What is the best approach to manage a new M (monoclonal) spike in an older adult patient with neuropathy, potentially related to conditions like multiple myeloma or diabetes?

Management of New M-Spike in a Patient with Neuropathy

The immediate priority is to determine whether the M-spike is IgM or non-IgM (IgG/IgA), as this fundamentally dictates both the diagnostic workup and treatment approach—IgM-associated neuropathy warrants rituximab-based therapy, while non-IgM cases require antimyeloma agents, with lenalidomide preferred when neuropathy is present. 1

Initial Diagnostic Workup

The presence of an M-spike with neuropathy requires urgent evaluation to distinguish between MGUS with associated neuropathy versus symptomatic plasma cell disorders (multiple myeloma, Waldenström macroglobulinemia, POEMS syndrome, or AL amyloidosis) 1:

• Complete blood count with differential to assess for cytopenias that would indicate symptomatic disease 1
• Comprehensive metabolic panel including calcium, albumin, and creatinine to evaluate for myeloma-defining events 1
• Serum protein electrophoresis with immunofixation to characterize the M-protein isotype (IgM vs IgG vs IgA) and quantify the spike 1, 2
• 24-hour urine protein electrophoresis and immunofixation to detect light chain excretion 1
• Serum free light chain assay to assess for light chain ratio abnormalities 1
• Bone marrow biopsy and aspiration with FISH cytogenetics to determine plasma cell percentage and risk stratification 1
• Skeletal survey or whole-body imaging to evaluate for lytic lesions 1

Neuropathy-Specific Testing

For patients with confirmed peripheral neuropathy and M-spike 1, 2:

• Anti-MAG (myelin-associated glycoprotein) antibodies if IgM monoclonal protein is present—approximately 50% of IgM-MGUS neuropathy patients have anti-MAG antibodies 1, 3
• Anti-ganglioside M1 antibodies if motor neuropathy is present 1
• Nerve conduction studies and electromyography to distinguish axonal from demyelinating patterns and confirm neuropathy is related to the monoclonal process 1, 2
• Neurologic consultation for comprehensive evaluation 1

Critical distinction: IgM-MGUS neuropathies demonstrate significantly higher frequency of sensory loss, ataxia, and demyelinating features on nerve conduction studies compared to IgG/IgA-MGUS neuropathies 4. Serum protein immunofixation electrophoresis is more sensitive than standard electrophoresis for detecting monoclonal gammopathies 2.

Treatment Decision Algorithm

If Symptomatic Disease is Confirmed (Multiple Myeloma, Waldenström Macroglobulinemia, etc.)

Treatment is indicated when patients meet criteria for symptomatic disease with features such as hyperviscosity, symptomatic neuropathy, anemia, hypercalcemia, renal insufficiency, or bone lesions 1:

For IgM-Related Disease:

Rituximab monotherapy is the recommended first-line approach for IgM-associated neuropathy, including anti-MAG polyneuropathy 1. Addition of chemotherapy to rituximab should be considered only in cases with severe symptoms requiring rapid tumor reduction 1. The duration of immunochemotherapy is generally shorter than for symptomatic Waldenström macroglobulinemia due to lower tumor burden 1.

For Non-IgM (IgG/IgA) MGUS-Related Neuropathy:

Lenalidomide-based regimens are the first choice in patients with neuropathy because lenalidomide does not cause or worsen peripheral neuropathy 1. This is critical given that bortezomib, while highly effective for M-protein reduction, causes peripheral neuropathy as its most important side effect even with subcutaneous or weekly administration 1, 5.

Avoid bortezomib-containing regimens in patients with pre-existing neuropathy unless absolutely necessary for life-threatening complications (e.g., severe renal disease requiring rapid M-protein reduction) 1, 5. The FDA label explicitly warns that patients with pre-existing peripheral neuropathy symptoms may experience worsening neuropathy (including ≥Grade 3) during bortezomib treatment 5.

For younger patients (≤65-70 years) with severe, progressive, or disabling symptoms:

• High-dose melphalan with autologous stem cell transplant can be considered to induce long-term remission 1
• Induction therapy may not be needed if the clone is small, but is advantageous for patients with poor performance status or significant plasma cell burden (M-protein ≥10 g/L) 1

If MGUS Without Symptomatic Disease

Treatment directed at the MGUS clone is only justified when there is a clear causal relationship between MGUS and the neuropathy, and only in cases of aggressive and disabling disease 1. Institution of supportive care alone may be sufficient for mild symptoms 1.

For observation without treatment:

• Risk stratification using bone marrow involvement percentage, serum IgM level, serum beta-2-microglobulin, and serum albumin 1
• Follow-up frequency based on risk: every 12 months for low risk, every 6 months for intermediate risk, every 3 months for high risk 1
• Monitoring includes: CBC, comprehensive metabolic panel, serum protein electrophoresis, and serum immunoglobulins 1

Critical Management Considerations

Avoiding Neurotoxic Agents

When symptomatic treatment is required, the hierarchy of neurotoxicity risk is crucial 6, 7:

• Highest risk: Thalidomide (should not be given >18 months), bortezomib, vinca alkaloids, cisplatin 6, 7
• Lower risk: Lenalidomide, carfilzomib (though carfilzomib has higher rates of hypertension, dyspnea, cardiac failure, and acute renal failure compared to bortezomib) 1
• Monoclonal antibodies (daratumumab, elotuzumab) have excellent tolerability profiles without significant neurotoxicity 1

If Bortezomib Must Be Used

Despite the preference to avoid bortezomib in neuropathy patients, if it must be used (e.g., for rapid M-protein reduction in renal crisis) 1:

• Monitor closely for symptoms of neuropathy: burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness 5
• Dose modification at first sign of new or worsening neuropathy 5
• In the Phase 3 relapsed myeloma trial, 39% developed Grade ≥2 peripheral neuropathy and 15% developed Grade ≥3 neuropathy with IV bortezomib 5
• Improvement or resolution of peripheral neuropathy occurred in 48% following dose adjustment or interruption, and in 73% who discontinued due to Grade 2 or had ≥Grade 3 neuropathy 5

Prognosis and Monitoring

Up to 20% of multiple myeloma patients have peripheral neuropathy at diagnosis, and as many as 75% may experience treatment-emergent neuropathy during therapy 7. The association between monoclonal gammopathies and neuropathy is well-established, with approximately 10% of patients with polyneuropathy of unknown etiology having a monoclonal gammopathy 2, 8.

Common pitfall: The presence of M-protein in a patient with neuropathy does not automatically indicate a causal relationship, as MGUS prevalence is 3-4% in individuals over age 50 8. However, IgM-MGUS is significantly more frequent in neuropathy cohorts than in the general MGUS population, suggesting a pathogenic role 4.