Multiple myeloma & MGUS
Multiple myeloma definition
Clonal plasma-cell malignancy with bone-marrow infiltration and a monoclonal (M) protein in serum and/or urine.In multiple myeloma, the overproduced monoclonal immunoglobulin is most often:
- IgG – 50–60% of cases
- IgA – about 20–25% of cases
- Less commonly: IgD, IgE, or light-chain only (Bence-Jones myeloma, ~15–20%)
- IgM is not typical for myeloma
Diagnostic criteria
The International Myeloma Working Group (IMWG) criteria have replaced Durie–Salmon for diagnosis.
To diagnose symptomatic multiple myeloma, you now need:
- Clonal bone marrow plasma cells ≥10% or
- Biopsy-proven plasmacytoma
- ≥1 myeloma-defining event (CRAB or SLiM)
CRAB (end-organ damage):
- C: Hypercalcaemia (>2.75 mmol/L)
- R: Renal insufficiency (creatinine ≥177 µmol/L or eGFR <40 mL/min)
- A: Anaemia (Hb <100 g/L or ≥20 g/L below normal)
- B: Bone lesions (lytic lesions on imaging)
- S: ≥60% clonal plasma cells in marrow
- Li: Involved/uninvolved serum free light-chain ratio ≥100, with involved chain ≥100 mg/L
- M: >1 focal lesion ≥5 mm on MRI
CRAB:
- hyperCalcaemia
- Renal impairment
- Anaemia
- Bone disease.
- S - Sixty: Bone marrow plasma cells ≥ 60% (clonal)
- Li - Light chains: Involved/uninvolved serum free light-chain ratio (sFLC) ≥ 100, and involved chain concentration ≥ 100 mg/L
- M - MRI: More than one focal lesion ≥ 5 mm on MRI scan
Epidemiology
- Incidence in the UK is 4.5–6.0 cases per 100,000 people per year
- Median age at diagnosis approximately 72 years
- Incidence rises with age.
- Men are affected more than women (m:f ratio is 5:3)
- Incidence is higher in people of African/Caribbean ancestry
- Most cases evolve from MGUS; an intermediate 'smouldering' phase which typically precedes symptomatic disease.
Clinical features
CRAB and other features:
- Hypercalcaemia: around 15% at presentation
- Renal impairment: often multifactorial with light-chain cast nephropathy, hypercalcaemia, dehydration and nephrotoxins contributing to renal impairment.
- Normocytic anaemia
- Bone pain/fractures from lytic disease (bony lesions in >80% of patients over the disease course).
- Other features: recurrent bacterial infections, peripheral neuropathy, hyperviscosity (e.g. visual change, headaches, mucosal bleeding, dyspnoea), spinal cord or nerve-root compression, and features of AL amyloidosis (e.g., macroglossia, carpal tunnel).
When to suspect myeloma
Consider in persistent or unexplained bone or back pain, anaemia, recurrent infections, renal impairment, or raised calcium/ESR.Initial tests
- FBC
- U&Es
- Calcium
- ESR or plasma viscosity
- Serum protein electrophoresis with immunofixation, and serum free light chains
- Urine Bence-Jones protein (light chains) if sFLC not available
Confirmatory work-up
- Bone-marrow aspirate/biopsy with immunophenotyping
- Imaging with whole-body MRI as the preferred modality (low-dose whole-body CT or PET-CT if MRI unsuitable)
- Quantify M-protein and sFLC (both elevated)
- Blood film (marked Rouleaux formation on a blood film and occasional plasma cells)
- Ig levels (demonstrate immunoparesis i.e. suppression of normal (polyclonal) immunoglobulins due to the overproduction of a monoclonal immunoglobulin by malignant plasma cells)
- β2-microglobulin
- Albumin
- LDH
- Cytogenetics/FISH
Differentials
- MGUS
- Solitary plasmacytoma
- AL amyloidosis
- Waldenström macroglobulinaemia/lymphoplasmacytic lymphoma
- Metastatic malignancy
- Other chronic inflammatory conditions
Monoclonal gammopathy of undetermined significance (MGUS):
Definition: Presence of a monoclonal protein (paraprotein) in the blood below myeloma thresholds, with no myeloma-defining events (no CRAB or SLiM criteria), no other B-cell/plasma cell malignancy, and <10% clonal plasma cells in the bone marrow.
Risk: Progresses to multiple myeloma, AL amyloidosis, or related disorders at a rate of about 1% per year, meaning ~10% at 10 years, ~20% at 20 years etc . Risk is higher with certain features (e.g., higher M-protein level, abnormal free light-chain ratio, non-IgG isotype).
Definition: Presence of a monoclonal protein (paraprotein) in the blood below myeloma thresholds, with no myeloma-defining events (no CRAB or SLiM criteria), no other B-cell/plasma cell malignancy, and <10% clonal plasma cells in the bone marrow.
Risk: Progresses to multiple myeloma, AL amyloidosis, or related disorders at a rate of about 1% per year, meaning ~10% at 10 years, ~20% at 20 years etc . Risk is higher with certain features (e.g., higher M-protein level, abnormal free light-chain ratio, non-IgG isotype).
Management
Smouldering myeloma: observation; treat on progression to symptomatic/defining-event disease.Newly diagnosed, transplant-eligible: induction (e.g., bortezomib-based combinations) then autologous stem-cell transplant. Eligibility is based on fitness/frailty and comorbidity rather than age alone.
Transplant-ineligible/less fit: non-intensive triplet/duplet regimens (e.g., bortezomib- or IMiD-based) tailored to frailty/comorbidities.
Supportive care and management of complications:
- Prompt treatment of hypercalcaemia and infection
- Prompt recognistion and treatment of spinal cord compression (emergency).
- For bone disease zoledronic acid is first-line to prevent skeletal events (pamidronate if contraindicated, clodronate if others unsuitable) with pre-treatment dental assessment.
- Manage painful or at-risk lesions with surgery/radiotherapy as appropriate.
- Consider plasma exchange for symptomatic hyperviscosity.
Prognosis
Multiple myeloma remains an incurable disease.
Survival continues to improve with modern therapies but is heterogeneous.
Prognosis is informed by staging and biology (e.g., β2-microglobulin, albumin, LDH, and adverse cytogenetics); long-term survival is possible, particularly in fitter/younger patients.
When grouping all stages of myeloma together overall 5 year survival is aaround 55%.