What is the recommended management approach for a patient with Monoclonal Gammopathy of Undetermined Significance (MGUS) and a history of long COVID, potentially misdiagnosed with tumor-induced osteomalacia?

Management of MGUS with Long COVID History and Suspected Tumor-Induced Osteomalacia

For a patient with MGUS (not multiple myeloma), the primary management is risk-stratified surveillance without treatment, while simultaneously investigating for tumor-induced osteomalacia if hypophosphatemia and bone symptoms are present. 1

Critical Distinction: MGUS vs Multiple Myeloma

• MGUS requires no treatment directed at the plasma cell clone unless there is a clear causal relationship with a severe, disabling M-protein-related disorder 1
• Treatment targeting the MGUS clone is only justified when there is documented aggressive and disabling disease directly caused by the M-protein 1, 2
• The majority of MGUS patients can receive appropriate follow-up in primary care without invasive interventions 1

Immediate Evaluation for Tumor-Induced Osteomalacia

If bone pain, fractures, or muscle weakness are present:

Laboratory workup:

• Serum phosphate (hypophosphatemia is the hallmark finding) 3, 4
• Serum FGF23 levels (elevated or inappropriately normal) 3, 4
• 1,25-dihydroxyvitamin D (low to low-normal) 3, 4
• 24-hour urine phosphate to document renal phosphate wasting 4
• Calcium, creatinine, complete blood count 1

Critical pitfall: Tumor-induced osteomalacia is misdiagnosed in >95% of cases initially due to nonspecific symptoms 3. The key is recognizing the combination of hypophosphatemia with elevated/normal FGF23 and low 1,25(OH)2D 4.

Tumor localization if TIO is confirmed:

1. Functional imaging first: 68Ga DOTA-based PET/CT has the best sensitivity for detecting FGF23-secreting tumors 3
2. Anatomical imaging: MRI or CT to confirm suspicious lesions 4
3. Selective venous sampling: If imaging is negative, measure FGF23 levels in venous samples to localize the tumor 4

These tumors are typically small, slow-growing mesenchymal tumors that can occur anywhere from head to toe with equal prevalence in soft tissue and bone 3, 4

MGUS Risk Stratification and Follow-Up

Use the Mayo Clinic risk stratification model 1, 5:

Low-risk MGUS (5% progression at 20 years):

• IgG isotype AND M-protein <15 g/L AND normal free light chain ratio
• Follow-up: 6 months initially, then every 1-2 years 1, 5

Intermediate-risk MGUS (21-37% progression at 20 years):

• One or two risk factors present
• Follow-up: 6 months initially, then annually 1, 5

High-risk MGUS (58% progression at 20 years):

• All three risk factors present (non-IgG, M-protein ≥15 g/L, abnormal FLC ratio)
• Follow-up: 6 months initially, then annually 1, 5

Follow-up consists of:

• History focusing on bone pain, fractures, renal symptoms, neuropathy, bleeding, infections 1
• Physical examination 1
• M-protein quantification 1
• Complete blood count 1
• Creatinine and calcium 1

Special Considerations for Long COVID

• MGUS patients with COVID-19 have higher mortality risk (HR 1.14,95% CI 1.01-1.27) and decreased survival time compared to the general population 6
• Ensure adequate vaccination status and consider precautionary measures for ongoing COVID exposure 6
• Monitor for post-COVID complications that may overlap with MGUS-related symptoms 6

Bone Health Management

If osteoporosis/osteopenia is present (assess with DXA scan):

• Bisphosphonates (alendronate or zoledronic acid) improve bone mineral density in MGUS patients with osteopenia/osteoporosis or fractures 1
• Calcium and vitamin D supplementation if dietary intake is insufficient 1

Critical distinction: If hypophosphatemia is present, this suggests TIO rather than MGUS-related osteoporosis, and bisphosphonates alone will not address the underlying pathophysiology 3, 4.

Treatment Algorithm

If TIO is confirmed:

1. Surgical resection is curative - complete tumor removal resolves the syndrome 3, 4, 7
2. If tumor cannot be localized or resected: Medical therapy with phosphate supplementation and active vitamin D metabolites 4, 7
3. Monitor for complications: Secondary/tertiary hyperparathyroidism, hypercalciuria, nephrocalcinosis 4
4. Novel therapies: Anti-FGF23 monoclonal antibody (KRN23) or anti-FGFR medications for refractory cases 4, 7

If no TIO and MGUS alone:

• No treatment for the MGUS clone 1
• Risk-stratified surveillance only 1, 5
• Initiate therapy only when symptomatic multiple myeloma or related malignancy develops 1

What NOT to Do

• Do not perform bone marrow examination or imaging routinely if IgG M-protein ≤15 g/L or IgA M-protein ≤10 g/L without symptoms 1
• Do not initiate preventive interventions to delay MGUS progression outside of clinical trials 1, 5
• Do not provide standard thrombosis prophylaxis (absolute VTE risk is low despite relative increase) 1
• Do not treat MGUS with chemotherapy or immunotherapy unless there is a documented severe, disabling M-protein-related disorder with clear causal relationship 1, 2