Myeloma is a cancer of plasma B-cells that accounts for 1% of all cancers. These are the antibody producing cells of the body. The cancer originates in one specific type of plasma cell and so it results in an overproduction of a single type of antibody.
There may be an increased production of an antibody without other features of myeloma or cancer, this is known as monoclonal gammopathy of undetermined significance (MGUS). It is usually an incidental finding, however, patients are followed up routinely for monitoring. It is when there is <3.0g/dL of a particular antibody present. The risk of progression of MGUS → multiple myeloma (MM) is about 1% annually.
MGUS can progress to smouldering myeloma when there are higher levels of antibody present (>3.0g/dL). It is the intermediate stage between MGUS and MM but is still considered premalignant. There is a specific type of smouldering myeloma known as Waldenstrom’s macgroblobulinaemia in which there is excessive production of IgM specifically.
Multiple myeloma is when the myeloma begins to affect multiple regions of the body (mostly bone and kidney).
Pathophysiology
Plasma B-cells are found in bone marrow (hence the name), and become activated for production of a certain antibody. They derive from B-lymphocytes which have differentiated to form a plasma B-cell for a specific antibody. Genetic mutations of B-lymphocytes result in differentiation into mature plasma cells that rapidly and uncontrollably differentiate.
These plasma cells produce one of the 5 main types of immunoglobulins (A, G, M, E, D) but it most frequently is IgG. The type of antibody produced by the cancerous cells is referred to as a monoclonal paraprotein (meaning abnormal proteins deriving from a single cell).
These cancerous cells infiltrate the bone marrow and also form light chain deposits in the renal tubules (these are known as Bence Jones proteins) which causes renal disease later on as well.
⚠️ Risk factors
- Older age
- Male
- Afro-Caribbean ethnicity
- Family history
- Obesity
😷 Presentation
We can remember the features of MM through the mnemonic CRAB HAI:
- Calcium - increased osteoclastic activity causes increased bone resorption which releases calcium, resulting in hypercalcaemia.
- Renal disease - due to:
- High flow of immunoglobulins through the tubules may lead to blockage. This is known as myeloma cast nephropathy.
- Hypercalcaemia causes damage to the kidneys and impairs their ability to function properly.
- Dehydration
- Nephrotoxic medications used to treat MM.
- Anaemia - bone marrow infiltration causes suppression of other cell lineages → anaemia, neutropenia, thrombocytopenia.
- Bone - increased osteoclastic activity and suppression of osteoclastic activity causes increased resorption of the bone → osteolytic lesions. This is due to cytokines released from the plasma cells and stromal cells of the bone. However, this resorption does not happen in a uniform manner and is quite patchy. It mostly occurs in the skull, spine, long bones and ribs. It leads to pathological fractures such as vertebral fractures and low-impact fractures.
- Patients may also develop plasmacytomas which is a mass of cancerous plasma cells which can grow within the bone (replacing the normal bony tissue) or soft tissue within the body.
- Hyperviscosity - plasma viscosity increases when there are more proteins in the blood. A raise of immunoglobulins as well as fibrinogen (due to inflammation) leads to hyperviscosity of the blood. It can lead to issues such as:
- Easy bruising
- Easy bleeding
- Visual disturbances
- Amyloidosis - amyloid deposits in multiple organs and tissues can lead to a wide array of sequelae such as neuropathies, cardiac failure etc.
- Infection - secondary to the to leukopenia.
🔍 Investigations
This is when considering myeloma. Consideration should be in place when anyone over 60 with constant bone pain and back pain or unexplained fractures.
- FBC - low WCC.
- Calcium - raised.
- ESR - raised.
- Plasma viscosity - raised.
- Peripheral smear - may show rouleaux formation (red blood cells grouped like a stack of coins).
If any of the above are positive we should move onto the following investigations:
The BLIP investigations should be done when suspecting myeloma.
- B - Bence-Jones proteins with urine electrophoresis.
- L - Serum-free Light-chain assay
- I - Serum Immunoglobulins
- P - Serum Protein electrophoresis
Imaging should be done to assess for bone lesions. Only one investigation is needed (selecting what is most suitable and tolerable by the patient), with the following preference:
- Whole body MRI
- Whole body CT
- Skeletal survey
- Signs that we may see include osteolytic lesions, punched out lesions, raindrop skull.
🥇 The gold-standard diagnostic test, however, is a bone-marrow biopsy. This is necessary to confirm a diagnosis.
Once a diagnosis is established, some prognostic indicators can be investigated:
- CRP - the higher the level the worse the prognosis.
- LDH - the higher the level the worse the prognosis.
- Beta-2 microglobulin - very high or very low levels indicate a poorer prognosis.
- FISH and cytogenetic analysis - not only give an indication of prognosis, but also help inform treatment.
- Serum creatinine
- Albumin - low albumin is associated with poorer prognosis.
💯 Criteria
The International Myeloma Working Group (IMWG) criteria for MM can be summarised as SLiM CRAB:
- Myeloma defining events (MDE)
- Sixty percent or greater clonal plasma cells in bone marrow.
- Ratio of abnormal light chains/normal light chains ≥100.
- MRI evidence of >1 focal lesion that is >5mm in size.
- CRAB
- Calcium: Serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL).
- Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177mol/L (>2mg/dL).
- Anemia: hemoglobin value of >20g/L below the lowest limit of normal, or a hemoglobin value <100g/L.
- Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
Clonal bone marrow plasma cells >10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features and myeloma-defining events:
Diagnostic criteria for MM involves the following in patients with signs and symptoms of MM:
→ 1 major and 1 minor criteria
OR
→ 3 minor criteria
Major criteria | Minor criteria |
Plasmacytoma | 10-30% plasma cells in bone marrow |
30% plasma cells in bone marrow sample | Minor elevations of M protein in blood/urine |
Elevated levels of M protein (myeloma protein) in blood/urine- this is an antibody that is found in unusually large amounts in the blood or urine of people with MM. | Osteolytic lesions |
Low levels of antibodies in the blood - this does not include the antibodies produced the cancer cells |
🧰 Management
MM often takes a relapsing-remitting course and so the aim of treatment is to improve quantity and quality of life while controlling the disease. An MDT approach to management is necessary.
Chemotherapy is the first-line treatment. The treatment usually involves an alkylating agent coupled with dexamethasone :
- Vincristine
- Doxorubicin
- Dexamethasone
VTE prophylaxis with aspirin or LMWH should be used when on certain chemotherapeutic regimes.
Other agents that may also be used are:
- Bortezomid - recommended in combination with the following 2 agents. It is a proteasome-inhibitor marketed for use with MM.
- Thalidomide
The above 2 agents in combination with dexamethasone are also recommended when managing acute renal disease caused by myeloma.
This is an option for patients with minimal comorbidities. They will require induction with chemotherapeutic and non-chemotherapeutic agents.
- Melphalan is a chemotherapeutic drug used prior to stem cell or bone marrow transplantation. It will be added to the regime prior to the transplant.
There is the option for autologous transplantation which has a low mortality rate, but low remission rate (40%). Allogeneic transplants have higher mortalIty rate but also a higher remission rate.
- Bisphosphonates suppress osteoclast activity and can improve MM bone disease.
- Radiotherapy to bone lesions can improve the pain.
- Orthopaedic surgery can treat fractures but can also aid stabilisation of the bones with prophylactic intramedullary rods, for example.
- Cement augmentation involves cement injection into vertebral fractures to aid spinal stability.
🚨 Complications
- Infection
- Renal failure
- Anaemia
- Peripheral neuropathy
- Spinal cord compression
- Hyperviscosity and thrombosis