Multiple Myeloma

PATHOPHYSIOLOGY

Signalment

•age: mean 8-9 years

•no sex predisposition although males over-represented in some reports

•breed predisposition: GSD

•more common in dogs although reported in cats (and not associated with either FeLV or FIV infection)

Etiology

•etiology is unknown

•proposed causes include viral infection, chronic immune stimulation, and exposure to carcinogens

•exposure to petroleum products and radiation therapy are risk factors in humans

General Considerations

•multiple myeloma is a systemic proliferation of malignant plasma cells arising from a clone of 1 cell and usually involves > 1 bone marrow site

•degree of differentiation of malignant plasma cell is very variable

•malignant plasma cells produce excessive amounts of an immunoglobulin component = M-component

•M-component can be represented by any class of immunoglobulin (IgG in cats, and IgA and IgG in dogs) or portions of molecules such as light chains (Bence Jones proteins) or heavy chains

•multiple myeloma is the cause of monoclonal gammopathy in 50% dogs, with other causes including lymphoproliferative tumors (i.e., mucocutaneous plasmacytoma, LSA, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia), and non-myelomatous infectious diseases (i.e., leishmaniasis and ehrlichiosis)

From: Withrow SJ & MacEwen EG (eds): Small Animal Clinical Oncology (3rd ed).

•multiple myeloma can produce high levels of circulating immunoglobulins, infiltrate organs with neoplastic cells or both resulting in bone disease, bleeding diathesis, hyperviscosity syndrome, immunodeficiency (and increased susceptibility to infection), cytopenias, and cardiac failure

Bleeding Diathesis

•bleeding diathesis can be caused by:

•M-component can interfere with coagulation by inhibiting platelet aggregation and platelet factor 3 release

•adsorption of minor clotting proteins

•generation of abnormal fibrin polymerization

•functional decrease in calcium

•33% dogs have evidence of hemorrhage and 50% have prolonged PT and APTT

•thrombocytopenia may be involved with significant bone marrow infiltration

Skeletal Lesions

•bone lesions can vary from discrete and isolated lesions (i.e., pathologic fracture) to diffuse osteopenia

•bone disease is present in 25%-33% dogs and commonly affects vertebrae, ribs, pelvis, skull, and proximal and distal long bones (i.e., areas with active hematopoiesis)

•skeletal lesions are rare in cats

Hyperviscosity Syndrome

•hyperviscosity syndrome is caused by increases in serum viscosity and is seen in 20% dogs

•viscosity changes are related to type, size, shape, and concentration of M-component in blood

•hyperviscosity syndrome is more common with IgM macroglobulinemia due to the high molecular weight of IgM, but it can also occur with IgA and IgG gammopathies

•hyperviscosity syndrome can cause:

•bleeding diathesis

•neurologic signs (i.e., dementia, depression, seizures, and coma)

•ophthalmic abnormalities (i.e., retinal hemorrhage and detachment)

•cardiomyopathy (due to increase cardiac work load)

Renal Disease

•renal disease is present in 33%-50% of dogs with multiple myeloma

•renal disease is multifactorial and caused by Bence Jones proteinuria, tumor infiltration into renal tissue, hypercalcemia, amyloidosis, dehydration, ascending UTI, and decreased perfusion secondary to hyperviscosity syndrome

•Bence Jones proteinuria occurs in 25%-40% dogs and frequently in cats

•excessive production of light-chain proteins overwhelms tubular filtration ability and results in precipitation in tubules, tubular injury, and tubular obstruction with laminated casts containing albumin, immunoglobulin, and light-chains

Hypercalcemia

•hypercalcemia occurs in 15%-20% of dogs with multiple myeloma, but is rare in cats

•hypercalcemia is probably caused by production of osteoclast-activating factor by tumor cells

•lymphotoxin, TNF, IL-1, and IL-6 may also be involved

Other

•increased susceptibility to infection (15-times in humans with multiple myeloma)

•various cytopenias including anemia due to bone marrow infiltration, anemia of chronic disease, blood loss from coagulation disorders, or erythrocyte destruction secondary to hyperviscosity syndrome

CLINICAL FEATURES

Clinical Signs

•variable

•lethargy and weakness (62%), lameness (47%), bleeding diathesis (37%), ophthalmic problems (35%), polyuria and polydipsia (25%), and CNS deficits (12%) are common in dogs

•cats will frequently present with lethargy, anorexia, and weight loss

Diagnosis

•hematology and coagulation profile: anemia

•serum biochemistry: increased urea nitrogen, creatinine, and ionized calcium

•serum electrophoresis or immunoelectrophoresis to demonstrate monoclonal spike

•survey bone radiographs, however, many dogs have < 5 lesions and some only have generalized osteopenia

•technetium scans are considered inaccurate in the diagnosis of multiple myeloma in both dogs and humans

•definitive diagnosis of multiple myeloma requires ≥ 2 of the following criteria:

•radiographic evidence of osteolytic lesions

•bone marrow biopsy with > 5% plasma cells

•monoclonal gammopathy in either serum or urine

•light-chain (Bence-Jones) proteinuria

TREATMENT

General Considerations

•melphalan: 0.1 mg/kg q 24 hrs for 10 days and then 0.05 mg/kg q 24 hrs

•prednisone: 0.5 mg/kg q 24 hrs for 10 days and then reducing dose

•prednisone increases the efficacy of melphalan

•prednisone should be discontinued after 60 days although melphalan should be continued until clinical relapse or bone marrow suppression

•hematology should be performed regularly as melphalan can cause myelosuppression

•dose reduction or pulsed therapy (7 mg/m 2 q 24 hrs for 5 consecutive days every 3 weeks) if clinical and hematological evidence of myelosuppression is detected (usually thrombocytopenia and neutropenia)

•alternatives: chlorambucil and cyclophosphamide

Other Treatment Options

•hypercalcemia: saline diuresis, calcitonin, and bisphosphonates

•hyperviscosity syndrome: plasmapheresis

•CRF: intravenous fluids and dietary management

•prophylactic antibiotics should be considered

•rescue therapy: doxorubicin-based protocols or thalidomide

Prognosis

Cats

•response rates tend to partial and lack durability

•MST 137 days

Dogs