Plasma cells are differentiated B lymphocytes capable of producing immunoglobulins. Neoplastic transformation results in monoclonal plasmacytic tumours, which can present in a variety of forms; in the dog, they most commonly include extramedullary plasmacytomas (EMP), solitary osseous plasmacytomas (SOP) and multiple myeloma (MM).
Plasma cell neoplasms can often be easily diagnosed via cytology due to their characteristic cytological appearance (Figure 1); plasma cells typically have a deep basophilic cytoplasm, an eccentric nucleus and a perinuclear clear zone that houses the Golgi apparatus. Histopathology may be required to diagnose plasma cell tumours in some circumstances, possibly with immunohistochemistry (IHC) if the plasma cell tumour cannot be differentiated from other round cell neoplasms. Immunohistochemistry for multiple myeloma oncogene-1 (MUM-1) is the most consistent specific marker for plasma cells. However, being B-cells, they can also label positively for CD79a and CD20, with variable vimentin labelling. Although less commonly used, PCR for antigen receptor rearrangement (PARR) can also be performed to confirm B-cell clonality if needed.
This article will focus on the clinical presentation, diagnosis and management of canine MM, with a discussion of canine EMP and SOP available in the first part of this series.
Aetiology and pathology
Canine MM is rare, accounting for less than 10 percent of all haematopoietic neoplasms in the dog. It typically occurs in older dogs, with Labradors, Golden Retrievers and German Shepherds possibly over-represented.
The aetiology is largely unknown. Factors such as environmental carcinogen exposure, chronic immune stimulation, viral infection and genetic mutations in genes such as c-kit have been proposed, but these are often based on case reports or small case series, so the aetiology remains poorly understood.
MM arises in the bone marrow, often in multiple sites. Typically, the plasma cells overproduce immunoglobulins with immunoglobulin A (IgA) most commonly secreted in canine MM (Fernandez and Chon, 2018; Thamm et al., 2014). Immunoglobulin secretion often comprises the entire immunoglobulin, although in rare cases, only the immunoglobulin light chain (also known as Bence Jones protein) may be secreted – this is termed light-chain myeloma (Harris et al., 2021). The immunoglobulin product secreted by the neoplastic plasma cells is known as the “M-component”.
The pathologies associated with MM are a direct result of high levels of circulating M-component, tissue infiltration with neoplastic cells or both. They comprise lytic bone lesions, bleeding diathesis, hyperviscosity syndrome (HVS), renal disease, ionised hypercalcaemia, immunodeficiencies, cytopenias and cardiac disease. The pathophysiology and clinical manifestations of each of these are summarised in Table 1.
|Lytic bone lesions||25 to 65 percent||Osteolytic lesions develop due to the expansion of neoplastic plasma cells||Multiple lytic lesions in bones associated with haematopoiesis (most commonly vertebrae, ribs, pelvis, skull and long bones (metaphyseal)) (Figure 2) can cause pain and lameness|
|Bleeding diathesis||10 to 50 percent||M-component inhibits platelet aggregation, tissue factor and proteins S and C; it causes abnormal fibrin polymerisation and reduces available calcium. Thrombocytopenia may also contribute to bleeding||10 to 30 percent of dogs have clinical signs of bleeding and 50 percent of dogs have prolonged PT and/or APTT|
|Hyperviscosity syndrome (HVS)||20 to 40 percent||Increased serum viscosity causes sludging of blood, reduced oxygen and nutrient delivery and coagulation abnormalities||Bleeding diathesis, neurological signs (depression, seizure and coma), cardiac disease due to increased workload and ophthalmological signs (retinal haemorrhage (Figure 3) and retinal detachment)|
|Renal disease||25 to 50 percent||Multifactorial, including Bence Jones proteinuria (proteins precipitate causing renal tubular injury), tumour infiltration into kidney, hypercalcaemia, amyloidosis, reduced renal perfusion secondary to HVS and pyelonephritis secondary to immunodeficiency||Azotaemia and pyelonephritis|
|Ionised hypercalcaemia||15 to 50 percent||Tumour production of osteoclast activating factor (OAF), tumour necrosis factor alpha (TNF-α) and interleukin 1 (IL-1) and 6 (IL-6)||Ionised hypercalcaemia, possible secondary acute kidney injury and polyuria/polydipsia|
|Immunodeficiencies||Marked reduction in “normal” immunoglobulin production. Leukopenias may also develop secondary to myelophthisis||Potentially severe and concurrent infections; can lead to death of patient|
|Cytopenias||30 to 80 percent||Anaemia, often non-regenerative and multifactorial (myelophthisis, bleeding, chronic disease/inflammation and erythrophagia (rare))||Non-regenerative anaemia seen in 50 to 65 percent of patients, leukopenia in 80 percent and thrombocytopenia in 30 percent|
|Cardiac disease||Multifactorial, including hyperviscosity (results in excessive cardiac workload, myocardial hypoxia), myocardial infiltration with amyloid and anaemia||Heart murmur and hypertrophic cardiomyopathy|
Diagnosis and investigations
The most common clinical signs in dogs with MM are non-specific and include lethargy, weakness, hyporexia and weight loss. However, more specific clinical signs linked to specific underlying pathologies may be present. These include:
- Lameness due to painful osteolytic lesions
- Ocular/fundoscopic abnormalities (retinal haemorrhage/detachment)
- Polyuria and polydipsia due to ionised hypercalcaemia or renal disease
- Bleeding in the form of epistaxis or gingival bleeding due to HVS or thrombocytopenia
- Neurological signs such as depression, seizure, myelopathy due to HVS, bleeding or spinal cord compression secondary to vertebral lesions
A definitive diagnosis of MM comes from demonstrating two or more of osteolytic bone lesions (present in up to 65 percent of cases), M-component (present in 99 percent of cases) and bone marrow plasmacytosis (present in 100 percent of cases). In the absence of osteolytic lesions, a diagnosis can still be achieved by demonstrating plasma cell clonality via PARR or documenting a progressive increase in M-component.
Based on these criteria, a typical diagnostic approach would initially include haematology, biochemistry, urinalysis and a coagulation profile. Hyperglobulinaemia is often documented, but this is not sufficient to prove detection of M-component, as hyperglobulinaemia can also be caused by infectious/inflammatory processes. A monoclonal, as opposed to polyclonal, gammopathy needs to be confirmed via serum protein electrophoresis (SPE) (Figure 4).
An alternative to measuring circulating M-component would be documenting the urinary excretion of light chains (Bence Jones proteins), as these are over-produced in MM. It is important to note that these cannot be detected on standard urinary dipsticks, and urine electrophoresis for Bence Jones proteins must be specifically requested.
Investigation for osteolytic lesions is best achieved with computed tomography (CT), although survey radiographs are an acceptable alternative. Confirmation of bone marrow plasmacytosis (currently defined as over 20 percent plasma cells) is obtained via bone marrow aspirates and core biopsy (Vail, 2019). Ideally, both aspirates and biopsy should be performed, as aspirates alone can occasionally be negative due to uneven clustering of neoplastic plasma cells in the bone marrow.
As only two criteria need to be met to diagnose MM, investigations can be selective in cases with financial constraints. As it is comforting to have some cytological/histological evidence of plasma cell neoplasia, a more restricted approach following a minimum database could include bone marrow aspirates/biopsy alongside SPE or urine electrophoresis for Bence Jones proteins without potentially costly diagnostic imaging for osteolytic lesions.
Treatment and prognosis
Overall, MM is a rewarding disease to treat, with most dogs tolerating treatment well and demonstrating a strong and durable initial response. However, MM is rarely cured, and relapse is expected at some point in most patients.
First-line treatment consists of oral melphalan and prednisolone. Two dosing schedules have been evaluated with similar outcomes (Fernandez and Chon, 2018). The “daily-dosing” protocol uses melphalan at 0.1mg/kg once daily for 10 days, followed by 0.05mg/kg once daily, ongoing. The “pulse-dose” protocol doses melphalan at 7mg/m2 once daily for five days, then repeats every three weeks, ongoing. For both, prednisolone is often administered at 0.5mg/kg once daily for 10 days, then 0.5mg/kg every other day, ongoing, for 60 days total.
Chemotherapy with melphalan is generally well tolerated, with myelosuppression (delayed thrombocytopenia) the most common adverse effect. Haematology should be monitored at two weeks and four weeks, and then every four weeks thereafter while on treatment. Around 80 to 95 percent of dogs will demonstrate a response to treatment, with median survival times between 1.5 and 2.5 years (Fernandez and Chon, 2018; Matus et al., 1986; Moore et al., 2021). Improvements in systemic signs are often observed within the first three to four weeks, with clinicopathological improvements (serum globulins, M-component and haematological changes) observed within three to six weeks. Radiological improvement of osteolytic lesions can take months and may only be partial.
At the time of relapse, first-line rescue chemotherapy protocols typically include single-agent alkylating agents, such as cyclophosphamide, lomustine or chlorambucil. Protocols including vincristine and doxorubicin have also been reported, but there is very limited literature assessing rescue treatment of MM. Rabacfosadine has also been assessed in a small group of naïve dogs with MM, with a reported 80 percent response rate and progression-free survival of six months, so could also be considered as a rescue therapy (Thamm et al., 2014).
Management of myeloma-related complications
Although treatment of the underlying MM will eventually resolve any myeloma-related complications, some cases will require specific management of these too. These may include severe ionised hypercalcaemia, which can be managed with interventions such as fluid therapy, corticosteroids, furosemide and bisphosphonates.
Painful osteolytic lesions may require specific treatments beyond “standard” multimodal analgesia, including bisphosphonates. Drugs such as pamidronate or zoledronate provide effective relief from bone pain and can reduce osteolysis. Rarely, surgical intervention may be required for pathological fractures, and extreme cases of HVS can be managed with plasmapheresis.
Although treatment of the underlying multiple myeloma will eventually resolve any myeloma-related complications, some cases will require specific management of these too
Monitoring treatment response is important and guides ongoing case management. Monitoring can consist of a combination of investigations, such as haematology, biochemistry (specifically globulin measurement), SPE, repeat imaging or repeat bone marrow evaluation. As bone lesions may not fully resolve and repeat bone marrow aspirate/biopsy is relatively invasive, monitoring based on blood tests is appropriate in most cases, alongside close monitoring of clinical signs. It is important to note, however, that assessment of serum globulins alone is crude and not predictive of true treatment response.
Longer-term monitoring of chemotherapy tolerance and assessment of treatment response often consists of repeat haematology and biochemistry every four to six weeks, with repeat SPE every three months
Repeat SPE, including densitometric quantification of M-component, is the most accurate method of assessing treatment response and predicts prognosis (Moore et al., 2021). Therefore, longer-term monitoring of chemotherapy tolerance and assessment of treatment response often consists of repeat haematology and biochemistry every four to six weeks, with repeat SPE every three months. Repeat SPE, imaging and/or bone marrow sampling can be performed to confirm relapse if suspected.