Management of myeloma-associated renal dysfunction in the era of novel therapies

Abstract

Multiple myeloma (MM) is a plasma cell neoplasm often associated with renal impairment (RI), with myeloma cast nephropathy recognized as the most common cause. While RI is present in over 50% of MM patients at some point in their disease course, it is associated with higher tumor burden, more aggressive disease, diminished quality of life, development of complications and increased mortality. The introduction of novel therapies, including bortezomib, lenalidomide and thalidomide, has revolutionized the management of MM. They are now considered first-line therapies in induction, maintenance and salvage therapy for MM. In addition to their anti-MM effect, they can improve outcome in patients with RI, especially when combined, and bortezomib with dexamethasone may have a renal protective effect. This review focuses on the use of these agents in patients with MM and RI, and evaluates their efficacy, safety, need for dose adjustment and impact on RI.

Keywords::

• bortezomib
• dexamethasone
• lenalidomide
• multiple myeloma
• renal dysfunction
• thalidomide

Medscape: Continuing Medical Education Online

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Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/experthematology; (4) view/print certificate.

Release date: January 23, 2012; Expiration date: January 23, 2013

Learning objectives

Upon completion of this activity, participants will be able to:

• • Analyze the diagnostic process of MM

• • Distinguish the predominant renal histologic subtype in cases of RI associated with MM

• • Analyze treatment options for MM in the setting of RI

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Editorial Director, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Mahmoud R Gaballa, MD

Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA, USA.

Disclosure: Mahmoud R Gaballa has disclosed no relevant financial relationships.

Jacob L Laubach, MD

Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Disclosure: Jacob L Laubach has disclosed no relevant financial relationships.

Robert L Schlossman, MD

Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Disclosure: Robert L Schlossman has disclosed no relevant financial relationships.

Katherine Redman

Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Disclosure: Katherine Redman has disclosed no relevant financial relationships.

Kimberly Noonan, NP

Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Disclosure: Kimberly Noonan has disclosed no relevant financial relationships.

Constantine S Mitsiades, MD, PhD

Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Disclosure: Constantine S Mitsiades has disclosed the following relevant financial relationships: he has received funding for clinical research from: Amgen Inc.; AVEO Pharma; Genzyme Corporation; and Johnson & Johnson Pharmaceutical Research & Development, LLC. He has served as a consultant or received honoraria from: Bristol-Myers Squibb Company; Celgene Corporation; Centocor Research & Development, Inc.; Merck & Co., Inc.; Millennium Pharmaceuticals, Inc.; and Novartis Pharmaceuticals Corporation.

Irene M Ghobrial, MD

Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Disclosure: Irene M Ghobrial has disclosed the following relevant financial relatioships: she has served on advisory boards for: Bristol-Myers Squibb Company; Genzyme Corporation; Millennium Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; and Onyx Pharmaceuticals, Inc.

Nikhil Munshi, MD

Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Disclosure: Nikhil Munshi has disclosed the following relevant financial relationships: he has served as a consultant for: Celgene Corporation; Millennium Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; and Onyx Pharmaceuticals, Inc.

Kenneth C Anderson, MD

Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Disclosure: Kenneth C Anderson has disclosed the following relevant financial relationships: he has served on advisory boards for: Bristol-Myers Squibb Company; Celgene Corporation; Merck & Co. Inc.; Millennium Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; and Onyx Pharmaceuticals, Inc.

Paul G Richardson, MD

Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Disclosure: Paul G Richardson has disclosed the following relevant financial relationships: he has served on advisory boards for: Bristol-Myers Squibb Company; Celgene Corporation; Johnson & Johnson Pharmaceutical Research & Development, LLC; Millennium Pharmaceuticals, Inc.; and Novartis Pharmaceuticals Corporation.

Figure 1. A simplified diagram illustrating the development of myeloma cast nephropathy.

Pathogenesis includes: (1) serum-free light chains produced in excess, overwhelming absorption mechanisms in the proximal tubule; (2) Bence–Jones proteins develop as a consequence of light chains entering the distal tubules; (3) Tamm–Horsfall proteins interact with Bence–Jones proteins in the distal tubule; (4) tubular cast formation and obstruction develop as the end product, with subsequent ‘myeloma cast nephropathy’ [23].

Figure 2. A simplified diagram illustrating clinical manifestations and complications of multiple myeloma related to excess production of free light chains.

Excess production of free light chains is responsible for tubular cast formation and obstruction (myeloma cast nephropathy), induction of proinflammatory cytokines and consequent direct tubular cell injury, functional impairment (Fanconi syndrome) and a state of chronic inflammation through interference with neutrophil apoptosis. In addition, deposition of fragments of free light chains causes amyloidosis in several organs, including the liver, small intestine and heart, with subsequent end-organ injury, resulting in hepatomegaly, constipation and cardiomyopathy, respectively [2,11,20–23,25,26].

Figure 3. Flowchart illustrating the main pathogenetic molecular mechanisms involved within the renal parenchyma, with endocytosis of free light chains by proximal tubular cells as an important contributor, and bortezomib is shown targeting key steps essential for MM survival.

While the pathogenesis of MM is complex, bortezomib as a multifaceted proteosome inhibitor targets pivotal steps in the chain of pathogenetic steps involved in MM cell survival. It was recently discovered that the pathogenesis inside the renal parenchyma might be potentiated by the endocytosis of free light chains by proximal tubular cells. Key factors targeted by bortezomib include NF-κB, IL-6 and VEGF [27,57–61].

BM: Bone marrow; BMEC: Bone marrow endothelial cell; MM: Multiple myeloma.

Figure 4. A simplified diagram illustrating the multiple myeloma cell interactions and the various mechanisms of action of thalidomide and bortezomib.

Multiple myeloma (MM) cells interact with surrounding osteoclasts, osteoblasts, endothelial cells and bone marrow (BM) stromal cells, which is crucial for their survival and growth. Immunomodulators and proteosome inhibitors used in current anti-MM regimens, including bortezomib and thalidomide, function by targeting those interactions and signaling pathways [51–54,126–129]. Bortezomib’s mechanism of action on: (1) MM cell: bortezomib disrupts IL-6 and NF-κB; (2) Endothelial cell: bortezomib inhibits VEGF, angiogenesis and cell migration; (3) BM stromal cell: bortezomib reduces NF-κB-dependent secretion of cytokines; (4) Osteoblast: bortezomib-dependent elevation of Runx2 activity mediates osteoblast differentiation and so induces osteoblast activation [55]. Thalidomide’s mechanism of action on: (A) MM cell: thalidomide causes MM cell growth arrest and apoptosis, as well as natural killer cell-mediated MM cell death via IL-2 and IFN-γ; (B) Osteoclast: thalidomide inhibits osteoclast-activating factors; (C) BM stromal cell: thalidomide inhibits adhesion of MM cells to BM stromal cells, inhibits IL-6 and TNF-α, and decreases VEGF and FGF, decreasing angiogenesis [51–54,127–130].

Multiple myeloma (MM) is a clonal B-cell malignancy of the bone marrow (BM) associated with a variety of clinical manifestations, including hypercalcemia, renal impairment (RI), recurrent infection, anemia and bone disease [1]. Reports indicate that MM patients with RI suffer more frequently from severe anemia, hypercalcemia, Bence–Jones proteinuria and skeletal abnormalities [2]. The presence of such complications, and in particular RI, impacts adversely on quality of life, as well as survival, and is an important determinant of treatment choice [3].

Although MM remains an incurable disease, the introduction of new drugs over the past decade has significantly improved patient outcome, extending the average life expectancy by between 2 and 3 years, from an average of 3–5 years to at least 5–7 years [4,5].

RI represents a serious manifestation of progressive MM, and usually indicates substantial tumor burden and more aggressive disease, resulting in a higher early mortality, approaching 28% in some series [6]. The pathophysiology of renal disease in MM is complex and is typically attributed to a variety of toxic effects on the kidney. This review includes an overview of MM and then focuses specifically on RI in MM, its causes and the manner in which it is best managed in the context of novel therapies.

Epidemiology

MM comprises approximately 1% of all malignancies and 13% of hematological malignancies [7], with an annual incidence of approximately 20,000 cases per year in the USA [8]. It is the second most common hematological malignancy after non-Hodgkin’s lymphoma [9]. RI is present in approximately 20% of MM patients at the time of diagnosis (defined as a serum creatinine level of 177 µmol/l [2 mg/dl] or higher) and over 50% of patients at some stage in the course of their disease [10,11]. Importantly, the risk of renal injury in MM is substantially increased in MM patients with light-chain paraproteinemias, especially λ light-chain disease [2,3,10,12].

Clinical presentation

The presentation of MM can be insidious and is often detected in asymptomatic patients through routine blood testing, although symptoms are present in the majority of patients by the time of diagnosis. A retrospective study of 1027 patients with MM identified the most common presenting symptoms and signs, which included elevated serum creatinine (in 48% of patients), anemia (73%), bone pain (58%), fatigue (32%), hypercalcemia (13%), unexplained weight loss (24%), paresthesias (at least 5%), hepatomegaly (4%), splenomegaly (1%), lymphadenopathy (1%) and fever (0.7%) [1]. In addition, extramedullary plasmacytomas are identified in at least 7% of MM patients at the time of diagnosis, and an increasing proportion of MM patients will develop extramedullary plasmacytomas later in the course of their disease [13].

Patients with RI and monoclonal immunoglobulin (Ig) deposition disease often suffer from hypertension, while conversely those with amyloid deposition may suffer from hypotension [3]. Symptoms suggestive of systemic amyloidosis or monoclonal Ig deposition include congestive heart failure, cardiac arrhythmias, hepatomegaly, portal hypertension and periorbital purpura [3,14]. Furthermore, gastrointestinal bleeding and high serum alkaline phosphatase suggest amyloid deposition affecting the GI tract and liver, respectively [3].

Diagnosis & evaluation

Diagnostic evaluation for patients with suspected MM includes obtaining the basic metabolic panel, serum β₂-microglobulin level, complete blood count, serum and urine protein electrophoresis, serum free light chains (SFLCs) and assessment of end-organ function (specifically to assess for RI, anemia, hypercalcemia and bone disease) [3,15]. Detection of serum or urine monoclonal Ig is critical in the diagnosis of MM [3]. Importantly, those with RI secondary to Ig deposition with clonal plasma cells in their BM are identified as having symptomatic MM, regardless of other features, including the extent of the monoclonal protein or the percentage of BM plasma cells [3,15]. Kidney biopsy may be considered in selected cases, including patients with significant nonselective proteinuria and predominant albuminuria, to assess for amyloidosis and monoclonal Ig deposition disease [16].

BM aspiration and biopsy are performed to assess the extent of plasma cell involvement and evaluate for cytogenetic abnormalities. The evaluation of cytogenetic abnormalities includes both conventional metaphase chromosome analysis and FISH, targeting recurrent genetic aberrations such as deletion (del) 13, del 17, translocation (t) (4;14), t(11;14) and t(14;16) [15]. Bone involvement is assessed using skeletal surveys, MRI and/or PET–computed tomography.

The SFLC assay is an important part of the diagnostic evaluation, particularly in patients with oligosecretory and nonsecretory disease. However, the use of SFLC assays in patients with RI can be challenging, as the clearance of all SFLCs decreases with decreasing glomerular filtration rate (GFR) [17]. This leads to an increase in their half-life and an abnormal SFLC ratio, as reported in a recent study by Hutchison and colleagues [17], which suggested that the reference range of SFLC ratio should be 0.37–3.1 (rather than the standard 0.26–1.65) in patients with RI requiring dialysis. Use of this modified range increases the specificity from 93 to 99% with no loss of sensitivity [17]. Measurement of SFLC levels together with the κ/λ ratio with these extended reference ranges appears to aid the diagnosis of MM in patients with RI, and decreases the number of false-positive results, therefore allowing for rapid diagnosis and early initiation of treatment [17]. Interestingly, it has also been noted that when cast nephropathy is the cause of RI, the SFLC levels tend to be much higher in comparison to other renal pathologies [17], with other studies suggesting that high SFLC levels are associated with an elevated risk of renal injury in patients with newly diagnosed MM [18]. Furthermore, recently developed nephelometric SFLC immunoassays have the ability to detect both monomers and dimers of κ and λ at concentrations less than 2–4 mg/l, without confounding the results from intact Ig, which may further refine the ability to evaluate tumor burden [19].

Pathophysiologic mechanisms of renal injury in MM

The pathophysiology of RI in MM is complex and is associated with various underlying processes. Renal injury in the majority of cases is attributed to tubulointersitial damage, where ‘myeloma kidney’ results as a direct consequence of the high SFLC levels [11]. Other causes include dehydration, hypercalcemia, hyperuricemia, amyloid deposition, infections, concomitant exposure to nephrotoxic medications, such as NSAIDs, plasma cell infiltration and contrast injury [2,11].

SFLCs are primarily metabolized by the kidneys through glomerular filtration, followed by endocytosis in the proximal tubule and degradation within lysosomes [20–22]. When Ig light chains are produced in excess, as in MM, absorption mechanisms are overwhelmed in the proximal tubule. Thus, light chains enter the distal tubules, with the subsequent appearance of Bence–Jones protein in urine. Bence–Jones protein then interacts with Tamm–Horsfall protein in the distal tubule, resulting in tubular cast formation and obstruction [23]. This obstructive cast formation in the tubules with light chains and other MM proteins is classically referred to as myeloma kidney or ‘myeloma cast nephropathy’ (see Figure 1).

In addition, excess SFLC can cause direct injury to proximal tubular cells [11], through the induction of proinflammatory cytokines (including IL-6, IL-8 and TNF) [24] and other pathways leading to tubular cell death [25]. They can also cause functional impairment, leading to Fanconi syndrome, which is characterized by proximal tubular damage in which glucose, amino acids, uric acid, phosphate and bicarbonate fail to be reabsorbed [26]. Light chains also interfere with apoptosis of neutrophils, contributing to a state of chronic inflammation [23]. Thus, urinary free light chains (FLCs) tend to cause renal injury through intratubular cast formation and direct tubular toxicity as well as inflammation (see Figure 2).

Most recently, it was found that endocytosis of light chains by proximal tubular cells might be a significant contributor to the chain of pathogenetic events, with subsequent activation of c-Src and NF-κB supporting MM cell survival (see Figure 3) [27]. Moreover, deposition of monoclonal light chains can occur in several organs, including the kidney, heart, liver and small intestine, leading to the development of amyloid light chain (AL) amyloidosis or light chain deposition disease (LCDD) [28]. LCDD is defined as the deposition of monoclonal amorphous light chains in multiple organs, which do not exhibit a fibrillar structure when examined ultrastructurally [28]. LCDD pathogenesis is similar to that of AL amyloidosis, except that light chain fragments do not have the required biochemical characteristics to form amyloid fibrils [28]. Notably, BM examination in patients with AL amyloidosis typically shows monoclonal plasma cells with overexpression of either κ or λ light chains with positive staining for CD138 and CD32B [29].

Hypercalcemia usually results from enhanced bone resorption by activated osteoclasts, which may be further enhanced by the increased secretion of bone-resorbing cytokines, such as lymphotoxin and IL-6 [30,31]. Hypercalcemia contributes to renal injury by causing vasoconstriction of the renal vessels, enhancing calcium deposition inside the renal tubules and augmenting the toxicity of filtered light chains [32,33].

Hyperuricemia results from the accelerated catabolism of purine nucleic acids to hypoxanthine and xanthine and then to uric acid via the enzyme xanthine oxidase. Being poorly soluble in water, excess uric acid can in turn lead to renal injury via crystal precipitation and deposition in the renal tubules [34,35].

Classification of renal disease with MM

Renal disease with MM can be classified either according to histological type or the primary site of injury (see Box 1). Several studies evaluating the histological characteristics of renal biopsy in MM patients with RI identified myeloma cast nephropathy as the major histological type, reaching as high as 60% of patients in some studies [2,36]. Other histological types include tubulointerstitial nephritis, amyloidosis, acute tubular necrosis, nodular glomerulosclerosis and plasma cell infiltration (see Table 1) [2,36]. In addition, several studies have confirmed myeloma cast nephropathy as the predominant cause of dialysis-dependent RI in patients with MM [37–39]. Similarly, nephrotic syndrome occurs in approximately 7% of individuals with RI [2], and its presence usually suggests the presence of either amyloidosis [40] or LCDD as the underlying etiology [41]. Moreover, studies have identified precipitating factors of RI in MM patients as dehydration (19–33%), hypercalcemia (24–31%), nephrotoxic medications (15–16%), sepsis (9–23%), recent surgical procedures (5%) and contrast agents (2%) [2,42]. Myeloma cast nephropathy represents the hallmark insult to the kidneys in the majority of patients.

Tumor burden & effect on prognosis

Early mortality in MM patients is typically attributable to the mutual effect of disease activity along with concurrent complications, including RI. A series of large multicenter trials assessing 3107 patients identified RI in 28% of patients who experienced early death (defined as death occurring within 60 days of diagnosis) [6]. Early mortality could not otherwise be predicted using traditional prognostic characteristics, and thus it is recommended that all patients with RI be considered at high risk during induction therapy [6].

Indeed, a recently published study of 198 patients with MM and RI has identified estimated (e)GFR <30 (or eGFR <50 in individuals >59 years of age) and β₂-microglobulin as very important prognostic factors that affect overall survival (OS), and a novel MM risk-stratification score predicting survival was developed [43]. Notably, the reversal of MM-associated RI is a key element of prognosis and often precedes the response to antimyeloma therapy as a predictor of improved survival [3,44].

Management

Management of MM begins with general measures, including intravascular volume repletion, hemodynamic support, controlling hypercalcemia (using intravenous saline, steroids and bisphosphonate therapy, dose adjusted according to renal function) and treating hyperuricemia (using allopurinol, rasburicase and/or hemodialysis) [45,46]. Certain medications should be avoided, including loop diuretics, NSAIDs and renin–angiotensin inhibitors. These standard management principles are often successful in correcting moderate degrees of RI [3].

The treatment landscape for MM has changed substantially over the past decade with the introduction of bortezomib, lenalidomide and thalidomide. Combinations of these agents with dexamethasone are now considered as options for first-line therapy for induction, maintenance and salvage therapy [47,48], with autologous stem cell transplantation (SCT) remaining a cornerstone of therapy for appropriately selected patients. Choice of treatment is guided by a number of factors, including age, comorbid conditions, eligibility for SCT and risk assessment, as determined by both International Staging System stage and cytogenetic findings [49,50]. Recent accumulating evidence suggests that therapies with novel agents are changing the perception that RI per se is an ominous sign in the course of MM [48]. We will review the use of these drugs both as single agents and in different combinations in this setting, and specifically in terms of efficacy, safety, potential dose adjustments and their impact on the reversibility of RI.

Bortezomib

Bortezomib is a 26S proteosome inhibitor that acts through various pathways (see Figure 4), including the disruption of IL-6 signaling [51–54]. It enhances bone integrity by inducing osteogenic differentiation and through interactions with FGF2 and the PDZ-binding motif (TAZ), with increased expression of transcription factor Runx2 [55]. It also protects renal tubular cells through its effect on the NF-κB pathway, leading to antiapoptotic gene expression [56]. As illustrated in Figure 3, MM pathogenesis within the renal parenchyma is contributed to by SFLC endocytosis through the proximal tubular cells, and bortezomib, as a multifaceted proteosome inhibitor, targets key factors involved, including NF-κB, IL-6 and VEGF [27,57–61]. Interestingly, bortezomib also reduces the serum level of cystatin-C, a marker of RI [62], especially in those with relapsed MM [63]. Bortezomib is hepatically metabolized and its clearance is therefore independent of renal function. Dose adjustment is therefore not required in the setting of RI, and this together with its other properties makes it an ideal drug for use in patients with RI [64].

The APEX Phase III study was the first large randomized controlled trial to show that bortezomib is more effective than high-dose dexamethasone in delaying disease progression in patients with relapsed MM [65]. It included 669 patients with relapsed MM who were randomized to receive either bortezomib or high-dose dexamethasone, with results from this pivotal study leading to full US FDA approval for the use of bortezomib in the treatment of patients with relapsed disease. Patients treated with bortezomib achieved higher combined complete and partial response rates compared with high-dose dexamethasone (38 vs 18%; p < 0.001), significantly longer time to progression (6.22 vs 3.49 months; hazard ratio [HR]: 0.55; p < 0.001) and longer 1-year OS (80 vs 66%; p = 0.003) [65]. Moreover, data from an updated analysis of the APEX study showed a median OS benefit of bortezomib over high-dose dexamethasone despite crossover (29.8 vs 23.7 months; p = 0.027) [66], while results from the study also demonstrated that using bortezomib in those with RI was not associated with increased toxicity in comparison to those with normal renal function [67,68]. In fact, rates of early discontinuation of treatment owing to serious side effects were higher with high-dose dexamethasone than with bortezomib [67,68]. Response rate, time to progression, OS and safety were not affected by renal function, with OS significantly longer in those treated with bortezomib versus high-dose dexamethasone, suggesting that bortezomib was more effective in overcoming the detrimental effect of RI in MM [68].

The benefit of bortezomib in MM patients with RI was also shown by a retrospective analysis involving 117 patients with MM and RI, including 14 who received dialysis. Overall, 41% of patients experienced reversal of RI after approximately 2.3 months of bortezomib treatment [69], with three patients (21%) in the dialysis group coming off dialysis after 1–4 months. In terms of anti-MM effect, a partial response (PR) was observed in 73% of patients, complete response (CR) in 19% and near-CR in 8% [69], with improvement in renal function seen among patients with different stages of RI and a 2-year OS estimated at approximately 50% [69]. To assess bortezomib in the dialysis-dependent population, a retrospective analysis in 24 MM patients requiring dialysis showed that bortezomib as a single agent or in combination achieved an overall response rate of 75%, with 30% CR and near-CR. Notably, one patient was spared dialysis while three others became independent of dialysis [70]. In another study of 20 patients with RI treated with bortezomib-based therapy, reversal of RI was evident in 40% of patients, with 85% of patients showing some decrease in serum creatinine [71].

Similarly, bortezomib plus dexamethasone in 18 MM patients with RI achieved reversal of nephropathy in approximately 39% of patients, in addition to about 33% of patients showing 50% reduction in serum creatinine [72]. Interestingly, all patients with a serum creatinine level <4 mg/dl normalized their renal function, in contrast to only one patient among those with serum creatinine >4 mg/dl, suggesting creatinine level as an independent prognostic factor of renal recovery in this setting [72]. In terms of MM response, an overall response rate of approximately 83% was reported, including 50% CR, approximately 17% very good partial response (VGPR), with a correlation between MM response and recovery of renal function seen in 13 out of 15 patients [72]. The use of bortezomib in other combinations, particularly the bortezomib–doxorubicin–dexamethasone regimen, has been shown to be highly effective in MM patients with light chain-induced RI [73], with responses in 72% of patients overall, including CR or near-CR in 38% and VGPR in 15%, as well as improvement in renal function in 62% of patients [73].

Finally, the use of bortezomib in newly diagnosed MM patients with RI was evaluated as part of the international Phase III VISTA study, comprising bortezomib, melphalan and prednisone (VMP) versus melphalan and prednisone (MP), with the results outlined in Table 2[74].

Results overall showed that VMP is superior to MP in terms of response rates and renal reversibility, and outcomes were similar to those with normal renal function [74]. Although adverse events (AEs) occurred more frequently with VMP in those with RI, the treatment duration, rates of drug discontinuation and dose reduction owing to AEs were the same in both individuals with RI and those with normal renal function. Peripheral neuropathy rates were not increased in those with impaired renal function. While it is not ideal to use melphalan in patients with severe RI because of the need for dose reduction and potentially increased toxicity, with other combinations excluding melphalan generally recommended, VMP proved to be superior to MP, with unaltered efficacy in patients with moderate RI [74].

In summary, these results correlate with data from several other studies [11,75–77] showing that bortezomib-based regimens are effective and safe in patients with RI, and lead to the reversal of RI in a significant number of cases, with bortezomib also having no detrimental effect on stem cell harvesting and engraftment in this setting [78].

Lenalidomide

Lenalidomide is an immunomodulatory drug (IMiD) with pleiotropic anti-MM effects, including inhibition of proinflammatory cytokines, including TNF-α, downregulation of IL-6 and NF-κB, enhancement of natural killer cell activity, inhibition of angiogenesis and induction of apoptosis [79–82]. Lenalidomide is predominantly excreted in urine (84% unchanged), and a single hemodialysis session can remove 31% of the dose [83]. As RI progresses, lenalidomide’s clearance decreases to 69, 38 and 43% in those with mild (creatinine clearance [CrCl] >50 ml/min), moderate (CrCl <50 ml/min) and severe (CrCl <30 ml/min) RI, respectively [83]. There is a 240 and 360% rise in the area under the curve of lenalidomide in patients with severe RI and end-stage renal failure, respectively [83]. Therefore, lenalidomide dose adjustment is recommended for those with moderate and severe RI [83].

The potent anti-MM activity of lenalidomide in conjunction with dexamethasone was demonstrated in two pivotal Phase III studies, where the combination proved superior to dexamethasone alone in terms of overall response (60–61% vs 19.9–24%; p < 0.001), CR (14.1–15.9% vs 0.6–3.4%; p < 0.001) time to progression (11.1–11.3 vs 4.7 months; p < 0.001), and OS (29.6 vs 20.2 months; p < 0.001) [84,85]. Despite the fact that it is renally cleared, lenalidomide can be used in patients with RI (defined as CrCl <50 ml/min). This was demonstrated by a recent study involving 50 patients, >50% of whom were refractory to thalidomide and/or bortezomib, and 24% of whom had RI. The overall response rate was 58% in patients with RI, versus 60.5% in those with normal renal function [86]. RI did not affect the response of MM to therapy, as reflected by a median progression-free survival of 9 months and OS of 16 months in all patients, regardless of renal function [86]. As for the renal response in the RI group (16 patients), three (25%) achieved complete recovery, with two more (16%) showing some improvement. Importantly, when lenalidomide was dose-adjusted according to the CrCl, the incidence of AEs was also comparable in those with impaired renal function versus those with normal renal function [86].

Given that earlier trials of lenalidomide excluded patients with serum creatinine levels >221 mol/l (creatinine >2.5 mg/dl) [87], these results are useful, although it is important to note that certain toxicities associated with lenalidomide (especially myelosuppression) are more likely to occur if the drug is used in patients with RI [88–90]. Furthermore, there have been isolated reports of progressive azotemia occurring during lenalidomide therapy in patients with MM and RI, so it is important to closely monitor renal function when lenalidomide is administered in this setting [89]. In aggregate, lenalidomide is highly effective and can be used in MM with RI if necessary, with dose adjustment to avoid toxicity.

Thalidomide

Like lenalidomide, thalidomide is an IMiD and exerts its anti-tumor effect by acting on TNF-α [91], natural killer cells, IL-2, IFN-γ, enhancement of cell-mediated immunity and modulating cellular adhesion molecules (see Figure 4) [92–95]. Thalidomide undergoes non-enzymatic hydrolysis in plasma, forming multiple metabolites, with <1% urine excretion of unchanged drug [96]. The exact metabolic route and fate of thalidomide is not yet understood [96], and it does not appear to be hepatically metabolized to any large extent [96].

Thalidomide, as a single agent or in combination, has proven to be useful in advanced and/or refractory MM, with a response rate ranging from 30 to 60% of patients [97–100]. In a study of 20 patients with RI (defined as serum creatinine >130 mmol/l) and advanced relapsed/refractory MM, in which three patients requiring chronic hemodialysis were included, the efficacy of thalidomide was evaluated. Eight patients received thalidomide as a single agent, while 12 patients received thalidomide plus dexamethasone. A >50% decrease in serum or urine M-component was observed in nine patients (45%), seven of whom were treated with thalidomide and dexamethasone and two with thalidomide alone. Six additional patients achieved a minimal response (defined as >25% paraprotein decrease). The overall response rate was reported as 75%, while improvement of renal function was observed in 12 out of 15 responding patients [50]. Two patients who were dependent on chronic hemodialysis showed a decrease in serum creatinine, and the side effects of thalidomide as a single agent or in combination did not appear to be affected by RI [50]. Studies suggest that serum levels of thalidomide are not affected by either RI or by hemodialysis [101]. It is thus considered safe to administer thalidomide in patients with advanced MM and RI without requiring dose modification, although in general dose reduction is considered prudent [50,101].

Treating patients with MM and associated light chain-associated amyloidosis resulting in RI is challenging, and thalidomide has also been assessed in this patient population. In a study of 16 patients with MM and amyloidosis, of whom 14 had RI, a response was seen in 25% of patients [102], which is similar to patients with other types of MM. However, AEs were frequent, as reflected by 25% of patients requiring dose reduction and another 25% discontinuing treatment altogether [102].

Recently, the use of thalidomide plus dexamethasone as induction therapy prior to autologous SCT was reported in 31 patients with MM and RI [103], resulting in PR or better of 74%, including 26% VGPR, which are comparable to those seen in patients with normal renal function in this setting [104–106]. Interestingly, improvement in renal function occurred in 82% of those achieving PR, versus 37% in those who failed to achieve PR. Peripheral blood stem cell mobilization was successful in 26 patients, and SCT was subsequently performed in 22 patients, suggesting that the combination of thalidomide and dexamethasone can be effective when used in conjunction with SCT in patients with MM and RI [103].

Importantly, the use of lower-dose thalidomide in patients with relapsed or refractory MM has been described with comparable response rates and lower toxicity, with no benefit of dose escalation seen [107]. In summary, thalidomide is relatively safe and effective to use in MM patients with RI; however, dose reduction is recommended in patients with light chain-associated amyloidosis in particular [108].

Reversibility of RI in the era of newer agents

Several studies investigating bortezomib, lenalidomide and thalidomide have shown impressive activity in reversing renal dysfunction (see Table 3) over and above their well-established anti-myeloma effects [11]. For example, in a study of 41 MM patients receiving high-dose dexamethasone with or without thalidomide and/or bortezomib, reversal of RI was shown in 73% of patients when dexamethasone was used alone (median duration of 1.9 months) and in 80% when it was used with thalidomide and/or bortezomib (median duration of 0.8 months) [109]. Predictors of failure to reverse renal function included more severe RI and marked Bence–Jones proteinuria prior to therapy. Consistent with other trials, in patients whose MM responded to treatment, the reversal of RI was 85%, whereas in patients not significantly responding, reversal of RI was less at 56% [109].

Similarly, bortezomib plus dexamethasone in 46 patients with RI and MM showed a renal response in 59% of patients, including 30% complete renal response, with two out of nine patients no longer requiring dialysis [110], with a similar safety profile to those with normal renal function. Previously untreated patients had a greater chance of complete renal recovery and those with light chain MM also had a higher chance of achieving renal response in a shorter time frame. Interestingly, in a subset of patients, cystatin-C levels >2 mg/l or those with a cystatin-C-calculated eGFR <30 ml/min were associated with lower chances of complete renal response [110].

In a recent study evaluating the use of dexamethasone and/or thalidomide in 12 patients requiring dialysis, encouraging results have also been reported [111]. Complete response and partial response were achieved in three and five patients, respectively. Eight cases (67%) became dialysis independent, including six treated with high-dose dexamethasone and two treated with a thalidomide-based regimen, after a median duration of 2 months [111]. It was noted that a high SFLC level correlated with the presence of advanced RI, and a significant drop in SFLC level preceded improvement of renal function and dialysis independence. It was concluded that dialysis-dependent RI can be reversed by dexamethasone and/or thalidomide even in advanced age, and that SFLC levels could be used in predicting the improvement and reversibility of renal function [111].

Finally, the use of different novel regimens as frontline therapies for reversing RI in MM patients has been evaluated in a large trial that included 96 consecutive patients with RI (defined as CrCl <50 ml/min), where 32 patients received conventional chemotherapy plus dexamethasone (VAD, VAD-like regimens or melphalan plus dexamethasone), 47 received IMiD-based regimens (thalidomide or lenalidomide with high-dose dexamethasone and/or cyclophosphamide or melphalan), and 17 patients received bortezomib- and dexamethasone-based regimens [112]. This study showed improvement of RI in 79 and 94% of patiens in the IMiD and bortezomib-treated groups, respectively, compared with 59% in the conventional chemotherapy-treated group (p = 0.02) [112]. Bortezomib therapy and CrCl >30 ml/min were identified as independent factors associated with a higher probability of achieving renal response and a shorter median time to achieve renal recovery [112]. The authors concluded that bortezomib-based regimens are preferred as frontline therapy for newly diagnosed myeloma patients with RI, which is a guideline now generally accepted in the field, on the basis of these results and other studies summarized previously [11,67–78].

Other treatment options

HCO: a new hope?

Based on the understanding that tubulointerstitial injury in MM occurs as a direct outcome of elevated SFLC levels, recent studies have investigated the benefit of direct SFLC removal on renal recovery. Although traditional plasma exchange is estimated to remove approximately 25% of the total SFLCs, a randomized clinical trial showed no significant clinical benefit of its use for preserving renal function [113]. One explanation might be that traditional plasma exchange only removes intravascular SFLCs with no effect on the extravascular SFLCs, which soon redistribute into the intravascular compartment. However, an additional promise has emerged with the development of high cut-off hemodialysis (HCO), as extended therapy allows the removal of both intravascular SFLCs and extravascular FLCs, with model calculations suggesting that 90% of FLCs can be removed by utilizing HCO in a 3-week period [114]. In this study, HCO succeeded in decreasing SFLCs by 35–70% in 2 h, although SFLC concentrations showed some rebound on subsequent days unless coupled with effective chemotherapy [114].

Faced with these encouraging results, a study was conducted investigating the clinical benefit of combining standard chemotherapy with HCO. In a total of 19 patients with acute renal failure secondary to MM, this trial showed that 13 patients (68%) succeeded in maintaining reduced SFLC levels (median 85%), with recovery of renal function to become dialysis independent (median duration 27 days). Patients achieving renal function recovery had significantly improved survival (p < 0.012) [115]. Another study of 39 patients with myeloma kidney showed that lowered SFLC levels significantly predicted recovery of renal functions (p = 0.003), demonstrating by day 21 a decrease of SFLC levels by 60% was associated with renal recovery in 80% of the patients. Strikingly, it showed that median survival was 42.7 months for patients with renal recovery, in contrast to 7.8 months for patients who did not recover renal function (p < 0.02), again supporting the notion that RI is a strong factor affecting survival [116]. With such data suggesting HCO as a hopeful new modality in the management of MM and RI, it will be important that future large-scale studies are conducted to confirm its benefit.

Integrating therapeutic modalities

Dialysis as part of renal replacement therapy is key for patients whose renal function fails to rapidly reverse with combination therapy utilizing bortezomib, dexamethasone and IMiDs, with or without the addition of cyclophosphamide [49]. Kidney transplantation is also an alternative treatment option to dialysis, although with limited success owing to the risk of MM recurrence and infections [3]. Integrating both renal transplantation and SCT in younger patients with HLA-identical siblings is also under study [3].

The use of high-dose melphalan in RI patients has proven to be toxic, so if melphalan is to be used the dose should typically not exceed 140 mg/m², to avoid serious AEs [117]. For patients with persistent RI, combination chemotherapy (e.g., doxorubicin in combination with bortezomib and dexamethasone) is another option [117]. SCT remains a reasonable treatment, especially for resistant/relapsed cases of MM with moderate RI (serum creatinine >2 mg/dl), with successful induction followed by stem cell mobilization using cyclophosphamide 2.5–3 g/m² plus melphalan 140–150 mg/m², followed by autologous SCT as one possible sequence [49].

With data suggesting a primary role of the proximal tubular cells in the pathogenesis of myeloma kidney (see Figure 4), newer agents are being developed, such as PACAP-38, which has been shown to prevent the process of proximal tubular cell activation by the FLCs, as well as inhibition of TNF-α and IL-6 [118]. These agents remain experimental; however, they may have promise as a new generation of immune modulators with the potential to augment existing treatment strategies.

Expert commentary

RI is present in approximately 50% of MM patients at some point in the course of their disease. As it is the most common cause of early mortality in MM, patients with RI during initial therapy should be considered high risk, especially during induction, with myeloma cast nephropathy the most common cause of serious renal compromise. Diagnosis and treatment at the early stages, while renal injury is still reversible, is thus fundamental for improving prognosis [117]. Diagnosis depends on traditional investigation, with special consideration to SFLC levels and SFLC ratios, while also considering the suggested extended reference ranges described previously.

Treatment with bortezomib, lenalidomide and thalidomide in patients with RI has proven to be of great value. Bortezomib has been shown to be safe and effective, and can lead to reversal of RI in a considerable number of patients, with evidence that bortezomib is a cornerstone drug in current combination therapies. In addition, there is sufficient evidence to confirm bortezomib’s safety in patients with RI, with the hope of renal recovery in a substantial portion of patients. Lenalidomide is renally cleared and thus severe RI can be associated with elevated serum levels and potentially higher toxicity. However, its use is often essential, so in patients with severe RI, dose adjustment is necessary to avoid toxicity, most notably myelosuppression. Thalidomide is also useful for salvage of patients with advanced MM, and all three agents have been used successfully in achieving reversal of RI. Melphalan can be toxic in patients with RI, and high-dose therapy should be used cautiously with dose reduction, as clinically indicated. Cyclophosphamide as an alternate alkylator is potentially more efficacious in this setting, and can be safely used, especially in combination.

Five-year view

The management of MM is constantly evolving as newer agents are developed. Although substantial data emphasize the overall benefit of novel agents in MM therapy, additional trials are required to identify which combination regimen gives the best long-term survival in this group of patients. We believe that novel therapies will continue to stand the test of time while evolving into newer generations, with particular emphasis on bortezomib and lenalidomide as platform drugs. Newer generations of current novel agents might aim on increasing efficacy, reducing AEs, and improving safety, especially in patients with RI. With recent data suggesting pomalidomide as one of the most potent immune-modulators [119,120], we believe future studies investigating its safety and efficacy in patients with RI are critical.

SCT still constitutes a cornerstone of therapy in conjunction with novel agents in younger patients; however, its optional use as a treatment approach in RI remains debatable. Further clinical trials are needed to identify which line of therapy confers the best overall long-term survival.

Newer modalities include extended HCO, which has shown promising results, but still needs further large-scale studies to support its benefit. Moreover, newer agents, such as PACAP-38, offer the hope of future additions to our current arsenal of novel agents.

Traditionally, RI has been known to be an adverse prognostic and survival factor. New treatments and novel combinations may be changing this as the treatment paradigm in MM continues to evolve [121]. Use of these newer agents upfront in patients with RI is recommended, provided dose reduction is used when indicated. Future large-scale studies are necessary to compare the efficacy and safety of these newer drugs in different novel combinations to be used in patients with MM and RI, and beyond. Moreover, these should provide sufficient data to formulate future management strategies involving newer drugs, as well as defining a clearer role for SCT in MM patients with RI and thus further improve patient outcome. Meanwhile, the search for newer agents will continue, with today’s innovation at both the bench and the bedside providing real hope for tomorrow [122].

Table 1. Tabulated data reflecting the frequency of different histologic types of renal injury found in multiple myeloma patients with renal impairment according to Herrera et al. and Sakhuja et al.

Pathology of renal injury	Herrera et al.[36](n = 77)	Sakhuja et al.[2](n = 27)
Myeloma cast nephropathy	∼30% of all cases, with an additional 20% of patients having occasional casts seen within the tubules	60% of cases
Tubulointerstitial nephritis	2.6%	14%
Amyloidosis	5.2%	11%
Acute tubular necrosis	33.8%	7%
Nodular glomerulosclerosis		3.6%
Plasma cell infiltration/tumor nodules	4%	3.6%
Autolysis	32.5%
Thrombotic microangiopathy	13%
Light chain deposition disease	2.5%

As shown, myeloma cast nephropathy represents a major histological type found among multiple myeloma patients. Common precipitating factors of renal impairment in multiple myeloma patients include dehydration, hypercalcemia, nephrotoxic medications, sepsis, recent surgical operations and contrast agents.

Data taken from [2,36].

Table 2. Renal impairment reversal rates according to the Phase III VISTA study.

Patient groups	Rate of RI reversal with VMP (%) (n = 340)	Rate of RI reversal with MP (%) (n = 337)
Patients with GFR <30 ml/min	37	7
Patients with GFR 30–50 ml/min	46	39
Rate of RI reversal for patients with baseline GFR <50 ml/min improving to >60 ml/min with treatment	44	34

GFR: Glomerular filtration rate; MP: Melphalan and prednisone; RI: Renal impairment; VMP: Bortezomib, melphalan and prednisone.

Data taken from [74].

Table 3. Summary of renal response in multiple myeloma patients treated with various newer anti-myeloma regimens.

Study (year)	Regimen type	Renal response	Ref.
Kastritis et al. (2007)	Dexamethasone	73% of patients showed renal reversal	[109]
	Dexamethasone with thalidomide and/or bortezomib	80% of patients showed renal reversal. 85% reversal of RI occurred in patients with MM responding to treatment, in contrast to 56% reversal of RI in patients with resistant MM
Matsue et al. (2010)	Dexamethasone and/or thalidomide in dialysis patients	25% of patients showed complete response 42% of patients showed PR 67% of patients became dialysis independent	[111]
Dimopoulos et al. (2009)	Bortezomib plus dexamethasone	59% of patients showed renal response, including 30% having complete renal response with two out of nine patients becoming dialysis independent	[110]
Li et al. (2009)	Bortezomib plus dexamethasone	Reversal of RI occurred in ∼39% of patients, with a 50% reduction in serum creatinine level seen in ∼33% of patients. In 13 out of 15 patients, MM response was associated with improvement of renal function	[72]
Ludwig et al. (2010)	Bortezomib–doxorubicin–dexamethasone regimen	MM response was shown in 72% of patients, while renal response was shown in 62% of patients	[73]
Morabito et al. (2010)	Bortezomib-based regimen	41% of patients showed renal reversal 21% of patients became dialysis independent	[69]
Chanan-Khan et al. (2007)	Bortezomib-based regimen	75% overall response rate and four out of 20 patients became dialysis independent	[70]
Roussou et al. (2008)	Bortezomib-based regimen	50% renal improvement and 85% of patients showed a decrease in serum creatinine	[71]
Dimopoulos et al. (2010)	Lenalidomide plus dexamethasone	25% of patients achieved a complete renal response, while 16% achieved a minor renal response	[86]
Roussou et al. (2010)	Conventional chemotherapy plus dexamethasone	Improvement of RI in 59% of patients	[112]
	IMiD-based regimens	Improvement of RI in 79% of patients
	Bortezomib and dexamethasone	Improvement of RI in 94% of patients
Tosi et al. (2004)	Thalidomide	Reversal of renal function in 12 out of 15 patients whose MM was responsive to treatment	[50]
Tosi et al. (2010)	Thalidomide plus dexamethasone as induction therapy prior to autologous SCT	82% renal improvement in patients achieving PR versus only 37% in patients failing to achieve PR	[103]

IMiD: Immunomodulatory drug; MM: Multiple myeloma; PR: Partial response; RI: Renal impairment; SCT: Stem cell transplantation.

Box 1. Classification of kidney disease in multiple myeloma according to the primary site of injury.

Glomerular

• • Primary amyloidosis (AL or AH)

• • Monoclonal immunoglobulin deposition:

  • – Light chain deposition disease

    – Heavy chain deposition disease

    – Light and heavy chain deposition disease

• • Miscellaneous (cryoglobulinemia, proliferative glomerulonephritis)

Tubular

• • Myeloma kidney (light chain cast nephropathy)

• • Distal tubular dysfunction

• • Proximal tubule dysfunction or acquired Fanconi syndrome

Interstitial

• • Plasma cell infiltration

• • Interstitial nephritis

Other causes

• • Hyperuricemia

• • Hypercalcemia

• • Drugs (e.g., NSAIDs)

Key issues

• • Renal impairment (RI) is a major problem complicating multiple myeloma (MM), being present in approximately 50% of patients during the course of their illness, with myeloma cast nephropathy representing the most common cause.

• • Newer agents, including bortezomib, lenalidomide and dexamethasone, have revolutionized MM management, and as part of their anti-MM effect, can help improve renal function.

• • Bortezomib-based regimens are effective and safe in patients with RI, and lead to the reversal of RI in a significant number of patients.

• • For newly diagnosed MM patients with RI, bortezomib-based regimens are preferred as the first-line therapy.

• • Since bortezomib is hepatically metabolized, its clearance is independent of renal function, and thus dose adjustment is not required in the setting of RI.

• • Since it is renally excreted, lenalidomide use in moderate and severe RI requires dose adjustment. Studies show that RI did not impact response to therapy, and a significant proportion of patients showed renal improvement.

• • Concerns about using lenalidomide with RI include myelosuppression and progressive azotemia, necessitating close monitoring of complete blood count and renal function.

• • The combination of thalidomide and dexamethasone can be effective when used in conjunction with stem cell transplantation in patients with MM and RI.

• • Thalidomide is relatively safe and effective to use in MM patients with RI; however, dose reduction is usually recommended in patients with light chain-associated amyloidosis, in particular.

• • High cut-off hemodialysis (HCO) with improved light chain removal has promise as a supportive modality.

• • Melphalan can be toxic in patients with RI, and high-dose therapy should be used cautiously with dose reduction as clinically indicated.

• • Future studies are necessary to evaluate different combinations of novel agents, while defining clearer indications for stem cell transplantation among the therapeutic algorithm.

Acknowledgements

The authors gratefully acknowledge the assistance of Michelle Maglio with this manuscript.

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Management of myeloma-associated renal dysfunction in the era of novel therapies

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. You are seeing a 70-year-old man with a 3-month history of fatigue and pain in his hips and low back. You note that he has had a 4-kg weight loss in the past 3 months. His serum creatinine level was above normal 2 months ago.

You consider whether this patient has multiple myeloma (MM) with renal insufficiency (RI). Which of the following statements regarding the diagnosis of MM and RI is most accurate?

• □ A Patients with MM and RI featuring monoclonal immunoglobulin (Ig) deposition disease usually have hypotension

• □ B Patients with MM and RI featuring amyloid deposition disease usually have hypertension

• □ C Detection of serum or urine monoclonal Ig is no longer important in the diagnosis of MM

• □ D Among patients with RI, elevated serum free light chain (SFLC) assay results may be misleading

2. The patient is diagnosed with both MM and RI and a renal biopsy is ordered. Which of the following histologic patterns is most common among patients with MM and RI?

• □ A Amyloidosis

• □ B Myeloma cast nephropathy

• □ C Tubulointerstitial nephritis

• □ D Acute tubular necrosis

3. Which of the following treatments would be considered first line for this patient?

• □ A Lenalidomide

• □ B Bortezomib

• □ C Thalidomide

• □ D Melphalan

4. What else should you consider regarding other therapeutic options for MM in the setting of RI?

• □ A Lenalidomide does not require dose adjustment in the setting of RI

• □ B High cut-off hemodialysis has been associated with renal recovery among patients receiving dialysis

• □ C Thalidomide is associated with a lower rate of adverse events compared with bortezomib

• □ D Melphalan is promising as a treatment in the setting of RI, but only at high doses

Notes

AH: Amyloid heavy chain amyloidosis; AL: Amyloid light chain amyloidosis.

Data taken from [2,123–126].