dogs and cats with MM are similar to those described in human patients. In a large retrospective study of 1027 people, the average age of diagnosis was 66 years and

MM is also a neoplasm of elderly horses, with mean age of 11 years at the moment of the diagnosis [1]. Horses with this condition have ranged in age from three months to 25 years. The youngest animals were a 1.6-year-old Quarter Horse mare [36] and a 3 month-old Quar‐ ter Horse colt [37]. Although it was suggested initially that it could be more common in Quarter Horses [1], there are too few reports in equids for statistical interpretation of this

**3. Current knowledge of the etiology and predisposing factors of MM in**

Factors associated with the development of MM in companion animals have not been identified. In human patients, exposure to high doses of ionizing radiation has been linked to MM development according to some studies [38-40]. In relation to x-rays, the results of many cohort studies in human beings have been inconsistent, in some cases suggesting that frequent exposure has a negligible effect and in other that it is a signifi‐ cant risk [41-43]. In one report of equine MM, one horse was used regularly for teaching radiology and Pusterla et al. [3] suggested that it might exists an association between ex‐

Genetic and hereditary factors may also play a role in MM development [44-45]. Recurrent infections or antigen stimulation have been proposed as predisposing factors, although epi‐ demiological studies have not been confirmed this association [46]. Infections with several virus diseases in human patients appear related to an elevated MM risk, although some data do not support a potentially causal relationship between these infections and MM [46-50]. In cats, a link between MM and virus such as feline leukemia virus (FeLV) and feline immuno‐ deficiency virus (FIV) has not been identified, but a diagnosis of the disease among sibling suggests a familiar association [29]. The role of oncogenes, tumor-suppresor genes, cyto‐ kines, and their interaction with the bone marrow environment in the etiopathogenesis of the MM are currently being investigated in animal models. Overexpression of cell cycle reg‐ ulators, such as cyslin D1 and disregulation of receptor tyrosine kinase have been implicated in the pathogenesis of plasma cell tumors and MM [51]. Progression of B cell lymphoma to MM and of solitary plasma cell tumors to MM in dogs and cats have been reported [52-53].

data. Both male (geldings and stallions) and female horses are represented equally.

females [27].

290 Multiple Myeloma - A Quick Reflection on the Fast Progress

59% were men [35].

**companion animals**

posure to x-rays and neoplastic transformation.

The infiltration of various organ systems by neoplastic cells, the production of cytokines by the tumor or the bone marrow microenvironment, and the high circulating level of a single type of immunoglobulin lead to a wide array of clinical manifestations. Therefore, the clini‐ cal signs of MM vary with the level of plasma cell proliferation, the location and spread of the neoplastic plasma cells, and the nature and extent of the proteinuria [3,4,9-10,15,33,54]. The clinical signs are generally non-specific and include lethargy, renal failure, hemostatic abnormalities, anorexia, diarrhea and vomiting in small animals and weight loss, anorexia, fever, increased susceptibility to infections and limb edema in horses [1,3,8,11,36].

#### **4.1. Increased susceptibility to infections**

MM patients are usually immunocompromised and thus highly susceptible to infections [55]. MM associated immunodeficiency is likely a multifaceted phenomenon secondary to decreased concentration of polyclonal immunoglobulin [56], suppression of macrophage-re‐ lated factors influencing the normal B cell differentiation to plasma cells [57] in response to antigenic stimulation [58], decreased T helper cell function, increased rate of γ-globulin ca‐ tabolism, neoplastic infiltration of bone marrow resulting in leukopenia [59], dysfunctional and/or decreased numbers of neutrophils, and defective complement activation [3-4].

In cats with MM, the most common infectious processes include periodontitis, chronic re‐ current upper respiratory infections and terminal bacteriemia [4]. In horses with MM, the most common system affected by infectious disease is the lung, with several cases of severe pneumonia [1,3,37,60].

#### **4.2. Bone pain and skeletal lesions**

Bone pain is considered one of the most common presenting complaints in human patients [61-62]. Skeletal abnormalities are commonly recognized in small animals, but uncommon in horses with MM [1,3,63]. Horses frequently had bone lesions, therefore, bone pain might manifest more as a gait abnormality and therefore, it could be misdiagnosed.

The percentage of cats with MM and radiographically-evident skeletal lesions was 58.3% [2,4,13,63-66], similar to the 50-60% occurrence reported for dogs [27,64]. Skeletal lesions can be either solitary (well-circumscribed with areas of osteolysis or punched-out lytic areas) or multiple (generalized osteopenias) [4,27]. Rarely, pathologic fractures are seen. Skeletal le‐ sions are typically identified in bones involved in active hematopoiesis (e.g. ribs, vertebrae, pelvis, and proximal and distal aspects of long bones). Other causes of focal osteolysis are rare in companion animals, but include carcinomas [67], giant cell tumors of bone [68], be‐ nign aneurismal bone cysts [69-71] and bone lesions secondary to tumor invasion [70,72-73]. Generalized osteopenias have also been diagnosed radiographically [4]. Demineralization of bone in humans is detected through measurement of bone mineral density, a technique not used routinely in veterinary medicine. Generalized osteopenias is not specific for MM, and may also be seen with nutritional, renal and metabolic disorders [74-77].

#### **4.3. Bleeding disorders**

Bleeding is a prominent feature of MM in human beings [78-82]. Clinically, hemorrhages oc‐ cur in approximately one-third of dogs and one fourth of cats with MM [4,27,29]. In horses, the most common clinical manifestation is epistaxis [1,3,6].

MM, excess light chain production overcomes the capacity of the tubular cells to catabolize the free light chains that appear in the tubular fluid of distal nephron segments. Therefore, they form tubular casts with Tamm-Horsfall protein (uromodulin), a glycoprotein-synthe‐ sized by the cells in the medullary thick ascending limb of the loop of Henle with affinity for monoclonal light chains. Light chains interact through their complementary determining re‐ gion with a specific binding site on the Tamm-Horsfall protein and form aggregates and casts that subsequently lead to the tubular obstruction of the distal tubule and the thick as‐ cending loop of Henle [95-97]. Tubular obstruction increases intraluminal pressure, reduces glomerular filtration rate and reduces interstitial blood flow, thus further compromising the renal function [90]). The rates of cast formation increase when light chains increase, al‐ though there is considerable diversity among the nephrotoxicity of light chains. The variable region of the light chain determines nephrotoxicity of the specific light chain by determining the affinity with Tomm-Horsfall protein [98-99]. It has been indicated that Tamm-Horsfall protein interacts with the hypervariable regions of the light chains. This region contains the amino acids that give diversity, and allow for interactions with several proteins to promote antigen binding by immunoglobulins [100-101]. In addition, the variable region of the light chain determines the specific type of renal damage. Both lambda and kappa light chains are nephrotoxic, but lambda light chains are more frequently involved in the formation of amy‐ loid than kappa [102]. The relationship between the type of light chain and the severity and

Multiple Myeloma in Horses, Dogs and Cats: A Comparative Review Focused on Clinical Signs and Pathogenesis

http://dx.doi.org/10.5772/54311

293

In addition of casts formation, endocytosis of light chains by renal tubular cells induces proinflammatory cytokine production (interleukin-6 and 8, tumor necrosis factor-α). These proinflammatory cytokines promote infiltration by inflammatory cells that produce metalloproteinases and increase transforming growth factor-b production, resulting in ma‐ trix protein deposition and fibrosis and further compromising the ability of the nephron to restore function [103]. Light chains endocytosis might also cause tubular cell necrosis, lead‐ ing to more severe renal dysfunction [104], but the exact mechanism has not been described. It has been hypothesized that the aggregation of light chains after endocytosis initiates a cas‐

Other mechanisms that lead to renal insufficiency are tumor infiltration within the renal pa‐ renchyma, hypercalcemia, amyloidosis, decreased renal perfusion due to the HVS, dehydra‐ tion, ascending urinary tract infections and Bence-Jones proteinuria [4, 27]. In human patients with MM, hypercalcemia is the second most common cause of renal failure. Hyper‐ calcemia is also probably an important predisposing factor to renal dysfunction in animals with MM, since a tight relationship between renal failure and hypercalcemia has been de‐ scribed in many reports in veterinary medicine [106-108] Hypercalcemia interferes with re‐ nal function and impairs renal concentrating ability, causes vasoconstriction of renal

Heart disease may occur in patients with MM as a consequence of HVS related to myocar‐ dial hypoxia and increased cardiac workload. In addition, amyloid deposition in the myo‐

type of renal damage has not been investigated in animals yet.

cade leading to tubular cell death [105].

vasculature and enhances diuresis.

**4.6. Heart disease**

The pathogenesis of bleeding diathesis is likely multifactorial. The M-component may inter‐ fere with normal coagulation and lead to hemostatic defects by various mechanism that in‐ clude inhibition of platelet aggregation and release of platelet factor, adsorption of minor clotting factors, induction of abnormal fibrin polymerization and functional decrease in cal‐ cium. In instances where myelophthisis is present due to profound bone marrow infiltra‐ tion, thrombocytopenia may develop and contribute to hemorrhagic events [24].

#### **4.4. Hyperviscosity syndrome**

The hyperviscosity syndrome (HVS) in characterized by clinico-pathologic abnormalities that occur secondarily to increased serum viscosity, which is associated with the M-com‐ ponent. HVS is most commonly associated with immunoglobulin-M macroglobulinemia due to the high molecular weight of IgM [85]. However, it also can occur in presence of IgA, and rarely with IgG [27]. HVS leads to bleeding diathesis, neurological signs (such as seizures, depression, coma), congestive heart failure, renal failure and ophthalmic ab‐ normalities, including tortuous and dilated retinal vessels, retinal hemorrhages and reti‐ nal detachment, sludging of blood within small vessels and impaired delivery of nutrients and oxygen to tissues [84].

Approximately 20% of dogs with MM develop this syndrome and it has been reported in cats [4,13,19,23,54,85]. There is a report that measured serum viscosity in a horse with MM [86]. The horse had a serum concentration of globulin of 9.6 g/dl (reference range 3.5-4.5 g/dl) and a relative serum viscosity of 7 (reference range 1.4-1.7). In horses, edema is a com‐ mon clinical signs in MM [1,3]. The genesis of limb edema is unknown, although blood hy‐ perviscosity may be contributory. Increased vascular permeability has been proposed as a cause of edema accompanying osteosclerosis myeloma in human beings [87].

#### **4.5. Renal disease**

Renal disease occurs in approximately 22-50% of dogs and about 30% of cats with MM [4,27]. The pathogenesis of renal disease is commonly multifactorial and several mecha‐ nisms have been implicated in human patients [88-89]. In the majority of the cases, renal im‐ pairment is caused by the accumulation and precipitation of light chains, which forms casts in the distal tubules, resulting in renal obstructions. In addition, myeloma light chains are also directly toxic on proximal renal tubules, further adding to renal dysfunction [89-90]. Circulating monoclonal light chains are relatively freely filtered through the glomerulus, reaching the proximal tubule, where they are catabolized. Free light chains are endocytosed by proximal tubule cells, through a receptor-mediated process, by binding to the tandem scavenger receptor system cubilin/megalin. Then, they are endocytosed through the cla‐ thrin-dependent endosomal/lysosomal pathways and degraded within lysosomes [91-94]. In MM, excess light chain production overcomes the capacity of the tubular cells to catabolize the free light chains that appear in the tubular fluid of distal nephron segments. Therefore, they form tubular casts with Tamm-Horsfall protein (uromodulin), a glycoprotein-synthe‐ sized by the cells in the medullary thick ascending limb of the loop of Henle with affinity for monoclonal light chains. Light chains interact through their complementary determining re‐ gion with a specific binding site on the Tamm-Horsfall protein and form aggregates and casts that subsequently lead to the tubular obstruction of the distal tubule and the thick as‐ cending loop of Henle [95-97]. Tubular obstruction increases intraluminal pressure, reduces glomerular filtration rate and reduces interstitial blood flow, thus further compromising the renal function [90]). The rates of cast formation increase when light chains increase, al‐ though there is considerable diversity among the nephrotoxicity of light chains. The variable region of the light chain determines nephrotoxicity of the specific light chain by determining the affinity with Tomm-Horsfall protein [98-99]. It has been indicated that Tamm-Horsfall protein interacts with the hypervariable regions of the light chains. This region contains the amino acids that give diversity, and allow for interactions with several proteins to promote antigen binding by immunoglobulins [100-101]. In addition, the variable region of the light chain determines the specific type of renal damage. Both lambda and kappa light chains are nephrotoxic, but lambda light chains are more frequently involved in the formation of amy‐ loid than kappa [102]. The relationship between the type of light chain and the severity and type of renal damage has not been investigated in animals yet.

In addition of casts formation, endocytosis of light chains by renal tubular cells induces proinflammatory cytokine production (interleukin-6 and 8, tumor necrosis factor-α). These proinflammatory cytokines promote infiltration by inflammatory cells that produce metalloproteinases and increase transforming growth factor-b production, resulting in ma‐ trix protein deposition and fibrosis and further compromising the ability of the nephron to restore function [103]. Light chains endocytosis might also cause tubular cell necrosis, lead‐ ing to more severe renal dysfunction [104], but the exact mechanism has not been described. It has been hypothesized that the aggregation of light chains after endocytosis initiates a cas‐ cade leading to tubular cell death [105].

Other mechanisms that lead to renal insufficiency are tumor infiltration within the renal pa‐ renchyma, hypercalcemia, amyloidosis, decreased renal perfusion due to the HVS, dehydra‐ tion, ascending urinary tract infections and Bence-Jones proteinuria [4, 27]. In human patients with MM, hypercalcemia is the second most common cause of renal failure. Hyper‐ calcemia is also probably an important predisposing factor to renal dysfunction in animals with MM, since a tight relationship between renal failure and hypercalcemia has been de‐ scribed in many reports in veterinary medicine [106-108] Hypercalcemia interferes with re‐ nal function and impairs renal concentrating ability, causes vasoconstriction of renal vasculature and enhances diuresis.

#### **4.6. Heart disease**

**4.3. Bleeding disorders**

292 Multiple Myeloma - A Quick Reflection on the Fast Progress

**4.4. Hyperviscosity syndrome**

nutrients and oxygen to tissues [84].

**4.5. Renal disease**

Bleeding is a prominent feature of MM in human beings [78-82]. Clinically, hemorrhages oc‐ cur in approximately one-third of dogs and one fourth of cats with MM [4,27,29]. In horses,

The pathogenesis of bleeding diathesis is likely multifactorial. The M-component may inter‐ fere with normal coagulation and lead to hemostatic defects by various mechanism that in‐ clude inhibition of platelet aggregation and release of platelet factor, adsorption of minor clotting factors, induction of abnormal fibrin polymerization and functional decrease in cal‐ cium. In instances where myelophthisis is present due to profound bone marrow infiltra‐

The hyperviscosity syndrome (HVS) in characterized by clinico-pathologic abnormalities that occur secondarily to increased serum viscosity, which is associated with the M-com‐ ponent. HVS is most commonly associated with immunoglobulin-M macroglobulinemia due to the high molecular weight of IgM [85]. However, it also can occur in presence of IgA, and rarely with IgG [27]. HVS leads to bleeding diathesis, neurological signs (such as seizures, depression, coma), congestive heart failure, renal failure and ophthalmic ab‐ normalities, including tortuous and dilated retinal vessels, retinal hemorrhages and reti‐ nal detachment, sludging of blood within small vessels and impaired delivery of

Approximately 20% of dogs with MM develop this syndrome and it has been reported in cats [4,13,19,23,54,85]. There is a report that measured serum viscosity in a horse with MM [86]. The horse had a serum concentration of globulin of 9.6 g/dl (reference range 3.5-4.5 g/dl) and a relative serum viscosity of 7 (reference range 1.4-1.7). In horses, edema is a com‐ mon clinical signs in MM [1,3]. The genesis of limb edema is unknown, although blood hy‐ perviscosity may be contributory. Increased vascular permeability has been proposed as a

Renal disease occurs in approximately 22-50% of dogs and about 30% of cats with MM [4,27]. The pathogenesis of renal disease is commonly multifactorial and several mecha‐ nisms have been implicated in human patients [88-89]. In the majority of the cases, renal im‐ pairment is caused by the accumulation and precipitation of light chains, which forms casts in the distal tubules, resulting in renal obstructions. In addition, myeloma light chains are also directly toxic on proximal renal tubules, further adding to renal dysfunction [89-90]. Circulating monoclonal light chains are relatively freely filtered through the glomerulus, reaching the proximal tubule, where they are catabolized. Free light chains are endocytosed by proximal tubule cells, through a receptor-mediated process, by binding to the tandem scavenger receptor system cubilin/megalin. Then, they are endocytosed through the cla‐ thrin-dependent endosomal/lysosomal pathways and degraded within lysosomes [91-94]. In

cause of edema accompanying osteosclerosis myeloma in human beings [87].

tion, thrombocytopenia may develop and contribute to hemorrhagic events [24].

the most common clinical manifestation is epistaxis [1,3,6].

Heart disease may occur in patients with MM as a consequence of HVS related to myocar‐ dial hypoxia and increased cardiac workload. In addition, amyloid deposition in the myo‐ cardium and anemia may exacerbate the severity of this condition [109]. Approximately 50% of the cats with MM in one study had idiopathic heart murmur [4]. Recently, three cases of cats evaluated for congestive heart failure with acute collapse, tachypnea, increased respira‐ tory effort, and pulmonary crackles, have been reported secondarily to HVS [54].

by biochemical evaluation, radiography and bone marrow aspirate. An electromyogram re‐ vealed positive sharp waves and fibrillation potentials in the skeletal muscles of the limbs, suggesting a polyneuropathy. Motor function started to improve four weeks after commenc‐ ing treatment. According to the authors, polyneuropathy in this dog appeared as a paraneo‐

Multiple Myeloma in Horses, Dogs and Cats: A Comparative Review Focused on Clinical Signs and Pathogenesis

http://dx.doi.org/10.5772/54311

295

Cutaneous involvement in MM has also been described in animals, although it seems to be unusual. Mayer et al. [24] described the case of an 8-year-old Rottweiler dog with more than 50 soft cutaneous and subcutaneous nodules, ranging from 0.5 to 2.5 cm in di‐ ameter, located primarily on the ventral aspects of the thorax and abdomen and the me‐ dial aspect of the thighs. Histopathological examination of excised subcutaneous modules revealed MM. More recently, Fukumoto et al. [16] presented the case of a 7-year-old male, mixed breed dog with more than 40 cutaneous nodules ranging from 0.5 to 1.0 cm in diameter, mainly on the abdomen and inguinal region. Cutaneous involvement has

Anemia is a prominent feature of MM, it is commonly associated with clinical progres‐ sion in human patients and occurs in more than two thirds of all patients [130-132]. Sim‐ ilarly, approximately 30% of dogs and 75% of cats with MM have a normocytic normochromic non-regenerative anemia [4,10,26-27,32-33] and anemia is also invariably

The pathogenic mechanisms involved in the anemia are chronic inflammation, tumor hemorrhage and/or hemostatic abnormalities, myelophthisis, increased red blood cell de‐ struction induced by the HVS, plasma expansion secondary to the osmotic effect of the paraproteins and red cell destruction by neoplastic cells [4,27,29]. In cats, erythrophago‐ cytosis by neoplastic plasma cells [32], mast cells [133]), lymphocytes [134-135] and histo‐ cytes [136] has been observed. In the same way, there are several reports of phagocytic plasma cells in people with MM [137]. Although erythrophagocytic plasma cells in hu‐ mans with MM are rare, neoplastic plasma cells have been observed with phagocytosed platelets and granulocytes [138]. The mechanism of hemophagocytosis in MM is unclear, as plasma cells have not phagocytic function under normal circumstances. Results of the direct antiglobulin test in humans are almost always negative, suggesting hemophagocy‐ tosis by neoplastic cells is not an autoimmune function [137]. It has been speculated that phagocytic plasma cells may arise as an expansion of a rare B-cell clone with innate phagocytic potential [137]. A single case of phagocytic plasma cells aberrantly expression CD15 (normally found on neutrophils and monocytes and involved in phagocytosis) has

Nevertheless, anemia of chronic disease appears to be of utmost importance in MM. Inter‐ leukin-1 and tumor necrosis factors are capable of suppressing erythropoiesis [130]. Anemia

**5. Diagnosis aids of multiple myeloma in veterinary medicine**

plastic syndrome secondary to MM [22].

not been described in horses with MM.

**5.1. Hematology**

present in horses with MM.

been reported in human beings [139].

#### **4.7. Other clinical signs**

Neurological manifestations often complicate the course of MM, but direct involvement of the central nervous system in rare in human patients, although there are some cases report‐ ed [110-113]. Similarly, neurological signs are uncommon manifestations of MM in animals. However, it is well recognized that MM may lead to abnormalities of the central nervous system either as a result of spinal cord compression by the neoplasm arising within a verte‐ bra or due to pathological fracture of a vertebra weakened by tumor infiltration [114-115]. It could also be due to the HVS where sludging of blood within the vasculature results in cen‐ tral nervous system hypoxia [116]. Neurological signs associated with MM have been re‐ ported in horses [1,7], cats [31] and dogs [22,114]. Edwards et al. [1] described the cases of three horses with rear leg paresis and/or ataxia. Spinal cord compression by an extradural tumor mass was observed in one of the two horses in which the spinal canal was examined. McConkey et al. [7] observed a horse with hind ataxia progressing to paralysis, with dys‐ phagia and ptyalism. These clinical signs were attributed to neoplastic involvement of the trigeminal nerve. Similarly, Appel et al. [31] presented the case of a cat with hind limb loco‐ motor difficulties, signs of pain along the lumbar portion of the vertebral column, with al‐ tered motor function and moderate muscle atrophy. In this case, survey radiographs revealed osteolytic lesions in lumbar vertebras [31].

In MM patients, peripheral neuropathy has for a long time been considered as mainly secon‐ dary to the tumor, following a direct compression (radicular or medullar), light chain depos‐ its (amyloidosis), cryoglobulinemia or an autoimmune mechanism [117-121]. A paraneoplastic polyneuropathy is seen in association with IgM monoclonal gammopathy as‐ sociated with MM, Waldenstrom's macroglobulinemia, primary amyloidosis and lympho‐ ma, as well as monoclonal gammopathy of undetermined significance. IgM-M proteins have autoantibody activity and have been shown to bind to myelin associated glycoprotein re‐ sulting in a demyelinating peripheral neuropathy [121]. However, increased levels of cyto‐ kines are thought to cause the paraneoplastic neuropathy rather than an immune-mediated mechanism [122-123]. Furthermore, with the use of new drugs, the iatrogenic neurotoxicity has become the leading cause of peripheral neuropathy in people [124-126]. The commonest nerve involvement appears to be in the form of sensory-motor axonal neuropathy followed by sensory-motor demyelinating neuropathy [117].

In companion animals, paraneoplastic neuropathies have been reported sporadically in ma‐ lignant tumors, and include bronchogenic carcinoma, insulinoma, leiomyosarcoma, heman‐ giosarcoma, undifferentiated sarcoma, synovial sarcoma and adrenal adenocarcinoma [114,127-129]. Viviers and Dobson [22] described the case of a 12-year-old female German Shepherd dog that developed progressive hindlimb followed by forelimb ataxia with tetra‐ plejia. Neurological examination suggested lower motor dysfunction. MM was diagnosed by biochemical evaluation, radiography and bone marrow aspirate. An electromyogram re‐ vealed positive sharp waves and fibrillation potentials in the skeletal muscles of the limbs, suggesting a polyneuropathy. Motor function started to improve four weeks after commenc‐ ing treatment. According to the authors, polyneuropathy in this dog appeared as a paraneo‐ plastic syndrome secondary to MM [22].

Cutaneous involvement in MM has also been described in animals, although it seems to be unusual. Mayer et al. [24] described the case of an 8-year-old Rottweiler dog with more than 50 soft cutaneous and subcutaneous nodules, ranging from 0.5 to 2.5 cm in di‐ ameter, located primarily on the ventral aspects of the thorax and abdomen and the me‐ dial aspect of the thighs. Histopathological examination of excised subcutaneous modules revealed MM. More recently, Fukumoto et al. [16] presented the case of a 7-year-old male, mixed breed dog with more than 40 cutaneous nodules ranging from 0.5 to 1.0 cm in diameter, mainly on the abdomen and inguinal region. Cutaneous involvement has not been described in horses with MM.
