What is the treatment for multiple myeloma in a patient with impaired renal function and elevated bilirubin?

Treatment of Multiple Myeloma with Renal Impairment and Elevated Bilirubin

Initiate bortezomib-based triplet therapy immediately without dose adjustment, as bortezomib requires no modification for renal dysfunction or hepatic impairment and achieves renal response in 40-50% of patients with severe renal impairment. 1

Immediate First-Line Regimen Selection

Bortezomib plus dexamethasone forms the backbone of treatment for multiple myeloma with renal impairment, as bortezomib can be administered at full dose (1.3 mg/m²) without adjustment for renal function and does not accumulate in renal failure 2, 1, 3. This combination should be initiated immediately without waiting for complete diagnostic workup, as rapid reduction of light chain production is the single most important determinant of renal recovery 1.

Recommended Triplet Combinations:

• Bortezomib + dexamethasone + cyclophosphamide - cyclophosphamide requires no dose adjustment in renal impairment 1
• Bortezomib + dexamethasone + daratumumab - daratumumab is safe without renal dose modification 1
• Bortezomib + dexamethasone + thalidomide - thalidomide may be administered without dose adjustment 2, 3

Critical advantage: Bortezomib accelerates clearance of free light chains, with median time to renal improvement of 17-35 days 1.

Hepatic Impairment Considerations

For elevated bilirubin specifically, reduce melphalan dose to 100-140 mg/m² if bilirubin >1.5 times upper limit normal or AST/ALT >2.5 times upper limit normal 2. However, melphalan should be avoided entirely in the initial treatment phase for transplant-eligible patients, as it is stem cell toxic 2.

Bortezomib, thalidomide, and dexamethasone do not require dose adjustment for hepatic impairment, making them the preferred agents in this clinical scenario 2.

Critical Supportive Care Measures (Initiate Simultaneously)

• Administer IV fluids aggressively targeting urine output of 100-150 mL/hour to reduce tubular light chain concentration 1
• Discontinue all nephrotoxic medications immediately including NSAIDs, IV contrast, and aminoglycosides 1
• Treat hypercalcemia aggressively using hydration plus bisphosphonates, denosumab, or calcitonin 1
• Initiate antiviral prophylaxis (acyclovir) to prevent herpes zoster reactivation, which occurs in 6-11% of bortezomib-treated patients 4

Extracorporeal Light Chain Removal

If serum free light chain >150 mg/dL, add daily plasma exchange to chemotherapy, which reduces free light chains by 45-75% per session 1. High cut-off hemodialysis is an alternative that removes 60-75% of free light chains per session 1.

Agents to AVOID in Renal Impairment

Lenalidomide and pomalidomide require significant dose reduction based on creatinine clearance and will lead to severe toxicity (thrombocytopenia, treatment discontinuation) if used at standard doses 2, 1. While lenalidomide can reverse renal insufficiency when given at reduced doses, it should not be first-line in acute renal failure requiring rapid response 3.

Transplant Eligibility Assessment

Renal dysfunction is NOT an absolute contraindication to autologous stem cell transplantation 2. High-dose melphalan with autologous stem cell transplantation can be safely performed in patients with severe renal impairment, including dialysis-dependent patients, using reduced-dose melphalan (140 mg/m² instead of 200 mg/m²) with comparable outcomes 2, 1, 3.

Chronologic age and renal function should not be the sole criteria for transplant eligibility - biological age, performance status (Karnofsky >90%), and comorbidity indices (HCT-CI, R-MCI) should guide decisions 2.

Response Assessment and Continuation

Assess depth of response with each cycle 2. Bortezomib-based regimens achieve renal response in 68% of evaluable patients, with 54% achieving major renal response 5. Continue triplet therapy continuously rather than fixed-duration when using proteasome inhibitor or immunomodulatory drug-based regimens 2.

Common Pitfalls to Avoid

• Do NOT delay antimyeloma therapy while completing diagnostic workup - immediate treatment initiation is essential for renal recovery 1, 3
• Do NOT use standard lenalidomide dosing without renal adjustment 1
• Do NOT exclude patients from transplant based solely on renal function or age 2
• Do NOT use melphalan in initial therapy for transplant-eligible patients due to stem cell toxicity 2

Monitoring for Bortezomib Toxicity

Monitor for peripheral neuropathy (occurs in 28% of patients), thrombocytopenia (52% incidence), and hypotension (8% incidence) 4. Dose reduction should be performed for grade 3-4 thrombocytopenia, and treatment should be interrupted for grade 4 thrombocytopenia 2. Consider prophylactic granulocyte colony-stimulating factor if high risk for febrile neutropenia 2.