What is the optimal approach to evaluate and treat renal impairment in a patient with multiple myeloma, including hydration, hypercalcemia management, and selection of anti‑myeloma therapy safe for reduced kidney function?

Multiple Myeloma and Renal Impairment: Evaluation and Management

Immediate Recognition and Initial Actions

Treat multiple myeloma with renal impairment as a medical emergency requiring immediate bortezomib-based chemotherapy, aggressive hydration, and correction of metabolic abnormalities to prevent irreversible kidney damage and reduce early mortality. 1, 2

Diagnostic Workup

The essential diagnostic evaluation includes:

• Serum studies: creatinine, electrolytes, eGFR (using MDRD or CKD-EPI equation, not creatinine alone), serum protein electrophoresis (SPEP), serum immunofixation (SIFE), and serum free light chain (sFLC) assay with κ:λ ratio 1, 2, 3
• Urine studies: 24-hour urine collection with protein electrophoresis (UPEP) and immunofixation (UIFE) to quantify Bence Jones proteinuria 1, 4
• Renal impairment definition: eGFR <40 mL/min/1.73 m² or serum creatinine >2 mg/dL 5, 2

Renal biopsy is not routinely necessary if proteinuria consists predominantly of light chains with high serum sFLC levels and renal insufficiency is clearly attributable to myeloma. 1 However, perform renal biopsy when albuminuria >1 g/24h is present to exclude AL amyloidosis or monoclonal immunoglobulin deposition disease (MIDD). 3

Pathophysiology and Risk Stratification

The primary mechanism involves monoclonal free light chains (FLCs) causing:

• Cast nephropathy: FLCs bind Tamm-Horsfall protein in the loop of Henle, forming obstructive casts that rupture tubules and trigger inflammatory injury 5, 2
• Direct tubular toxicity: FLCs activate NFκB and MAPK pathways, generating hydrogen peroxide and inflammatory cytokines 5, 2
• Light chain deposition disease (LCDD) and AL amyloidosis: monoclonal light chains deposit in kidney tissue or form amyloid fibrils 5, 2

Critical risk thresholds: Serum FLC >50 mg/dL significantly increases acute kidney injury risk, with dramatic escalation when FLC exceeds 80-200 mg/dL. 5

Immediate Supportive Care

Initiate the following measures promptly:

• Aggressive hydration: Minimum 3 liters daily (or 2 L/m²/day) intravenous saline to achieve urine output of 100-150 mL/hour, reducing tubular light chain concentration 1, 2
• Monitor fluid status carefully to avoid hypervolemia, especially in oliguric renal failure 1
• Correct hypercalcemia: Use hydration plus bisphosphonates (pamidronate or zoledronic acid with dose adjustment for renal function), denosumab, and/or calcitonin 1
• Discontinue all nephrotoxic medications: NSAIDs, aminoglycosides, IV contrast agents, and nephrotoxic antibiotics 1, 2
• Correct hyperuricemia if present 1

Anti-Myeloma Therapy Selection

Bortezomib-based regimens are the standard of care for multiple myeloma with renal impairment and should be initiated immediately:

• Bortezomib/dexamethasone can be administered at full doses to patients with severe renal impairment and those on dialysis without dose adjustment and are not nephrotoxic 1, 5, 6
• Add a third agent that does not require dose adjustment: cyclophosphamide, thalidomide, anthracycline, or daratumumab 1
• Goal: Achieve ≥50-60% reduction in serum FLC by day 12 of treatment, with target serum FLC <50 mg/dL by end of cycle 1 5, 2

Alternative Agents and Dose Adjustments

• Thalidomide: Can be used at full dose without adjustment in renal impairment 1, 3
• Lenalidomide: Requires dose adjustment based on creatinine clearance; use with caution and monitor for thrombocytopenia 1, 3
• Pomalidomide: Full dose of 4 mg/day is safe in all categories of renal insufficiency, including dialysis patients 1

High-Dose Therapy Considerations

Autologous stem cell transplantation (ASCT) can be safely performed in patients with renal insufficiency, including those on dialysis:

• Use reduced-dose melphalan (≤140 mg/m²) in patients with severe renal impairment, which has outcomes comparable to standard-dose melphalan 1, 7, 3
• Consider ASCT for patients <65 years with chemotherapy-sensitive disease 7, 3

Dialysis and Extracorporeal Therapies

Initiate renal replacement therapy for severe acute kidney injury or end-stage renal disease:

• High-flux or high-cutoff hemodialysis membranes are recommended because routine hemodialysis cannot effectively remove serum free light chains 3
• Plasmapheresis is recommended for patients with hyperviscosity syndrome or cast nephropathy presenting with acute kidney injury, potentially improving dialysis independence 1, 3
• Limited evidence supports plasmapheresis or high-cutoff dialysis for mechanical removal of pathogenic light chains, but benefit is not definitively established 1

Monitoring and Prognostic Factors

Serial monitoring strategy:

• Use the same serum free light chain assay throughout treatment, as different assays are not mathematically convertible 4, 2
• Monitor for light chain escape (evolution to light chain-only disease), which increases nephrotoxic burden 2
• Confirm all responses per International Myeloma Working Group (IMWG) criteria 4

Factors associated with lower probability of renal recovery:

• Severe renal impairment at presentation 2, 6
• Failure to achieve 50-60% FLC reduction by day 12 5, 2
• Large amount of proteinuria at baseline 2, 6
• Extensive tubular atrophy and interstitial fibrosis on biopsy 2

Recovery of kidney function reverses the negative impact on overall survival, making aggressive early treatment essential. 2 Early mortality reaches 30% during the first 3 months in patients with renal failure. 7

Common Pitfalls to Avoid

• Do not delay chemotherapy while awaiting complete diagnostic workup if cast nephropathy is strongly suspected; early mortality is high 7, 3
• Do not use serum creatinine alone to assess renal function; always calculate eGFR using validated equations 2, 3
• Do not administer bisphosphonates at standard doses in renal impairment; use dose-adjusted pamidronate or zoledronic acid per guidelines 1
• Do not assume normal serum FLC levels exclude cast nephropathy; high urinary FLC excretion with abnormal κ:λ ratio can occur with deceptively normal serum levels due to rapid renal clearance 4