Multiple myeloma

Multiple myeloma is a malignant tumour of plasma cells which grows within the bone marrow.

What is the origin and function of plasma cells?

Mature B cells differentiate to form plasma cells which produce antibodies (or immunoglobulins). Antibodies consist of two heavy chains and two light chains. The heavy chain determines the isotype of antibody: IgM, IgA, IgG, IgD or IgE. There are two types of light chains: kappa or lambda.

In healthy individuals plasma cells produce heavy chains and light chains separately and combine them to form antibodies. Different clones of plasma cells produce different types of antibodies, which is important in ensuring immunity. Even in healthy individuals, plasma cells produce more light chains than heavy chains leading to a small amount of excess free light chains which enter the circulation.(1)

Multiple myeloma is the second most common haematological malignancy in the UK.(2)

What is the pathophysiology of myeloma?

In myeloma patients, the malignant clone of plasma cells produces a massive excess of one type of antibody (most commonly IgG) and a corresponding excess of one type of free light chain (usually kappa). These excess antibodies and free light chains (also termed paraprotein) enter the circulation (causing paraproteinaemia) and can be detected as an "M-protein" band on serum electrophoresis. Free light chains may also pass into the urine of myeloma patients and when present in urine are referred to as "Bence Jones protein".

The malignant clone of plasma cells also suppresses normal polyclonal antibody production thus, patients with myeloma have a massive excess of one type of antibody and a suppression of all other types. This phenomenon is termed "immunoparesis" and causes an increased risk of infection in patients.(1)

How does myeloma cause renal disease?

Nephron Image Source: https://commons.wikimedia.org/wiki/File:Kidney_dry.png#filelinks

In healthy individuals, the small amount of circulating free light chains are freely filtered through the glomerulus and enter the proximal convoluted tubule where they are reabsorbed. Thus, no free light chains pass through to the distal nephron or enter the urine.(3)

In patients with myeloma however, there is a massive excess of circulating antibodies and free light chains:

1. These antibodies and/or free light chains can get deposited at the glomerulus, causing damage to the structure of the glomerulus and making it more leaky.(3) This leads to NEPHROTIC SYNDROME.

2. The massive excess of circulating free light chains are freely filtered at the glomerulus and enter the proximal convoluted tubule. Although these light chains are normally reabsorbed at the proximal tubule, in this state of massive excess they are in fact toxic to the proximal tubule leading to ACUTE TUBULAR NECROSIS.(3)

3. Excess free light chains continue to pass through the nephron into the distal Loop of Henle, where they combine with Tamm-Horsfall (THF) protein forming waxy casts.(3) These casts obstruct the tubule leading to tubular atrophy and interstitial inflammation. This is known as CAST NEPHROPATHY.

Renal disease is an important complication of myeloma and approximately 40% of patients with myeloma will have a degree of renal disease at presentation. The most common finding in the kidneys of patients with myeloma is CAST NEPHROPATHY.(1) It is important to diagnose this early as it can rapidly progress to end-stage renal failure if left untreated. Cast nephropathy can be diagnosed on histology from a renal biopsy specimen.

Patients with myeloma can present with Nephrotic syndrome or AKI because of renal involvement. They may also present with CKD although this is much more rare.

What are the key clinical features of myeloma?

Remember the acronym: CRABI

C - Hypercalcaemia. Signalling by malignant plasma cells causes increased osteoclast activation and bone resorption leading to increased serum calcium levels. Patients with hypercalcaemia may present with renal stones, abdominal pain (because of constipation), low mood, polydipsia and polyuria.

R - Renal impairment. Patients with myeloma can commonly present with nephrotic syndrome (proteinuria, hypoalbuminaemia, oedema and hypercholesterolaemia) or AKI. More rarely, myeloma can also be a cause of CKD.

A - Anaemia. Patients with myeloma can have a normocytic, normochromic anaemia (anaemia of chronic disease). This occurs because bone marrow infiltration by malignant plasma cells causes suppression of normal RBC production. Thrombocytopenia and neutropenia can also occur.

B - Lytic bone lesions. These occur because signalling by malignant plasma cells causes increased osteoclast activation leading to bone resorption. Patients with lytic bone lesions present complaining of back pain or bone pain and may be found to have lytic lesions or pathological fractures on X ray.

I - Infections. Patients with myeloma are at an increased risk of recurrent infections because of immunoparesis. Neutropenia as a result of chemotherapy may also contribute to the risk.

What are the components of a myeloma screen?(2)

1. Full blood count - Normocytic anaemia

2. Serum corrected calcium - Hypercalcaemia

3. Plasma viscosity and ESR - raised in 90% of patients with myeloma due to increase in antibodies(1)

4. Serum immunoglobulins - would expect to see an excess of one type of antibody and a suppression of all other types (immunoparesis)

5. Serum free light chains - would expect to see an excess of one type of light chain (usually kappa)

6. Serum protein electrophoresis and Urine protein electrophoresis - Would expect to see a large "M-protein" or "Bence Jones protein" peak. It is important to do both as approximately 20% of myeloma patients will have peak only on urine electrophoresis.(1)

As a general rule, any patient older than 50 years of age with new onset back pain should be screened for myeloma.

How is myeloma diagnosed?

The diagnostic criteria for symptomatic myeloma are as follows:

1. Serum M-protein >30g/L on serum protein electrophoresis

AND/OR

2. Bone marrow plasma cells >10% on bone marrow biopsy

PLUS

3. Evidence of end-organ damage - at least one of the CRABI features

Asymptomatic myeloma is the presence of criteria 1 and/or 2 without evidence of end-organ damage. 10% of patients with asymptomatic myeloma will progress to symptomatic myeloma within 5 years.(2)

How can prognosis be assessed in myeloma?

The International Staging System (ISS) for myeloma classifies the disease into three stages based on 2 markers, serum beta-2 microglobulin and serum albumin. Increasing beta-2 microglobulin and decreasing albumin predict poor prognosis.(1)

What are the complications of myeloma?

Acute Kidney Injury

Cast nephropathy obstruct the renal tubules, resulting in a renal cause of AKI

Recurrent Infections

Immunoparesis - decreased production of normal antibodies means less protection against infection

Hyperviscosity syndrome

Due to increased Ig in plasma. Leads to cognitive impairment, stroke, epistaxis, heart failure

Hypercalcaemia

Bone pain, renal stones, altered mental state, abdominal pain

Pathological fractures

Lytic lesions means the bone structure is weak, making fracture more likely

Metastatic spinal cord compression

Saddle anaesthesia, faecal incontinence, urinary retention, bilateral lower limb weakness

Neutropenic Sepsis

Reduced function of the marrow. Presents with temperature and features of sepsis

Tumour lysis syndrome

Rapid turnover of cells when chemotherapy is delivered. causes an increase in potassium, phosphate, and uric acid.

Death

Commonest reason is infection, followed by renal failure.

How is myeloma treated?

Supportive Treatment

VTE prophylaxis
Analgesia for bone pain (avoid NSAIDs)
Bisphosphonates to reduce fracture risk
Surgical stabilisation of spine
Blood transfusions ± EPO to treat anaemia
Rehydration + monitor fluid balance Emergency dialysis if severe AKI
Broad-spectrum antibiotics if infection present
IV Ig infusions for recurrent infections

Definitive Treatment

Myeloma can be treated using chemotherapy (bortezomib, lenalidomide, and dexamethasone are some of the main drug treatments). patients are enrolled in clinical trials through which they receive chemotherapy.

Autologous stem cell transplantation can also be used.

References

1. Provan D, Dokal I, Vos J, Baglin T. Oxford Handbook of Clinical Haematology. 4th ed. Oxford: Oxford University Press; 2015.

2. National Institute for Health and Care Excellence. Clinical knowledge summaries: Multiple Myeloma. Available from: https://cks.nice.org.uk/multiple-myeloma

3. Dimopoulos MA, Kastritis E, Rosinol L, Blade J, Ludwig H. Pathogenesis and treatment of renal failure in multiple myeloma. Leukaemia. 2008; 22(8): 1485-93.