High-Cutoff Hemodialysis Therapy for Patients with Light Chain Cast Nephropathy and AKI Requiring Dialysis: PRO

Advances in myeloma-directed therapy in the recent decades have improved the median survival from 3 to 8–10 years.1 Although newer agents have convincingly improved multiple myeloma outcomes, all drugs take days to weeks to begin lowering serum free light chain (sFLC) levels. Clinical data indicate that high cutoff hemodialysis (HCO HD) rapidly reduces sFLC levels, and this rapid reduction is associated with better renal outcomes.2,3 Patients with cast nephropathy are more likely to recover renal function if there is a 50% decrease in sFLC concentrations.4 Intuitively then, HCO HD should acutely lower sFLC levels in the interval it takes for the antimyeloma drugs to have a therapeutic effect and would thus be expected to improve dialysis independence. The results of the Studies in Patients With Multiple Myeloma and Renal Failure Due to Myeloma Cast Nephropathy (MYRE) and European Trial of Free Light Chain Removal by Extended Haemodialysis in Cast Nephropathy (EuLITE) trials were a surprise and disappointment to clinicians who had eagerly anticipated confirmation that HCO HD would allow patients with multiple myeloma and AKI requiring HD to achieve dialysis independence. These two randomized, prospective, controlled clinical trials compared HCOHDwith standard HD among patients with newly diagnosed biopsy-proven myeloma cast nephropathy. Earlier case series and retrospective studies which had shown that up to 80% of patients treated with HCO HD achieved dialysis independence compared with historical data showing that 30% of those treated with standard HD achieved this end point. By dissecting the methodology of MYRE and EuLite (Table 1), we aim to demonstrate that these studies did not definitively rule out a role for HCOHD in those who present with dialysis requiring AKI. Observed outcomes in these trials were limited by insufficient patient recruitment, imprecise randomization and inattention, and timely intervention for HCO HD-related complications. The primary end point in MYRE was dialysis independence at 3 months. The study was powered to detect a dialysis independence rate of 60% in the HCO HD group compared with the HD group. This was based on previous data that showed that hemodialysis independence rates as high as 60% had been achieved with HCO HD.2,5–7 A closer inspection of these preceding reports on which the MYRE end points were based indicate that renal outcomes had already significantly improved with newer myeloma-directed therapy alone, and so MYRE may not have been appropriately powered to detect the additional effects fromHCOHD. Before the introduction of proteosome inhibitors in 2005 and thalidomide and lenalidomide in 2006, fewer than 25% of patients with biopsy-proven cast nephropathy and dialysis-dependent renal failure achieved dialysis independence.2 Bortezomib-based triplet therapy without HCO HD has been reported to achieve dialysis independence in 48% of patients.8 In EuLite, all patients received triplet chemotherapy and 51% of the HD group achieved dialysis independence versus 25% as expected in the statistical plan. In the study of HCO HD versus retrospective HD control patients by Gerth et al.,5 76.2% of patients in the HCO HD group were treated with bortezomib, thalidomide, or lenalidomide compared with only 25.5% of patients in the conventional HD arm. The observation in this cohort that 64.3% of patients in the HCO HD group achieved dialysis independence compared with 26.4% in the HD group may have been in part due to the use of newer and more effective chemotherapy. In MYRE, hematologic response at 3 months was significantly different between the HCO HD and HD groups (89.1% versus 62.5%, P 0.003). Previous studies have shown that those who achieve earlier hematologic response have better renal outcomes. Thus, the HCO HD group would have been expected to have better renal outcomes on the basis of better hematologic response at 3 months. In addition to being underpowered for the primary end point, MYREmay not have allowed sufficient time to achieve the primary end point at the prespecified interval of 3 months.