What is the treatment for cast nephropathy?

Treatment of Cast Nephropathy in Multiple Myeloma

The optimal treatment for cast nephropathy involves rapid initiation of bortezomib-based regimens combined with plasma exchange (PLEX) for patients with high free light chain levels (>150 mg/dL), targeting >50% reduction in free light chains by the end of cycle 1. 1

Pathophysiology and Diagnosis

• Cast nephropathy occurs when excess monoclonal free light chains (FLCs) interact with Tamm-Horsfall protein in the loop of Henle, forming obstructive casts that damage renal tubules 1
• Serum FLC concentrations >80-200 mg/dL significantly increase risk of acute kidney injury (AKI), with higher levels correlating with greater risk 1
• Diagnostic workup should include serum creatinine, electrolytes, estimated glomerular filtration rate (eGFR), 24-hour urine collection, serum electrophoresis, and serum free light chain measurement 1
• Renal biopsy may not be necessary if proteinuria predominantly consists of light chains with high serum FLC levels, but should be considered when the etiology is unclear 1

Initial Management

• Correct reversible factors first, including hypercalcemia, volume depletion, and hyperuricemia; discontinue nephrotoxic medications 1
• Stratify treatment approach based on involved FLC levels 1:
  • FLC <150 mg/dL: Consider kidney biopsy to confirm diagnosis
  • FLC >150 mg/dL and urine M-spike <200 mg/day or albuminuria >10%: Presumed light chain cast nephropathy (LCCN)
  • FLC >150 mg/dL (preferably with urine M-spike >200 mg/day and albuminuria <10%): Treat with combination therapy

Pharmacological Treatment

First-line Therapy

• Bortezomib-based regimens should be initiated immediately as they do not require dose adjustment in renal impairment and can be safely used in dialysis patients 1

• Recommended regimens include 1:

  • Daratumumab with bortezomib, cyclophosphamide, and dexamethasone (Dara-VCD)
  • Bortezomib, thalidomide, and dexamethasone (VTD)
  • Bortezomib and dexamethasone (VD)
  • Bortezomib, cyclophosphamide, and dexamethasone (VCD)

• Target >50% reduction of involved FLC from baseline and an FLC level <50 mg/dL by the end of cycle 1 1

Medication Considerations

• Bortezomib is preferred as it is not renally cleared or nephrotoxic 1
• Lenalidomide requires dose adjustment based on renal function 1:
  • CrCl >30 but ≤50 mL/min: 10 mg daily
  • CrCl <30 mL/min (not on dialysis): 15 mg every 48 hours
  • Dialysis patients: 5 mg daily after dialysis
• Pomalidomide 4 mg/day appears safe in all degrees of renal impairment, including dialysis 1
• Carfilzomib should be used with caution due to risk of renal toxicity and thrombotic microangiopathy 1

Extracorporeal Therapies

• For patients with FLC >150 mg/dL, daily plasma exchange (PLEX) should be added to chemotherapy 1
• PLEX can reduce serum FLC levels by 45-75% per session 1, 2
• High cut-off hemodialysis (HCO-HD) is an alternative to PLEX that can remove 60-75% of FLCs per session 1, 2
• The MYRE trial showed HCO dialysis resulted in significantly higher renal recovery at 6 months (56.4% vs 35.4%) and 12 months (60.9% vs 37.5%) compared to standard dialysis 1

Treatment Algorithm

1. Assess FLC levels and renal function:

   • If FLC <150 mg/dL: Consider kidney biopsy to confirm diagnosis 1
   • If FLC >150 mg/dL: Proceed with treatment 1

2. Initiate bortezomib-based therapy immediately 1

   • Preferred regimen: Daratumumab-VCD or VTD 1, 3

3. Add extracorporeal therapy if FLC >150 mg/dL:

   • Daily PLEX for first 10 days 1
   • Alternative: HCO-HD if available 1

4. Monitor response:

   • Target >50% reduction in FLC by end of cycle 1 1
   • Target FLC <50 mg/dL by end of cycle 1 1

Prognostic Factors and Outcomes

• Renal recovery is associated with improved overall survival 1
• Factors associated with renal recovery include 4:
  • Lower baseline creatinine
  • Achievement of very good partial response or better
  • ≥50% drop in serum FLC levels
• Early mortality remains higher in patients without kidney recovery despite treatment 1
• Approximately 40% of dialysis-dependent patients can become dialysis-independent with appropriate therapy 4

Pitfalls to Avoid

• Delaying initiation of bortezomib-based therapy can worsen outcomes 1
• Failing to correct reversible factors like hypercalcemia and volume depletion 1
• Inadequate monitoring of FLC levels during treatment 1
• Overlooking the need for thromboprophylaxis in patients on immunomodulatory drugs 3
• Not providing herpes zoster prophylaxis for patients on proteasome inhibitors 3