4 Our understanding of the biology of clonal FLC in producing AKI in MM indicates that aggressive early reduction of FLC levels may be an important factor in promoting the recovery of kidney function. This concept is now being supported by clinical studies that clearly show a relationship between an early fall in sFLC levels and renal recovery [27, 28]. It is now clear that novel chemotherapeutic agents that are having a substantial impact on improving overall outcomes for patients with MM may be particularly important in the setting of MM and AKI, in part through early disease response. 4. Novel Agents and Outcomes of Patients with Renal Impairment There are two crucial considerations in the assessment of the utility of novel chemotherapeutic agents in MM and AKI: ﬁrstly, the eﬃcacy and safety of these agents in this setting and, secondly, the potential for these agents to reverse renal impairment. Whilst it is self-evident that an agent that rapidly reduces tumour burden should also result in an improvement in renal outcome, little work has been done to speciﬁcally address this question. This section will focus on the clinical utility in this setting of three novel agents used in both denovo and relapsed MM: Thalidomide, Bortezomib and Lenalidomide. If used in the setting of MM and AKI, these agents should probably be used in regimens that incorporated dexamethasone at cytotoxic doses; this is because they act synergistically and early work comparing vincristine and doxorubicin alone or with high- dose dexamethasone suggested that most of the plasma cell reduction was due to the high-dose dexamethasone [29, 30]. Table 1 shows those chemotherapy studies that have reported both the renal characteristics of the participants and their renal outcomes [31, 32]. 4.1. Thalidomide. Thalidomide was ﬁrst developed in the 1950s and was then used widely for numerous indications; however it was subsequently found to have devastating ter- atogenic eﬀects and clinical use ceased. It was subsequently postulated that the teratogenic limb defects caused by the drug were caused by inhibition of angiogenesis, and this prompted investigations into its potential as an antitumour agent [41]. In 1965 the use of Thalidomide was ﬁrst reported in a patient with MM, with a subsequent delay in disease progression. However, it was not until 1997 that patients were ﬁrst recruited into a clinical trial examining the eﬀect of Thalidomide in MM [42, 43]. Since then there have been numerous studies using the drug that have established its eﬃcacy in MM, and it is now recommended for use in patients with MM in a range of clinical settings [44]. Thalidomide is safe in renal impairment; it is not renally excreted (the primary route of clearance appears to be hepatic), and there is no dose adjustment needed for renal impairment or in patients undergoing dialysis [45, 46]. Tosi et al. considered the use of Thalidomide-containing regimens on the renal outcomes of patients. They enrolled 20 patients (two who were dialysis dependent) with a serum creatinine of ≥130 μmol/l and deﬁned renal recovery as Bone Marrow Research achieving a serum creatinine of <130 μmol/l [38]. All patients received Thalidomide at the same dose, in combination with a range of other agents. They reported a 67% renal recovery rate, although neither of the dialysis patients recovered independent renal function [38]. More recently Thalidomide use has been reported in larger numbers of patients who have been dialysis dependent at presentation; in a study of high cut oﬀ haemodialysis 14/19 patients received Thalidomide and recovered renal function [27]. 4.2. Lenalidomide. Lenalidomide is a derivative of Thalido- mide but has a diﬀerent side eﬀect proﬁle, it was introduced in 2004, and there has been subsequent interest in its role in the treatment of MM. There have been several large studies of Lenalidomide in relapsed or refractory MM that show excellent clinical outcomes with response rates (deﬁned variously as complete, near complete, partial, or very good partial responses) in the region of 50–60% [47– 50]. However there has been little work examining the role of Lenalidomide in patients with renal impairment, as traditionally trials excluded patients with renal impairment (to varying degrees), largely because early pharmacokinetic studies demonstrated that over 60% of the drug is excreted in the urine as a result of glomerular ﬁltration and tubular secretion [51]. Subsequently, Chen et al. carried out a multicentre, open label study to investigate the eﬀect of renal impairment and dialysis on the pharmacokinetics of Lenalidomide. They enrolled 30 patients, whom they stratiﬁed on the basis of renal function [52]. They conﬁrmed that Lenalidomide is predominantly excreted by the kidneys (80% of total drug clearance) and that a creatinine clearance of <50 mls/min is the threshold at which dose modiﬁcation is needed in respect of renal function [50]. For patients on dialysis there was a substantial decrease in trough concentrations postdialysis, indicating that an extradose is needed following dialysis treatment [50]. Dimopoulos et al. reported a subgroup analysis of the MM-009 and MM-010 trials; this analysis focused on the impact of renal impairment on safety and eﬃcacy of Lenalidomide and also on the renal outcomes of the cohort [40]. The degree of renal impairment was quantiﬁed by the calculation of creatinine clearance by the Cockcroft- Gault formula, and patients were divided into subgroups depending upon their renal function at baseline; these were mild or no renal impairment (CrCl >60 mls/min), moderate renal impairment (CrCl 30–60 mls/min), or severe renal impairment (CrCl <30 mls/min); however all patients had to have a baseline serum creatinine of <2.5 mg/dL [39]. Renal recovery was deﬁned as improvement in renal function as deﬁned by transition to a subgroup with better renal function. There was no diﬀerence in disease response rates between subgroups, and response was not inﬂuenced by the degree of renal impairment. In moderate or severe renal impairment, 72% of the patients had an improvement in their renal function [40]. While individuals with very severe renal failure were excluded and deﬁnitions for renal recovery are not precise, this work suggests that Lenalidomide is safe and eﬀective with a creatinine of up to 2.5 mg/dL and in this setting may improve renal function.