Multiple Myeloma

What is multiple myeloma?

Multiple myeloma is a disease of plasma cells (antibody-producing B lymphocytes). Normally a large variety of plasma cells produce various forms of immunoglobulin, however, in myeloma one particular plasma cell clone begins to replicate in an uncontrolled manner, resulting in one specific type of immunoglobulin being massively overproduced by the large group of identical plasma cell clones. This spike in a specific form of immunoglobulin can be seen as a monoclonal band on serum and urine electrophoresis.

These plasma cell clones accumulate in the bone marrow, crowding out the normal healthy tissue responsible for producing normal blood cells. As a result, the production of normal levels of healthy blood cells is prevented, which results in issues such as anaemia, impaired immune function and low platelets.

In addition to crowding out the bone marrow and interfering with normal blood cell production, the abnormal plasma cells produce a paraprotein. These paraproteins are abnormal immunoglobulin light chains, which can cause damage to the kidneys by forming protein casts in the renal tubules. The abnormal plasma cells also secrete factors which activate osteoclasts to break down bone, resulting in widespread lytic lesions, bone pain and hypercalcaemia.

Types of myeloma

Myeloma is classified based on which type of immunoglobulin is produced:¹

• IgG – approximately 2/3 of cases
• IgA – approximately 1/3 of cases
• IgD and IgM – rare

Clinical features

CRAB is a useful mnemonic to help remember the most common features of myeloma: ¹

• HyperCalcaemia
• Renal failure
• Anaemia
• Bone lesions

Bone pain

• Bone pain is the most common symptom of myeloma (70% of patients experience this symptom).
• Common areas of pain include the spine and ribs.
• Pain typically worsens with activity.
• Persistent pain in a particular area should raise suspicion of a pathological fracture.
• Pain occurs due to increased osteoclast activity within the bones creating lytic lesions.
• Lytic lesions are best visualised on plain X-ray, they appear as punched-out areas (the skull can appear to have a “pepper pot” appearance as a result of this).
• Due to the resorption of bone, hypercalcaemia also develops.

Anaemia and thrombocytopaenia

• Production of red cells and platelets is inhibited by plasma cells invading the bone marrow, resulting in anaemia and thrombocytopaenia.

Anaemia

• Symptoms include shortness of breath and fatigue
• Typically normocytic and normochromic
• Repeated transfusions are often required to maintain an adequate haemoglobin level

Thrombocytopenia

• Often asymptomatic
• If platelets reach critically low levels  (e.g. <10), symptoms such as petechiae, bruising and bleeding develop.
• Patients often require monitoring of platelets and repeated platelet transfusions

Renal failure

• Renal failure occurs primarily as a result of the tubulopathic effects light chains have on renal tubules.
• Hypercalcaemia results in nephrocalcinosis, further contributing to renal failure.
• Amyloidosis can also contribute (however only to a small degree).
• Direct invasion of renal tissue by plasma cells is rare, however, can sometimes occur.
• Recurrent urinary tract infections secondary to reduced immune function can further worsen renal function.

Common symptoms

• Nausea/vomiting/weight loss/lethargy – due to uraemia
• Pruritis/muscle cramping – due to ↑ phosphate
• Shortness of breath/oedema – pulmonary oedema secondary to an inability to excrete fluids

Infection

• Patients have abnormally high levels of immunoglobulin, due to the diseased plasma cells. However despite this, the immunoglobulin is mutated, faulty and ineffective. Production of normal immunoglobulin is also impaired and as a result, patients are significantly immunocompromised.
• The most common infections are respiratory and urinary.
• Patients are also more susceptible to viral infections. These infections need to be recognised and treated quickly, as they can often progress rapidly.
• Some patients with particularly low levels of immunoglobulins can have intravenous immunoglobulin replacement.

Common symptoms

• Fevers
• Rigors
• Productive cough
• Dysuria
• Rash
• Headache

Neurological symptoms

• Confusion, weakness and fatigue – hypercalcaemia
• Headaches and visual disturbances – hyperviscosity (present in some paraproteinaemia)
• Peripheral neuropathy – amyloid deposition
• Limb weakness and loss of bowel/bladder control – spinal cord compression

Investigations

Bloods

Basics

• Full blood count – anaemia/neutropaenia/thrombocytopaenia
• Urea and electrolytes – raised creatinine/hypercalcaemia
• Erythrocyte sedimentation rate (ESR) – persistently raised
• Blood film – rouleaux formation (red cells stacked on top of each other)

Other blood/urine tests

Immunoglobulin measurement:

• Measurement of IgG/IgM/IgA can be useful to identify immune paresis

Protein electrophoresis of blood and urine (Bence Jones protein):

• May demonstrate a paraprotein band
• In rare cases, multiple myeloma can be nonsecretory (not producing paraproteins)

Free light chain levels:

• Useful for assessing response to treatment
• Can identify relapse of disease before the onset of clinical symptoms

Imaging

Skeletal survey

• Series of x-rays of the skull, axial skeleton and proximal long bones
• Looking for the typical lytic lesions of multiple myeloma

MRI

• MRI is more sensitive at detecting lytic lesions, especially in the vertebrae

Bone marrow biopsy

• Bone marrow biopsy is performed to assess the percentage of bone marrow occupied by plasma cells (this helps with diagnostic stratification).
• Immunohistochemistry is used to identify plasma cells.
• Cytogenetics can also be performed to assess for particular mutations and translocations (this can be useful for prognostic purposes, allowing clinicians to tailor treatment to the individual patient’s disease).

Diagnosis

The International Myeloma Working Group developed criteria for the diagnosis of myeloma. ¹

The criteria separate out 3 distinct diagnoses, within the myeloma spectrum of disease:

• Symptomatic myeloma
• Asymptomatic myeloma
• Monoclonal gammopathy of undetermined significance (MGUS)

Symptomatic myeloma

The below criteria must be met for a diagnosis of symptomatic myeloma:

1. Clonal plasma cells >10% on bone marrow biopsy or in a biopsy from other tissues
2. A monoclonal protein (paraprotein) in either serum or urine
3. Evidence of end-organ damage related to the plasma cell disorder

Active treatment is considered for most patients able to tolerate it.

Asymptomatic myeloma

• This type of myeloma is often referred to as “smouldering myeloma”.
• It is differentiated from symptomatic myeloma by the absence of end-organ damage.
• Often these patients do not receive treatment initially.
• Instead, a watch and wait approach is adopted, with regular reviews in a haematology clinic.
• Patients are monitored for signs of early end-organ damage developing (progression).
• If patients begin to develop end-organ damage, treatment is considered.

The below criteria must be met for a diagnosis of asymptomatic (smouldering) myeloma:

1. Serum paraprotein >30 g/L
2. +/- Clonal plasma cells >10% on bone marrow biopsy
3. NO myeloma-related organ or tissue impairment

Monoclonal gammopathy of undetermined significance (MGUS)

• MGUS is part of the myeloma spectrum of disease.
• It involves the presence of an elevated serum paraprotein.
• However at a lesser level than actual myeloma (<30g/L).
• The bone marrow has a smaller number of clonal plasma cells within it.
• In addition, there is no end-organ damage (e.g. renal failure)
• MGUS therefore usually requires no treatment.
• It does, however, need to be monitored, as it can evolve into myeloma (about 1-2% per year).

To confirm the diagnosis of MGUS, all of the below criteria must be met:

1. Serum paraprotein <30 g/L
2. Clonal plasma cells <10% on bone marrow biopsy
3. NO myeloma-related organ or tissue impairment

Management

The overall goal of management in multiple myeloma is to reduce the disease-causing plasma cell population, therefore reducing symptoms and signs of disease.

Initial therapy

For patients < 65

Stem cell transplantation (SCT)

• Patients receive an initial course of induction chemotherapy.
• Most then undergo autologous haemopoietic stem cell transplantation:
  • This involves the extraction of a patient’s stem cells prior to chemotherapy
  • Then re-introduction post-chemotherapy
• A small number of patients receive allogeneic stem cell transplantation: ³
  • This involves the transplantation of another healthy individual’s stem cells into the patient
  • This offers the potential of a cure
  • However, it is associated with a much greater mortality rate (5-10%)

For patients >65 with significant concurrent illness

• Most are unable to tolerate a stem cell transplant.
• With these patients, common treatment regimes involve chemotherapy alone.

Maintenance

• Once patients have received induction chemotherapy/SCT they receive maintenance treatment.
• This involves having chemotherapy regularly (usually at a lower dose than induction chemotherapy).
• Maintenance chemotherapy has been shown to increase progression-free survival.
• The decisions regarding maintenance therapy are tailored to each patient.
• Patients are regularly reviewed and blood levels monitored to assess disease response.
• Treatments may be rotated if one becomes ineffective at controlling the disease.

Relapse

• Although myeloma is often treatable, it is unfortunately very difficult to cure.
• The disease almost always relapses at some point.
• If relapse occurs, the patient may undergo re-treatment with the original agent they previously received.
• Alternatively, they may be treated with another chemotherapy agent.
• Some patients who are relatively healthy may undergo a second autologous stem cell transplant.

Resistance

• As the disease progresses, treatment resistance can develop, rendering previously effective agents ineffective.
• In this circumstance, a change to another agent is tried, to see if adequate disease control can be achieved.
• Sometimes, through the process of switching to a new agent, the patient becomes re-sensitised to the original treatment.

Prognosis

• With high dose chemotherapy followed by autologous stem cell transplantation, the median survival has been estimated to be 4.5 years.
• The overall 5-year survival rate is around 35%.

References

1. International Myeloma Working Group (2003). “Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group”. Br. J. Haematol. 121 (5): 749–57
2. Kyle, R.A., Rajkumar, S.V. (2008). “Multiple myeloma”. Blood. 111 (6): 2962–72.doi:10.1182/blood-2007-10-078022. PMC 2265446. PMID 18332230.
3. Kyle RA, Rajkumar SV (2004). “Multiple myeloma”. N. Engl. J. Med. 351 (18): 1860–73. doi:10.1056/NEJMra041875. PMID 15509819.
4. San Miguel, J.F. et al. (2008). “Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma”. N. Engl. J. Med. 359 (9): 906–917.