Plasma Cell Leukaemia

Plasma cell leukaemia is the rarest and most aggressive form of plasma cell cancers, where abnormal plasma cells circulate through the bloodstream instead of staying confined to bone marrow as in typical multiple myeloma.

Table of contents

• What is plasma cell leukaemia?
• Types of plasma cell leukaemia
• Signs and symptoms
• What causes plasma cell leukaemia?
• How is it diagnosed?
• Treatment options
• Outlook and prognosis

What is plasma cell leukaemia?

Plasma cell leukaemia is an aggressive type of multiple myeloma, which is a cancer of plasma cells. Plasma cells are a type of white blood cell that normally live in the bone marrow and produce antibodies to fight infections. In plasma cell leukaemia, these abnormal cells circulate in the bloodstream, which differs from typical multiple myeloma where the abnormal plasma cells stay in the bone marrow.^[1]

This condition is extremely rare. It represents the rarest form of multiple myeloma, making up only about 2% to 3% of all plasma cell cancers.^[1] Primary plasma cell leukaemia affects approximately 1 person out of every 1 million people in the general population.^[1] The condition is most common in men between the ages of 55 and 65, and it occurs more frequently among people who are Black.^[1]

Plasma cell leukaemia is clinically and genetically distinct from multiple myeloma. The disease is characterized by its aggressive nature and poor prognosis.^[2]

Types of plasma cell leukaemia

There are two distinct types of plasma cell leukaemia, classified based on whether the disease appears on its own or develops from an existing condition.^[1]

Primary plasma cell leukaemia occurs without a history of multiple myeloma. This means that abnormal cells are already circulating in the bloodstream at the time of diagnosis. Primary plasma cell leukaemia makes up about 60% of all plasma cell leukaemia cases.^[1]

Secondary plasma cell leukaemia develops in patients who already have multiple myeloma, representing a worsening of their existing condition. According to research, 0.5% to 4% of multiple myeloma cases eventually transform into secondary plasma cell leukaemia. Secondary plasma cell leukaemia affects up to 4 in 100 people with multiple myeloma and makes up about 40% of all plasma cell leukaemia cases.^[1] This form typically occurs at a late and advanced stage of multiple myeloma, with patients experiencing the leukemic transformation after a median time of approximately 21 months from their original diagnosis.^[3]

In recent years, there has been an increase in the incidence of secondary plasma cell leukaemia, likely related to more effective therapies that contribute to improved survival but also allow for clonal selection over time.^[9]

Signs and symptoms

Plasma cell leukaemia symptoms vary for each person and tend to be more severe than those seen in typical multiple myeloma. The clinical presentation indicates a far more aggressive disease, with features being a combination of those found in multiple myeloma and acute leukaemia.^[3]

Common symptoms include:^[1]

• Anaemia, a condition where the blood has fewer red blood cells than normal
• Bleeding easily
• Bone pain
• Bone fractures
• Fatigue or extreme tiredness
• Hypercalcaemia, which means high calcium levels in the blood
• Infections that linger or come back frequently
• Kidney damage

Patients with plasma cell leukaemia often exhibit additional complications compared to multiple myeloma patients. These include relatively high frequencies of splenomegaly (enlarged spleen), lymphadenopathy (swollen lymph nodes), hepatomegaly (enlarged liver), kidney failure, and bone marrow failure, which can cause thrombocytopenia (low platelet count), anaemia, and rarely, leucopenia (low white blood cell count). Some patients may also develop central nervous system defects and peripheral neuropathies due to the invasion of these tissues by plasma cells.^[3]

Compared to multiple myeloma patients, those with plasma cell leukaemia also show high rates of developing a hypercalcaemic crisis, which is a potentially life-threatening episode of high calcium levels in the blood, as well as higher levels of certain blood markers and lower rates of bone tumours but higher rates of soft tissue plasma cell tumours called plasmacytomas.^[3]

What causes plasma cell leukaemia?

Plasma cell leukaemia is caused by acquired genetic changes that occur during plasma cell development. However, researchers are not sure why these changes take place to begin with.^[1]

The disease results from the development of an excessively high number of genetic abnormalities in plasma cells or their precursor cells. This genetic instability is due to a variety of acquired abnormalities including gene mutations, deletions and duplications of parts of chromosomes or entire chromosomes, and changes in gene expression. These genetic abnormalities affect important cellular processes including cell cycle regulation, cell signalling, metabolism, and cell adherence.^[3]

Many of the genetic aberrations observed in newly diagnosed plasma cell leukaemia are typically found in advanced multiple myeloma. These abnormalities lead to increased proliferation, enhanced inhibition of cell death, escape from immune surveillance, and independence from the bone marrow microenvironment.^[11]

How is it diagnosed?

To diagnose plasma cell leukaemia, a healthcare provider needs to measure the number of abnormal plasma cells in the blood. The diagnosis is based on the presence of circulating plasma cells in the peripheral blood.^[1]

According to updated consensus by the International Myeloma Working Group, plasma cell leukaemia should be defined by the presence of 5% or more circulating plasma cells in peripheral blood in patients otherwise diagnosed with symptomatic multiple myeloma.^[5] This represents a change from earlier criteria that required both more than 20% circulating plasma cells and an absolute count greater than 2 × 10⁹ per litre plasma cells in peripheral blood.^[2] The reason for this change is that patients with lower levels of circulating plasma cells (5% or more) have been found to have the same adverse prognosis as those meeting the older, more restrictive criteria.^[2]

The diagnostic process includes:^[1]

• A blood test to measure the percentage of abnormal plasma cells
• A bone marrow biopsy, which involves taking a small sample of bone marrow to measure the number of abnormal plasma cells
• Imaging tests such as CT scans (computed tomography scan) or MRI (magnetic resonance imaging) to check for bone damage that can result from these cells

Establishing the presence of a malignant clonal population is important, as reactive plasmacytosis (increased plasma cells) can occur due to a variety of infections, cancers, or inflammatory conditions. Multiparametric flow cytometry can be used to characterize plasma cell clonality.^[9]

Treatment options

Healthcare providers treat plasma cell leukaemia on a case-by-case basis. They might recommend one type of treatment or a combination. Plasma cell leukaemia treatments include the same ones that are used in multiple myeloma.^[1]

Treatment approaches typically include:^[1]

Chemotherapy uses drugs to kill cancer cells. This may include chemotherapy drugs like doxorubicin, cisplatin, and cyclophosphamide.^[1]

Targeted therapy includes proteasome inhibitors like bortezomib, carfilzomib, and ixazomib, as well as immunomodulators like lenalidomide and pomalidomide.^[1] These drugs work by targeting specific features of cancer cells.

Immunotherapy helps the body’s immune system fight cancer. This treatment includes monoclonal antibodies like daratumumab, bispecific antibodies like teclistamab, and chimeric antigen receptor (CAR) T-cell therapy.^[1]

Autologous stem cell transplant may be considered for eligible patients. Providers usually do this type of stem cell transplant after chemotherapy if the patient qualifies.^[1] This involves collecting the patient’s own stem cells, administering high-dose chemotherapy, and then returning the stem cells to help rebuild the bone marrow.^[6]

For patients with secondary plasma cell leukaemia who have already had several treatments for multiple myeloma, their disease may have become resistant or refractory to the treatments. For these patients, more intensive treatments using combinations of drugs may be considered.^[4]

Maintenance therapy following initial treatment has shown a positive effect on overall survival.^[8] Due to limited therapeutic studies specifically evaluating plasma cell leukaemia, patients should be considered for clinical trials whenever possible.^[9]

Outlook and prognosis

Treatment can manage symptoms and prolong life, but it usually does not cure the cancer.^[1] Plasma cell leukaemia is usually associated with a poor prognosis and a survival expectancy that is shorter than that of patients with typical multiple myeloma.^[4]

The outcomes of patients with plasma cell leukaemia have only modestly improved with novel therapies. Survival has improved after implementation of high-dose chemotherapy with stem-cell support, bortezomib, and lenalidomide in the treatment, yet the prognosis remains poor.^[2] New treatments can prolong the lives of people with plasma cell leukaemia, but there is still much work to do.^[1]

With modern therapies, median overall survival is approximately 1 year for older patients and 3 years for those who receive transplants.^[8] Secondary plasma cell leukaemia arising from multiple myeloma in particular is associated with a dismal outlook.^[9]

Newer drug combinations, immunotherapy, and cellular therapy are under investigation, and these approaches hopefully will demonstrate efficacy to improve the prognosis of plasma cell leukaemia.^[9]