23rd July 2024

Multiple myeloma (MM)

Background of MM

Multiple myeloma is the second most common haematological malignancy and accounts for 1-2% of all diagnosed malignancies. Diagnosis is most frequent between the ages of 65 and 74. It has a slight male predominance. MM is more common in Afro-Caribbeans and less common in Asians.

No clear aetiological factors have been identified. There may be a genetic component.

Common chromosomal aberrations are seen across MM. Hyperdiploidy or translocations involving the immunoglobulin heavy chain (IgH) region at 14q32 are seen in the majority of cases.

Myeloma is classified according to the combination of immunoglobulin (Ig) heavy chain (G, A, D, E or M) and light chain (kappa or lambda) secreted by the malignant cells.

IgG kappa myeloma is the most common subtype. Around 15% of patients exhibit light chain myeloma (Bence-Jones myeloma) where only light chains are secreted. IgM myeloma can occur in MM but is very rare; IgM production is more commonly seen in Waldenström’s macroglobulinaemia.

Diagnostic criteria for MM

Diagnosis is made using the International Myeloma Working Group diagnostic criteria. These criteria serve to differentiate active MM from monoclonal gammopathy of undetermined/unknown significance (MGUS) and smouldering myeloma.

MGUS is an asymptomatic premalignant stage that almost always precedes the development of MM. IgM MGUS is more likely to progress to Waldenström’s macroglobulinaemia, but all other types, if they progress, are likely to progress to MM.

Smouldering myeloma is an intermediate, asymptomatic stage between MGUS and MM, which has a higher chance of progression to MM than MGUS.

Myeloma-defining events (MDE) form part of the diagnostic criteria, and their presence differentiates smouldering myeloma from MM. MDEs include the well-known CRAB criteria, which are evidence of end-organ damage that can be attributed to a plasma cell proliferative disorder:

• C – hyperCalcaemia: 0.25 mmol/L above the normal upper limit or serum calcium >2.75 mmol/L
• R – Renal impairment: serum creatinine >177 µmol/L or creatinine clearance < 40 mL/min
• A – Anaemia: Hb 20 g/L below the lower limit of normal or Hb < 100 g/L
• B – Bony lesions: ≥1 osteolytic lesions on imaging

These are the diagnostic criteria:

* A plasmacytoma is a mass of malignant plasma cells that can occur in bone or soft tissue

Presentation and investigations in MM

MM may be picked up incidentally. It may also present with signs and symptoms from the CRAB criteria.

Symptoms of anaemia are the most common presenting complaint. Anaemia can be from bone marrow failure or from erythropoietin deficiency. Bony pain is also very common. In MM there is osteoclast activation and osteoblast inhibition, leading to osteolytic bone lesions and hypercalcaemia. The lytic lesions may also result in pathological fractures. Renal failure may cause fatigue and generalised weakness. Renal failure can occur in MM due to light chain cast nephropathy (‘myeloma kidney’) or hypercalcaemia. If patients do not secrete light chains, then they are not at risk of developing myeloma kidney. Other signs of renal failure and hypercalcaemia may be present.

Investigations for diagnosis may include:

• Bloods: full blood count, urea and electrolytes, bone profile, serum protein electrophoresis, serum immunoglobulins, serum free light chains
• Blood film: may show rouleaux formation (stacking of red blood cells)
• Urine: urinalysis, urine Bence-Jones protein
• Bone marrow aspirate
• Imaging: whole-body low-dose CT (preferred over skeletal survey to identify lytic lesions), FDG-PET, MRI

Image Source: Wikimedia Commons (2012). Rouleaux, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Rouleaux.jpg#/media/File:Rouleaux.jpg (Accessed: 16 January 2024)

Image Source: Wikimedia Commons (2023). Raindrop skull, Licensed under a creative commons licence. Available for free at: https://radiopaedia.org/articles/raindrop-skull?lang=gb (Accessed: 16 January 2024)

Management and prognosis of MM

MGUS and smouldering myeloma do not require treatment; they are managed with surveillance.

Treatment of MM depends on eligibility for autologous stem cell transplant (SCT). Generally, patients <65 years old with no significant comorbidities are eligible for SCT in MM.

• If SCT eligible, treatment is with induction therapy, which can be chemotherapy based (e.g. vincristine, doxorubicin, dexamethasone) or non-chemotherapy based (e.g. thalidomide and dexamethasone), followed by autologous SCT and maintenance therapy.
• If SCT ineligible, treatment is with induction therapy followed by maintenance therapy.

MM is incurable. Even following remission, relapse normally occurs after 2-5 years.

Prognosis is predicted using a combination of serum beta-2 microglobulin level, serum LDH and presence of high-risk chromosomal abnormalities.