What is the differential diagnosis, work‑up, and management for a patient with elevated beta‑2 microglobulin and new or worsening peripheral neuropathy, especially if they are receiving bortezomib?

Elevated Beta-2 Microglobulin and Peripheral Neuropathy

Direct Answer

In a patient with elevated beta-2 microglobulin and peripheral neuropathy receiving bortezomib, immediately implement dose reduction or switch to weekly subcutaneous dosing, as bortezomib-induced peripheral neuropathy (BIPN) is the most likely diagnosis and early dose adjustment maintains anti-tumor efficacy while reducing neurotoxicity. 1

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Differential Diagnosis

The combination of elevated beta-2 microglobulin and peripheral neuropathy in the context of multiple myeloma or Waldenström macroglobulinemia requires consideration of:

Primary Disease-Related Causes

• Multiple myeloma-associated neuropathy: The plasma cell dyscrasia itself can cause neuropathy through light chain deposits (amyloidosis), cryoglobulinemia, or autoimmune mechanisms 1
• POEMS syndrome: A rare but important consideration when beta-2 microglobulin is elevated 1
• Direct nerve compression: From radicular or medullary involvement 1

Drug-Induced Neuropathy (Most Common in Treatment Context)

• Bortezomib-induced peripheral neuropathy (BIPN): The leading iatrogenic cause, presenting as primarily sensory, painful, axonal distal neuropathy with "glove and stocking" distribution 1, 2, 3
• Thalidomide-induced neuropathy: Usually sensory and sensorimotor, with 25-75% incidence and poor reversibility (25%) 4
• Vincristine: Presents with mechanical allodynia, sensory/tactile disorders, and autonomic manifestations 2

Rare but Critical: Immune-Mediated Neuropathy

• Bortezomib-associated inflammatory autoimmune neuropathy: Rare but treatable condition characterized by rapid onset, severe motor involvement (unlike typical BIPN), demyelinating or mixed pattern on electrophysiology, and CSF albumin-cytological dissociation 5, 6

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Work-Up Algorithm

Step 1: Clinical Assessment

• Characterize the neuropathy pattern: BIPN is typically sensory, painful, distal, and symmetric with small fiber involvement 3
• Look for red flags suggesting immune-mediated disease: Rapid progression, prominent motor weakness (especially asymmetric), unexplained worsening despite drug discontinuation 5, 6
• Document pre-existing risk factors: Diabetes mellitus, renal insufficiency, hypothyroidism, vitamin deficiencies, alcohol abuse, or baseline neuropathy 2, 4

Step 2: Electrophysiological Studies

• Nerve conduction studies: BIPN shows axonal sensory neuropathy with reduced sensory nerve conduction velocities 1
• If demyelinating or mixed axonal-demyelinating pattern with motor involvement: Consider immune-mediated neuropathy 6

Step 3: Laboratory Evaluation

• CSF analysis if immune-mediated neuropathy suspected: Look for albumin-cytological dissociation 6
• Screen for treatable causes: Fasting glucose/HbA1c, vitamin B12, thyroid function 7
• MRI of spine/nerve roots if indicated: May show lumbar root enhancement in immune-mediated cases 6

Step 4: Assess Bortezomib Exposure

• Calculate cumulative dose: BIPN is dose-dependent and related to cumulative exposure 3
• Review dosing schedule: Twice-weekly intravenous dosing has higher neuropathy rates than once-weekly or subcutaneous administration 1

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Management Strategy

Immediate Actions for Typical BIPN

For Grade 1-2 Neuropathy (Sensory, No Functional Impairment):

• Switch to once-weekly subcutaneous bortezomib: Reduces neuropathy rates while maintaining efficacy 1
• Implement dose reduction algorithm: Early dose adjustment maintains anti-tumor efficacy 1

For Grade 3-4 Neuropathy (Functional Impairment):

• Discontinue bortezomib immediately: BIPN is mostly reversible (64%) with drug cessation 4
• Consider switching to carfilzomib: Second-generation proteasome inhibitor with low neurotoxicity risk (no grade ≥3 neuropathy in studies) 1

Symptomatic Pain Management

First-Line Pharmacological Treatment:

• Duloxetine 60-120 mg/day: The only agent with appropriate evidence for chemotherapy-induced peripheral neuropathy, though benefit is limited 7, 8, 2
• Alternative first-line agents: Pregabalin 300-600 mg/day or gabapentin 300-2,400 mg/day 7, 8

Second-Line Options:

• Tricyclic antidepressants (amitriptyline 25-75 mg/day): Effective but significant anticholinergic side effects; contraindicated in cardiovascular disease, glaucoma, or fall risk 8

Management of Immune-Mediated Neuropathy (If Diagnosed)

This is a treatable condition requiring different approach:

• Initiate polyvalent immunoglobulins (IVIg): Favorable outcome in 4/5 patients in case series 5, 6
• Alternative: High-dose corticosteroids: Effective in some cases 6
• Do NOT simply discontinue bortezomib and wait: Active immune treatment is required 5

Preventive Strategies

Before Initiating Bortezomib:

• Baseline neurological evaluation: Document pre-existing neuropathy, as this significantly increases BIPN risk 2, 4
• Prefer weekly subcutaneous dosing from start: Especially in patients with diabetes, age >65-75 years, or other risk factors 1, 2
• Herpes zoster prophylaxis: Strongly recommended for all patients receiving proteasome inhibitors 1

During Treatment:

• Monitor neurological symptoms before each cycle: Early detection allows dose adjustment before severe neuropathy develops 1, 2
• Avoid co-administration with other neurotoxic agents: Additive risk 2

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Critical Pitfalls to Avoid

Pitfall 1: Missing Immune-Mediated Neuropathy

• Do not assume all bortezomib-associated neuropathy is toxic: If prominent motor involvement, rapid progression, or worsening after drug discontinuation occurs, perform CSF analysis and consider immune treatment 5, 6

Pitfall 2: Continuing Standard Dosing Despite Early Symptoms

• Early dose adjustment is key: Waiting for severe neuropathy before modifying treatment reduces reversibility and quality of life 1, 4

Pitfall 3: Inadequate Pain Management

• Start duloxetine early: It is the only evidence-based treatment for chemotherapy-induced neuropathy and benefits appear as early as week 1 8

Pitfall 4: Ignoring Alternative Proteasome Inhibitors

• Carfilzomib is neuropathy-sparing: In patients with pre-existing neuropathy or high risk, consider carfilzomib-based regimens from the start (87% response rate, 0% grade ≥3 neuropathy) 1

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Ongoing Monitoring

• Reassess neurological status before each treatment cycle: Use standardized grading 1, 2
• Monitor pain and quality of life: Adjust symptomatic treatment as needed 7
• Watch for "coasting phenomenon": Some drug-induced neuropathies worsen for 2-3 months after therapy completion before improving 2
• Long-term follow-up: BIPN is mostly reversible but may take weeks to months 1, 4