HaematologyTier 1Disease (DEADMAN)

Monoclonal gammopathy of undetermined significance

Description

A clonal plasma cell / lymphoplasmacytic population producing a paraprotein, without end-organ damage
An obligate precursor state - essentially every myeloma is preceded by MGUS
The commonest premalignant condition in medicine

Three subtypes - they progress to different diseases

Subtype	Paraprotein	Progresses to
Non-IgM (IgG, IgA, IgD) - ~85%	Intact immunoglobulin	Multiple myeloma, AL amyloidosis
IgM - ~15%	IgM	Waldenstrom macroglobulinaemia, other B-cell lymphoma; rarely myeloma
Light chain MGUS - ~3%	Abnormal FLC ratio, no heavy chain	Light-chain myeloma, AL amyloidosis, MIDD

*"Undetermined significance" is a statement about the current absence of damage, not about the future*
Monoclonal gammopathy of clinical significance (MGCS) - a small clone causing disease by the properties of the protein rather than by tumour bulk
- AL amyloidosis, MIDD, C3 glomerulopathy with monoclonal gammopathy, cryoglobulinaemia, POEMS, Schnitzler, cold agglutinin disease, acquired angioedema, scleromyxoedema
- *These do not meet CRAB criteria but do require clone-directed treatment*

Epidemiology

Prevalence >3% of people over 50; >5% over 70; ~7-8% over 85
Detected in ~1% of unselected adults
M>F; 2-3x more common in people of African ancestry; less common in East Asian populations
2-3x inc risk in first-degree relatives of MGUS or myeloma patients
*Population screening is not recommended* - iStopMM showed detection does not improve survival and does cause harm from anxiety and investigation

Aetiopathogenesis

Clonal plasma cell expansion following an initiating genetic event in a post-germinal-centre B cell

Primary (initiating) events - present already at MGUS

	Frequency	Note
IgH translocations	~40-50%	t(11;14) CCND1 (also mantle cell; associated with venetoclax sensitivity and AL amyloidosis), t(4;14) FGFR3/MMSET, t(14;16) MAF, t(6;14)
Hyperdiploidy	~50%	Trisomies of odd-numbered chromosomes; better prognosis

Secondary events - drive progression

1q gain, del(17p)/TP53, del(1p), MYC rearrangement, RAS/BRAF mutations
Increasing marrow angiogenesis, loss of immune surveillance, bone microenvironment remodelling
The genetic lesions are already present at the MGUS stage - progression reflects accumulated secondary events and microenvironmental change, not the appearance of the primary hit

Risk factors

Age, male sex, African ancestry, family history
Obesity, chronic immune stimulation, autoimmune disease
Occupational/environmental: pesticides (agricultural workers), benzene, firefighters and 9/11 responders, Agent Orange
HIV, hepatitis C, immunosuppression

Diagnosis

Definition - all three required

	Threshold
Serum M-protein	<30 g/L (and urinary monoclonal protein <500 mg/24 h)
Clonal marrow plasma cells	<10%
End-organ damage	Absent - no CRAB, no amyloidosis, no MGCS

Light chain MGUS: abnormal FLC ratio, involved FLC raised, no heavy chain on immunofixation, clonal marrow plasma cells <10%, urinary M-protein <500 mg/24 h

CRAB - what must be absent

Calcium >2.75 mmol/L (or >0.25 above upper limit)
Renal - creatinine >177 micromol/L or eGFR <40
Anaemia - Hb <100 g/L or >20 g/L below normal
Bone - one or more lytic lesions on skeletal survey, CT or PET-CT

Myeloma-defining biomarkers (SLiM) - also must be absent

Sixty percent or more clonal marrow plasma cells
Light chain ratio - involved:uninvolved serum FLC >=100 (involved FLC >=100 mg/L)
MRI - >1 focal lesion >=5 mm

Investigations at first detection

Serum EPG + immunofixation, serum free light chains, quantitative immunoglobulins
FBE, calcium, UEC, albumin, LDH, beta-2 microglobulin
Urine EPG + immunofixation (24 h or spot with creatinine ratio)
*Bone marrow biopsy and whole-body imaging are NOT needed for low-risk MGUS* - reserve for intermediate/high risk, IgM >10 g/L, abnormal FLC ratio with symptoms, or any CRAB/SLiM feature
IgM MGUS: CT chest/abdo/pelvis for nodes and spleen; marrow if IgM high or symptomatic
Test for amyloidosis if there is unexplained proteinuria, cardiomyopathy, neuropathy, hepatomegaly or autonomic failure - serum FLC + fat pad/organ biopsy with Congo red and mass spectrometry typing**

Mayo/IMWG risk model - 3 factors

1. M-protein >=15 g/L

2. Non-IgG isotype (IgA, IgM, IgD)

3. Abnormal serum free light chain ratio

Risk factors	Category	20-yr progression risk
0	Low	~5%
1	Low-intermediate	~21%
2	High-intermediate	~37%
3	High	~58%

Management

*No treatment. The management is surveillance, symptom vigilance, and bone health.*

A. Surveillance schedule - risk-adapted

Risk	Schedule
Low risk	Repeat at 6 months, then every 2-3 years (or if symptoms develop). No marrow, no imaging
Intermediate / high risk	Repeat at 6 months, then annually for life
IgM MGUS	6 months, then annually - watch for lymphoma features as well as myeloma

Each visit: EPG + FLC, FBE, calcium, creatinine, and a symptom review
Re-score risk at each visit - migration to a higher category warrants more frequent monitoring
*No routine skeletal surveys or PET in stable low-risk disease*

B. What to tell the patient to report

New or persistent bone pain (especially back), fracture from minimal trauma
Fatigue, weight loss, night sweats, recurrent infection
Frothy urine, oedema, postural dizziness, macroglossia, paraesthesia (amyloid)
New lymphadenopathy

C. Bone health

MGUS is an independent risk factor for osteoporosis and fracture (~2x)
DEXA at diagnosis; calcium, vitamin D, weight-bearing exercise
Treat osteoporosis conventionally

D. When to escalate

Any CRAB or SLiM feature -> treat as myeloma
M-protein >=30 g/L or marrow plasma cells 10-60% without CRAB/SLiM = smouldering myeloma
- Progression ~10%/yr for the first 5 years, then 3%/yr, then 1-2%/yr
- 20/2/20 model (M-protein >20 g/L, marrow plasma cells >20%, FLC ratio >20) stratifies risk
- *High-risk smouldering myeloma is now often treated - lenalidomide +/- dexamethasone, or daratumumab (AQUILA); this is a real change from observation-only*
MGCS - symptomatic organ disease from the protein -> clone-directed therapy regardless of clone size

E. Practical points

Avoid nephrotoxins and iodinated contrast where possible if the FLC ratio is abnormal
A stable paraprotein with a new unexplained neuropathy, nephrotic syndrome or cardiomyopathy is amyloid until excluded - the paraprotein size is irrelevant

Associations

Multiple myeloma, smouldering myeloma, plasmacytoma
Waldenstrom macroglobulinaemia and other B-cell lymphomas (IgM MGUS)
AL amyloidosis, monoclonal immunoglobulin deposition disease
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes; VEGF elevated)
Anti-MAG demyelinating peripheral neuropathy (IgM kappa)
Cryoglobulinaemia (type I and II), cold agglutinin disease, acquired angioedema (C1-INH)
Monoclonal gammopathy of renal significance - C3 glomerulopathy, proliferative GN with monoclonal deposits, light chain cast nephropathy, Fanconi syndrome
Schnitzler syndrome (IgM + urticaria + fever), scleromyxoedema, necrobiotic xanthogranuloma, pyoderma gangrenosum
Osteoporosis and fracture (~2x)
Increased venous and arterial thrombosis risk; increased infection risk
Gaucher disease, HIV, HCV, autoimmune disease

Natural history & complications

Progression ~1% per year, and the risk does not decline with time - it persists beyond 25 years of follow-up
- Therefore lifelong follow-up for anything other than low-risk disease
Low-risk MGUS: ~5% cumulative progression at 20 years - most such patients die of something else
High-risk MGUS: ~58% at 20 years
Light chain MGUS: ~0.3%/yr - lower, but progresses to light-chain myeloma and AL amyloidosis
IgM MGUS: ~1.5%/yr, to Waldenstrom and lymphoma rather than myeloma

Predictors of progression

M-protein size (the strongest single factor), non-IgG isotype, abnormal FLC ratio
Marrow plasma cell percentage, immunoparesis (suppression of uninvolved immunoglobulins), evolving pattern of rising paraprotein
Abnormal marrow plasma cell immunophenotype; circulating plasma cells

Excess morbidity even without progression

Osteoporosis and fragility fracture
Infection risk ~2x (immunoparesis)
Venous and arterial thromboembolism
Excess all-cause mortality compared with matched controls, only partly explained by progression

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