The role of thalidomide, bortezomib and lenalidomide in multiple myeloma patients presenting with renal impairment was evaluated in 133 consecutive newly diagnosed patients who were treated with a novel agent-based regimen. A significant improvement of renal function (⩾ renalPR (renal partial response)) was observed in 77% of patients treated with bortezomib, in 55% with thalidomide and in 43% with lenalidomide (P= 0.011). In multivariate analysis, bortezomib-based therapy was independently associated with a higher probability of renal response compared with thalidomide-or lenalidomide-based therapy. Other important variables included eGFR (estimated glomerular filtration rate)⩾ 30 ml/min, age⩽ 65 years and myeloma response. Patients treated with bortezomib achieved at least renalPR in a median of 1.34 months vs 2.7 months for thalidomide and> 6 months for lenalidomide-treated patients (P= 0.028). In multivariate analysis bortezomib-based therapy, higher doses of dexamethasone (⩾ 160 mg during the first month of treatment), an eGFR⩾ 30 ml/min and age⩽ 65 years were independently associated with shorter time to renal response. In conclusion, bortezomib-based therapies may be more appropriate for the initial management of patients with myeloma-related renal failure; however, thalidomide and lenalidomide are also associated with significant probability of improvement of their renal function.