6 4.3. Bortezomib. Bortezomib is a proteasome inhibitor that is the ﬁrst in class, and it was synthesised in 1995 and was ﬁrst used in humans until 1999. On the basis of a large phase II clinical trial it was recommended by the FDA for use in relapsed/refractory MM [52]. It undergoes hepatic clearance with no renal clearance, and therefore no dose adjustments are recommended for patients with impaired renal function [53]. There have now been many large studies investigating the use of Bortezomib, initially in relapsed/refractory MM and more recently in de novo MM. A number of these have analysed the drug in impaired renal function, but few consider the renal outcomes of treated patients. The largest study of renal outcomes is a subgroup analysis of the VISTA study; this was a randomised phase III study comparing melphalan and prednisolone (MP) to melpha- lan, prednisolone, and Bortezomib (VMP). However the study excluded patients with a serum creatinine >2 mg/dL (176 μmol/l) so was not applicable to patients with severe AKI [31]. Despite this there was some indication of a beneﬁt in the Bortezomib group with better renal outcomes in the patients treated with the drug (44% renal recovery in treatment arm; 34% in the control arm; P = .001 the time to renal recovery was also faster in the VMP arm [31]. Ludwig et al. also considered the renal outcomes of patients treated with Bortezomib; in their study it was used as part of a BDD (Bortezomib, doxorubicin, and dexametha- sone) regimen; they enrolled 68 patients with light-chain- induced renal failure (deﬁning acute renal failure as a recent decline in glomerular ﬁltration rate (GFR) <50 mLs/min where other causes of renal failure had been clinically excluded) [37]. All patients received the same treatment regimen, though only 58 patients were available for analysis (seven died before the 2nd cycle, one discontinued after the 2nd cycle because of toxicity, one had progressive disease, and one had incomplete data) [36]. They reported complete response rates of 31% and an overall response rate of 62%, the renal outcomes of the cohort were also reported, and the median GFR increased from 20.5 mls/min (3.7– 49.9 mls/min) to 48.4 mls/min (6.7–135.5 mls/min) [37]. It is important to note that the number of patients with histological evidence of cast nephropathy was small; only six patients had had a renal biopsy (of whom two were not enrolled because of a diagnosis of amyloid), and the numbers requiring dialysis at the outset and the end were also not reported. Chanan-Khan et al. considered the use of Bortezomib in dialysis-dependent renal impairment. They retrospectively examined the records of 24 patients who were treated for MM and required dialysis at that time [33]. Of the 24 patients initially considered there was insuﬃcient data available in six, so results on 18 patients were available for analysis [33]. Of the remaining patients, 23% were independent of dialysis at analysis (one never actually needed dialysis, two became dialysis independent after a complete response (CR) and one after a minimal response (MR)) [33]. There was no increase in adverse events reported compared to patients without renal impairment [33]. As a result the authors concluded that Bortezomib was safe and eﬀective in patients requiring dialysis. Bone Marrow Research Encouraging evidence with Bortezomib and dexametha- sone in patients with renal impairment has led to an Interna- tional Myeloma Working Group recommendation that high- dose dexamethasone and Bortezomib are the recommended treatment for MM in patients with any degree of renal impairment [30]. Given the previously poor prognosis for patients with renal impairment and MM it is logical to focus on treatment with chemotherapy regimens that have a high response rate and where that response is associated with a rapid early decline in tumour (and therefore clonal FLC) load. Where Bortezomib is not available, usually as a consequence of cost, then Thalidomide should be used, again in combination with dexamethasone. In addition to an evolution in the chemotherapy options for patients with AKI and MM, there has been a recent reevaluation of the role of extracorporeal removal of sFLC. Whilst this may seem an attractive addition to therapies that are available, it is critical to understand that this adjunctive therapy will only add beneﬁt in the setting of eﬀective chemotherapy. Furthermore, any proposed use must be validated by properly designed prospective randomised controlled trials. 5. Extracorporeal LC Removal Strategies Plasma exchange has been variably used in clinical practice for the removal of FLC; however, there is no convincing evidence of beneﬁt compared to treatment regimens that do not include plasma exchange. More recently, novel protein permeable dialysis membranes have been developed, and their utility in FLC removal has attracted considerable interest. 5.1. Plasma Exchange. Plasma exchange (PE) involves ex- tracorporeal processing of a patient’s blood to remove pathogenic substances from the plasma; dependent on the clinical indication these can include autoantibodies, cryo- globulins, or other abnormal plasma proteins or immune complexes [54]. A single plasma exchange removes approx- imately 75% of the patient’s own plasma and the abnormal constituent in the plasma [54]. Therefore PE was considered as for the removal of remove FLCs in MM and was investigated in a series of studies. The largest and most robust study to date, reported by Clark et al., examined the outcomes of 104 patients (of whom 97 completed 6-month followup) with acute renal failure at the time of presentation of MM [55]. There were several design shortfalls in the study; these included the absence of histological diagnosis of cast nephropathy and the presence of dialysis dependency at randomisation in only 28% of those recruited [55]. The patients were randomised to receive either conventional therapy with the addition of between ﬁve and seven plasma exchanges or conventional therapy alone. The results showed that there was no beneﬁt derived from plasma exchange by a composite end point of death, dialysis dependence, or renal function at six months [55]. Other studies of PE have shown conﬂicting results, but these are all limited by small sample sizes and other methodological ﬂaws [56, 57]. Collectively, these studies