Synonyms: multiple myeloma, plasma cell neoplasm, myelomatosis

Pathogenesis

In myeloma there is malignant proliferation of plasma cells. This produces diffuse bone marrow infiltration causing bone destruction and bone marrow failure. There is also overproduction of a monoclonal antibody (immunoglobulin or 'paraprotein') by the malignant plasma cells, detectable in serum and/or urine. It is also characterised by osteolytic bone lesions, renal disease and immunodeficiency.

Myelomas are subclassified by the type of antibody they produce. Immunoglobulin G (IgG) myeloma is the most common type.

Aetiology

• This is uncertain.
• The vast majority of cases of myeloma occur as new cases with no family history, although some family clusters have been observed.¹
• The onset of myeloma may occasionally be preceded by a finding of monoclonal gammopathy of undetermined significance (MGUS). MGUS is present in approximately 2% of individuals aged over 50 years and 3% aged over 70 years. It represents a 1% annual risk of progression to myeloma.²
• Excess bodyweight may be a risk factor for myeloma.³
• Recent studies have suggested that workers in some petroleum-related industries and those with more than a 20-year exposure to hair dyes have an increased risk of myeloma.⁴

Epidemiology

• Annual incidence in the UK is approximately 60-70 per million.²
• Median age at presentation is 60-61 years.⁵
• More common in Afro-Caribbeans than Caucasians.
• More common in men.¹

Presentation

Presenting features include:²

• Bone pain, particularly backache.
• Pathological fractures.
• Spinal cord/nerve root compression.
• Lethargy (due to anaemia).
• Anorexia.
• Dehydration (due to proximal tubule dysfunction from light chain precipitation).
• Recurrent bacterial infection.
• Bleeding and/or bruising.
• Features suggesting amyloidosis (e.g. cardiac failure, nephrotic syndrome).
• Signs and symptoms of hypercalcaemia (e.g. thirst, constipation, nausea, confusion).
• Dizziness, confusion, epistaxis, cerebrovascular event (CVE) - due to hyperviscosity.

Blood testing may be carried out for other reasons and show:

• Impaired renal function.
• Anaemia: normochromic, normocytic.
• Leukopenia.
• Thrombocytopenia.
• Hypercalcaemia.
• Persistently raised plasma viscosity or erythrocyte sedimentation rate (ESR)

Screening tests for myeloma

If symptoms or the results of routine investigations suggest that a patient may have myeloma, then the following investigations should be performed:²

• FBC.
• ESR or plasma viscosity.
• Urea, electrolytes and creatinine.
• Calcium.
• Albumin.
• Uric acid.
• Serum protein electrophoresis: shows the type of paraprotein.
• Urine protein electrophoresis: looks for the presence of Bence Jones' protein
• Quantitative immunoglobulin levels (e.g. IgG, IgA, IgM levels): non-myelomatous immunoglobulin can be suppressed. The level of the myeloma paraprotein can also be used to assess response to treatment.
• Plain X-ray of symptomatic areas

Diagnostic tests for myeloma

Further tests are then needed to confirm the diagnosis:

• Bone marrow aspirate +/- trephine biopsy.
• Immunofixation of serum and urine to confirm and show the subtype of the paraprotein.
• A skeletal survey.

The diagnosis of myeloma can be confirmed by the presence of:

• a monoclonal protein in the serum or urine and/or
• lytic lesions on X-ray with
• an increased number of plasma cells in the bone marrow

Diagnostic criteria

• Because there is a high prevalence of monoclonal gammopathy of undetermined significance (MGUS) and because serum protein electrophoresis is frequently carried out, most people who have serum monoclonal proteins detected will not have myeloma but will have MGUS.
• Diagnostic criteria have been set to distinguish MGUS from myeloma.
• The criteria also separate asymptomatic and symptomatic myeloma.
• Asymptomatic myeloma is basically myeloma with no signs of organ or tissue impairment. It was previously referred to as indolent or smouldering myeloma.
• Patients with MGUS and asymptomatic myeloma require monitoring but no immediate treatment.
• Patients with symptomatic myeloma need immediate treatment because there is organ impairment.

Myeloma-related organ or tissue impairment

The International Myeloma Working Group established criteria to distinguish asymptomatic multiple myeloma (no immediate need for treatment) from active disease, when treatment is essential.

The main indicators for treatment are signs of end-organ damage including:

• Hypercalcaemia: corrected serum calcium >0.25 mmol/L above the upper limit of normal or >2.75 mmol/L.
• Renal impairment attributable to myeloma.
• Anaemia: Hb 2 g/dL below the lower limit of normal or Hb <10 g/dL.
• Lytic lesions or osteoporosis with compression fractures.
• Symptomatic hyperviscosity.
• Amyloidosis.
• Recurrent bacterial infections (more than 2 episodes in 12 months).

Other investigations

• CT scanning: can be used to detect small lytic lesions that may not be visible on plain X-ray. Consider if bony symptoms are present but plain X-rays are negative. It can show soft-tissue disease and can be used to guide biopsy and plan radiotherapy or surgery.
• MRI scanning: can be used to assess soft-tissue disease. It is the investigation of choice if spinal cord compression is suspected. It can also show pattern of bone marrow involvement.
• Chromosome analysis: this can be carried out using karyotyping and fluorescence in situ hybridisation (FISH). This can detect chromosome abnormalities that have been associated with a poorer prognosis. However, how much this information can be used to direct patient management is unclear.
• β₂-microglobulin levels: used for staging and to predict prognosis (see below).
• Serum viscosity: should be assessed if there is epistaxis, neurological symptoms or very high paraprotein levels.

Staging

The Durie-Salmon system of staging was used until 2005 as a prognostic indicator for myeloma. A new International Staging System is now in use. It is based on serum albumin and β₂-microglobulin levels as these have been shown to correlate with survival.

Differential diagnosis

A monoclonal protein can also be present in:

• Monoclonal gammopathy of undetermined significance (MGUS): a paraprotein is found in the blood but there are no other symptoms or signs of myeloma.
• Amyloid light-chain (AL) amyloidosis.
• Solitary plasmacytoma.
• B-cell non-Hodgkin's lymphoma (including Waldenström's macroglobulinaemia).
• Chronic lymphocytic leukaemia.

Management

Myeloma is currently seen as an incurable disease that is chronic, relapsing and remitting. Treatment is aimed at controlling the disease, prolonging survival and maximising quality of life.² Emotional and psychological support for patients, carers and relatives should not be forgotten.

High-dose therapy (HDT) with autologous stem cell transplantation (ASCT)

Current guidelines suggest that this should be considered to be the primary treatment strategy in newly diagnosed patients <65 years old and patients aged over 65 years whose general health is good. However, a recent systematic review and meta-analysis compared HDT with standard dose therapy. HDT showed benefit in progression-free survival but not overall survival and there was significant treatment-related mortality.⁶ If HDT is planned, there are the following phases to treatment:

• Initial chemotherapy with vincristine, doxorubicin (formerly 'adriamycin') and dexamethasone (VAD) or vincristine, doxorubicin (formerly 'adriamycin'), methotrexate and prednisolone (VAMP) or VAMP + cyclophosphamide (C-VAMP).
• Autologous stem cell transplantation.

Allogenic stem cell transplantation

This can also be considered in patients up to the age of 50. Despite being associated with greater risks (graft-vs-host disease), it may increase the possibility of complete remission (the patient is not at risk of being reinfused with myeloma cells). All patients considered must have the full risks explained to them in advance.

Conventional therapy

This is usually offered to those who are thought not able to tolerate high-dose therapy. These are usually older patients who may have other medical problems. In such cases, either melphalan or cyclophosphamide ± prednisolone should be used. Patients in whom autologous stem cell transplant is planned are not usually treated with mephalan because it can cause stem cell injury.⁴

Novel agents

There are a wealth of data which suggest novel drugs in combination with dexamethasone, with or without conventional treatments, are better for induction treatment before stem cell transplantation than the use of conventional treatments alone.⁵ They have also improved duration of response, progression-free and overall survival for patients with newly diagnosed, relapsed and refractory multiple myeloma.

Continuing clinical trials are assessing thalidomide, bortezomib, and lenalidomide for maintenance treatment after autologous stem cell transplantation. The National Institute for Health and Clinical Excellence (NICE) has arranged a cost-sharing deal for lenalidomide with the manufacturer in the UK.⁷

Pain control

• Analgesics: a variety of drugs may be used for pain relief including ranging from simple analgesics such as paracetamol to potent opioids. Use the analgesic ladder. Non-steroidal anti-inflammatory drugs (NSAIDS) should be avoided where possible (renal effects and gastric irritation).
• Adjuvant drugs: amitriptyline, carbamazepine or gabapentin can help in neuropathic pain.
• Corticosteroids: these can help to relieve bone pain in late stages.
• Alternative techniques: for example, relaxation, aromatherapy, and hypnotherapy may be helpful.
• Radiotherapy: this can be used in bone and soft-tissue disease.
• Chemotherapy: if the underlying disease is treated, this should help pain as treatment response occurs.
• Surgery: for example, stabilisation of fractures, treatment of vertebral collapse.

Bisphosphonates

These inhibit bone resorption, but might also inhibit proliferation of multiple myeloma cells:

• These can help to prevent bone pain, hypercalcaemia and pathological fractures.
• Start in all patients who are starting chemotherapy.
• Oral clodronate, intravenous (IV) pamidronate or IV zoledronic acid can be used.
• Continue treatment for at least 2 years (and perhaps indefinitely).
• Monitor renal function.
• There is not enough evidence to suggest should be started in asymptomatic disease.
• Side-effects include renal impairment and osteonecrosis of the jaw.⁸

Complications

These include:

• Hypercalcaemia
• Renal impairment
• Anaemia
• Infection
• Spinal cord compression
• Pathological fractures
• Hyperviscosity
• Peripheral neuropathy
• Bleeding
• AL amyloidosis

Management of complications

• Hypercalcaemia:
  • 30% of people with myeloma develop hypercalcaemia.²
  • Treat mild hypercalcaemia with oral rehydration.
  • Moderate-severe hypercalcaemia may need intravenous fluids ± furosemide
  • Start a bisphosphonate (if not already prescribed).
  • IV corticosteroids and calcitonin may be needed in refractory cases.
• Renal impairment:
  • Can be caused by:
    • Light chain damage to the proximal tubules.
    • Dehydration.
    • Hypercalcaemia.
    • Hyperuricaemia.
    • Infection.
    • Nephrotoxic drugs.
    • Amyloid.
  • Try to avoid by ensuring adequate hydration (3 litres/day) and avoidance of nephrotoxics.
  • Treat any underlying cause.
  • Plasma exchange or dialysis may be needed.
• Anaemia:
  • There is a risk of exacerbating hyperviscosity when giving red cell transfusions in people with high paraprotein levels.
  • Consider recombinant human erythropoietin therapy (rhEPO) if there is symptomatic anaemia.
• Infections:
  • Treat any febrile patient with broad-spectrum antibiotics, avoiding aminoglycosides if possible.
  • Consider prophylactic trimethoprim-sulfamethoxazole for the first 2 months when starting chemotherapy.
  • Consider influenza, Streptococcus pneumoniae and Haemophilus influenzae vaccination.
  • Prophylactic immunoglobulins may be needed in recurrent infections.
• Cord compression:
  • A medical emergency.
  • Affects 10-20% at some point.⁴
  • Investigate using MRI.
  • Commence dexamethasone.
  • Local radiotherapy is the treatment of choice.
• Hyperviscosity:
  • Treat with plasma exchange.
  • Venesection may be needed if plasma exchange is not available.
  • Start chemotherapy.

Monitoring

• Symptomatic myeloma: response to therapy should be regularly monitored. Review should include serum and urine paraprotein levels using electrophoresis and assessment for new myeloma-related organ or tissue damage. Recognised criteria need to be met before complete response to treatment can be identified. These can be found in the first reference below. Essentially, complete remission occurs when there is no detectable paraprotein by immunofixation. (People can have no paraprotein detectable on electrophoresis but still have paraprotein detectable on immunofixation.)
• Monoclonal gammopathy of undetermined significance (MGUS): follow up every 6-12 months depending on the level of paraprotein. Clinical assessment and serum paraprotein analysis should be carried out.
• Asymptomatic myeloma: follow up more frequently, usually every 3 months. Clinical assessment and analysis of serum and urinary paraprotein should be routine. Bone marrow assessment and skeletal X-rays should be carried out if new symptoms or signs develop.

Prognosis

• With the onset of new potential therapies, the prognosis for myeloma is improving. The 5-year survival rate has increased from 25% in 1975 to 34% in 2003.⁸
• The risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to either myeloma or other B-cell malignancy is about 1% per year.⁹
• The median time of progression from asymptomatic to symptomatic myeloma is 12-32 months.^10,11,12
• There is an increased risk of infection in people with MGUS and asymptomatic myeloma even if there is no disease progression.

Document references

1. Alexander DD, Mink PJ, Adami HO, et al; Multiple myeloma: a review of the epidemiologic literature. Int J Cancer. 2007;120 Suppl 12:40-61. [abstract]
2. The diagnosis and management of multiple myeloma, British Committee for Standards in Haematology (October 2010)
3. Larsson SC, Wolk A; Body mass index and risk of multiple myeloma: a meta-analysis. Int J Cancer. 2007 Dec 1;121(11):2512-6. [abstract]
4. Grethlein SJ et al; Multiple Myeloma, eMedicine, Oct 2010
5. Raab MS, Podar K, Breitkreutz I, et al; Multiple myeloma. Lancet. 2009 Jul 25;374(9686):324-39. Epub 2009 Jun 21. [abstract]
6. Koreth J, Cutler CS, Djulbegovic B, et al; High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant. 2007 Feb;13(2):183-96. [abstract]
7. Dyer C; Health department sets up cost sharing deal for multiple myeloma drug. BMJ. 2009 Feb 2;338:b423. doi: 10.1136/bmj.b423.
8. National Comprehensive Cancer Network; Clinical Practice Guidelines in Oncology. Multiple Myeloma. 2008. (American guidelines)
9. Kyle RA, Rajkumar SV; Monoclonal gammopathies of undetermined significance: a review. Immunol Rev. 2003 Aug;194:112-39. [abstract]
10. Wisloff F, Andersen P, Andersson TR, et al; Incidence and follow-up of asymptomatic multiple myeloma. The myeloma project of health region I in Norway. II. Eur J Haematol. 1991 Nov;47(5):338-41. [abstract]
11. Dimopoulos MA, Moulopoulos A, Smith T, et al; Risk of disease progression in asymptomatic multiple myeloma. Am J Med. 1993 Jan;94(1):57-61. [abstract]
12. Weber DM, Dimopoulos MA, Moulopoulos LA, et al; Prognostic features of asymptomatic multiple myeloma. Br J Haematol. 1997 Jun;97(4):810-4. [abstract]

Internet and further reading

• Nau KC, Lewis WD; Multiple myeloma: diagnosis and treatment. Am Fam Physician. 2008 Oct 1;78(7):853-9. [abstract]
• Supportive care in multiple myeloma, British Committee for Standards in Haematology (October 2010)

Acknowledgements