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Pathogenesis and treatment of renal failure in multiple myeloma

Abstract

Renal failure is a frequent complication in patients with multiple myeloma (MM) that causes significant morbidity. In the majority of cases, renal impairment is caused by the accumulation and precipitation of light chains, which form casts in the distal tubules, resulting in renal obstruction. In addition, myeloma light chains are also directly toxic on proximal renal tubules, further adding to renal dysfunction. Adequate hydration, correction of hypercalcemia and hyperuricemia and antimyeloma therapy should be initiated promptly. Recovery of renal function has been reported in a significant proportion of patients treated with conventional chemotherapy, especially when high-dose dexamethasone is also used. Severe renal impairment and large amount of proteinuria are associated with a lower probability of renal recovery. Novel agents, such as thalidomide, bortezomib and lenalidomide, have significant activity in pretreated and untreated MM patients. Although there is limited experience with thalidomide and lenalidomide in patients with renal failure, data suggest that bortezomib may be beneficial in this population. Clinical studies that have included newly diagnosed and refractory patients indicate that bortezomib-based regimens may result in rapid reversal of renal failure in up to 50% of patients and that full doses of bortezomib can be administered without additional toxicity.

Introduction

Renal failure is a common feature of multiple myeloma (MM) that may provide a clue to diagnosis and cause a major management problem. Depending on the definition of renal failure, this complication occurs in 20–40% of newly diagnosed patients with MM.1, 2, 3, 4 When a serum creatinine level higher than 2 mg per 100 ml is used to define renal impairment, about 20% of patients with MM have renal failure at diagnosis.1, 2, 5 When renal failure is defined by a serum creatinine >1.5 mg per 100 ml, the frequency of renal insufficiency increases up to 30% or even 50% in some series.5 Although the degree of renal failure is usually moderate and serum creatinine levels are lower than 4 mg per 100 ml, in series from tertiary hospitals up to 10% of patients with newly diagnosed MM have renal failure severe enough to require renal replacement with dialysis at the time of diagnosis.6 Although it has been generally considered that an additional 25% of patients develop renal failure later in the course of the disease, this is not the experience of the authors of this review. Patients with no nephrotoxic light chains, who do not present with renal failure, are less likely to develop renal insufficiency later during the course of their disease. In cases with late renal failure, the usual cause is hypercalcemia, which in turn is becoming much less frequent with the use of bisphosphonates to treat myeloma bone disease.

In this review, we will focus on the mechanisms underlying renal pathology in MM, and the management of patients with myeloma-related renal failure will be discussed.

Pathogenesis

Renal failure in patients with MM results from the toxic effects of monoclonal light chains to renal structures, mainly renal tubules, and less often to glomeruli, whereas hypercalcemia is a less common cause of renal insufficiency. Other contributing factors include dehydration, nephrotoxic drugs (antibiotics, non-steroidal anti-inflammatory drugs) and perhaps the use of contrast agents. Usually, these factors aggravate the toxic effects of light chains and are rarely the primary reason of renal failure. Monoclonal light chains cause renal damage by distinct mechanisms and in various segments of the nephron, glomeruli, tubules, interstitium and blood vessels that are responsible for different pathologic and clinical findings. Myeloma cast nephropathy (so-called myeloma kidney) is by far the most frequent form of renal damage. Other clinicopathological conditions include amyloidosis, light chain deposition disease (LCDD) or acquired adult Fanconi syndrome. These entities may sometimes coexist in the same patient.

Circulating monoclonal light chains are relatively freely filtered through the glomerulus and reach the proximal tubule where they are catabolized. Free light chains are endocytosed by proximal tubule cells, through a receptor-mediated process, by binding to the tandem scavenger receptor system cubilin/megalin. Then, they are endocytosed through the clathrin-dependent endosomal/lysosomal pathway and degraded within lysosomes7, 8, 9, 10 (Figure 1). In MM, excess light chain production overcomes the capacity of the tubular cells to catabolize the free light chains that appear in the tubular fluid of distal nephron segments where they form tubular casts with Tamm-Horsfall protein (uromodulin), a glycoprotein synthesized by the cells in the medullary thick ascending limb of the loop of Henle with affinity for monoclonal light chains. Light chains interact through their complementary determining region with a specific binding site on the Tamm-Horsfall protein and form aggregates and casts that subsequently lead to the tubular obstruction of the distal tubule and the thick ascending loop of Henle.11, 12, 13 Factors such as dehydration, hypercalcemia, acidosis and furosemide promote light chain/Tamm-Horsfall protein aggregate formation.13, 14, 15, 16 Tubular obstruction increases intraluminal pressure, reduces glomerular filtration rate and reduces interstitial blood flow, thus further compromising the renal function. The reduced tubular clearance of light chains further increases their concentration in the tubules and contributes to the vicious circle that results in myeloma cast nephropathy. The rates of cast formation increase when light chains increase, but there is considerable diversity among the nephrotoxicity of light chains and some patients have significant renal damage with small amounts of light chains, whereas in others even large amounts cause minimal dysfunction. It is also interesting to note that when a light chain is nephrotoxic, it usually causes renal function impairment early in the course of the disease, even before other clinical manifestations of MM become apparent.17 Light chains also differ significantly with the type of renal damage. In general, the variable region of the light chain determines nephrotoxicity of the specific light chain by determining, for example, the affinity with Tamm-Horsfall protein.14, 16 It has been suggested that Tamm-Horsfall protein interacts with the hypervariable regions of the light chains. This region contains the amino acids that give diversity, conformation flexibility and allow for interactions with various proteins to promote antigen binding by immunoglobulins.18, 19 Furthermore, the variable region of the light chain probably determines the specific type of renal damage that a light chain can cause. Both lambda and kappa light chains are nephrotoxic, but lambda light chains are more frequently involved in the formation of amyloid than kappa,20 and kappa are more frequently involved in other types of renal damage, such as LCDD21 and acquired adult Fanconi's syndrome.22

Figure 1
figure1

Light chains are filtered through the glomerulus and reach the lumen of the proximal tubule. Proximal tubule cells endocytose free light by binding to the tandem scavenger receptor system cubilin/megalin. Then, they are endocytosed through the clathrin-dependent endosomal/lysosomal pathway and degraded within lysosomes. (Adapted with permission from Santostefano et al10).

Cast formation is not the only pathophysiologic mechanism in myeloma kidney. Endocytosis of light chain by renal tubular cells also induces pro-inflammatory cytokine production, such as intereleukin-6, -8 and tumor necrosis factor-a, by these cells, mainly mediated through activation of nuclear factor-kappa B and mitogen-activated protein kinases.23, 24 These proinflammatory cytokines promote infiltration by inflammatory cells that produce metalloproteinases and increase transforming growth factor-b production, resulting in matrix protein deposition and subsequent fibrosis and further compromising the ability of the nephron to restore function.25 Light chains endocytosis may also cause tubular cell necrosis, leading to more severe renal dysfunction.26 The exact mechanism has not been clarified, but it has been suggested that aggregation of light chains after endocytosis may initiate a cascade resulting in tubular cell death. Light chains may lead to functional impairment of tubular cells, in which case Fanconi syndrome may present.22 Focal loss of microvilli and inhibition of Na-K-ATPase may lead to reabsorption defects.27 Some myeloma patients also have a urine concentration defect, probably due to tubulointestistial changes, and nephrogenic diabetes insipidus due to unresponsiveness to ADH, thus further promoting dehydration.28 In patients with cast nephropathy, the glomerulus is unaffected and thus free light chains (Bence Jones protein) will predominate in the urine.

Hypercalcemia is the second most common cause of renal failure in MM.17 Hypercalcemia interferes with renal function and impairs renal concentrating ability, causes vasoconstriction of renal vasculature and enhances diuresis, which may result in hypovolemia and pre-renal azotemia. Concentrated urine and reduced urine flow enhance cast formation, thus leading to further renal damage.

Light-chain glomerulopathy is caused by the deposition of immunoglobulins either in the form of amyloid or non-amyloid. In both glomerulopathies, the development of non-selective proteinuria is the dominant syndrome. The amyloid deposits are fibrillar structures that consist of the N-terminal fragments of the variable regions of light chains.29 Amyloid deposits can be found in every portion of the kidney, but they predominate within the glomeruli and give a positive Congo red staining. Glomerular depositions of amyloid usually present with significant proteinuria but renal failure is evident in no more than 20% of patients at diagnosis. However, 5–10% of patients with amyloidosis may have predominantly vascular rather than glomerular depositions and present with renal failure rather than nephrotic syndrome.30 Nephrotic range proteinuria without significant renal impairment and with other conditions, such as orthostatic hypotension, exertional dyspnea, fatigue and thickening of cardiac walls, should lead to the suspicion of systemic amyloidosis. Electrophoresis of a sample from a 24 h urine collection showing non-selective proteinuria may further support the suspicion of amyloidosis. Biopsy is needed for the confirmation of amyloidosis, and subcutaneous fat, rectal or renal biopsy may lead to the diagnosis.

In LCDD, the light chain deposits are non-fibrillar and Congo red staining is negative.31 Typically, granular depositions of light chains are observed within the mesangial areas, whereas a thickening of the peripheral basement membrane may resemble type II membranoproliferative glomerulonephritis or diabetic lesions. These deposits may also be present in arterioles and capillaries. Diagnosis is supported by immunofluorescence (although in 10% of cases it may be negative) and by electron microscopy. Linear peritubular deposits of monotypic light chains are usually found but these deposits are also found along the basement membrane, mesangial nodules, Bowman's capsule, vascular structures and in the interstitium. In addition to the glomerular findings, the presence of interstitial fibrosis is a constant finding.32 In the early phases of the disease, the glomerular lesions may be minimal, and in this case the diagnostic suspicion comes from the finding of eosinophilic, periodic acid Schiff (PAS positive) material, consisting of light chains, along the outer part of the tubular basement membrane. In contrast to amyloidosis, in which the light chain is of lambda type in 80% of cases,30 in LCDD the light chain is usually of kappa type.32 As in primary systemic amyloidosis, the characteristic clinical picture is of a nephrotic syndrome, but renal function is more severely and rapidly impaired than in amyloidosis: almost all patients with LCDD present with renal failure. Extrarenal involvement is less frequent than in amyloidosis.

Acquired Fanconi syndrome is an exceedingly unusual disorder characterized by failure in the reabsorptive capacity of the proximal renal tubules, resulting in glycosuria, aminoaciduria, hypophosphatemia and hypouricemia.22 The renal damage is caused by partially catabolized light chains that form crystalline inclusions within the proximal tubular cells interfering with membrane transporters. Kappa light chains are found in 90% of the cases. The most common clinical findings in patients with acquired Fanconi syndrome are bone pain from osteoporosis or slowly progressive renal insufficiency. Most patients are asymptomatic and the diagnosis usually comes from an unexplained hypouricemia during the investigation of a patient with monoclonal gammopathy of undetermined significance.

When should a renal biopsy be performed in a patient with MM?

In patients with clinical features of MM with or without renal failure, in whom proteinuria consists mainly of light chains, a renal biopsy is not necessary. In cases where the main finding is a nephrotic syndrome with or without renal failure, the first diagnostic possibility is an associated systemic amyloidosis or, less likely, LCDD. In this case, a subcutaneous fat aspirate should be done. If negative for amyloid, a rectal biopsy may follow. If there is no demonstration of amyloid, the next step should be a kidney biopsy in search for amyloid, LCDD or an unrelated glomerulopathy, such as glomerulonephritis.

The impact of renal failure in the prognosis of myeloma patients

The median survival of patients with MM has been about 3 years.3, 33 After the introduction of novel agents, the prognosis of myeloma patients is steadily improving.34 In several series, the median survival of patients with MM and renal failure has been less than 2 years,4, 35, 36, 37 but this figure is likely to improve with the incorporation of the novel agents. In some series, patients who ultimately recovered their renal function had a better outcome compared to those who did not2, 5 and patients who restored their renal function had a similar outcome to patients without renal failure at diagnosis. However, in other series, reversal of renal failure was not associated with a superior outcome when compared with cases of patients with sustained renal impairment.1, 38 Patients who present with acute renal failure have increased early mortality, reaching up to 30% within the first two months in some series.2, 37 Furthermore, renal impairment may adversely affect the outcome of myeloma patients in various ways. Drug dosing is often complicated, whereas many potentially nephrotoxic but useful drugs are deferred. Patients with renal failure of any cause are also more susceptible to infections, electrolyte imbalance complications and are more likely to require prolonged hospitalization, severely compromising their quality of life. Thus, restoring renal function is of paramount importance.

The definition of renal failure is not straightforward, although serum creatinine levels have been used to define renal impairment. In most studies, a cutoff of serum creatinine of 2 mg per 100 ml is used to define the presence of renal impairment in newly diagnosed myeloma patients. This cutoff is sufficient to include patients with at least moderate renal impairment. Furthermore, it may exclude patients who are likely to have a rapid improvement with simple means of hydration or management of hypercalcemia. Creatinine is not a sensitive marker of renal function, especially in patients who have mild or moderate renal impairment. Calculation of glomerular filtration rate (GFR) is more accurate and mathematic formulas for GFR calculation have been used extensively giving adequate estimations of renal function. Other, more precise methods are complicated, have a high cost and are infrequently used. Cystatin-C measured in the serum is a sensitive marker of renal dysfunction and has been used by nephrologists for some years. In MM patients, Terpos et al.39 measured cystatin-C in the serum of newly diagnosed and pretreated patients and showed that cystatin-C is elevated in myeloma patients, even in those with normal serum creatinine.

The evaluation of response to treatment in myeloma patients with renal failure may be difficult, especially in patients who do not have measurable disease by serum electrophoresis. Urine quantification of light chains may be unreliable in cases of oliguria or when renal function is deteriorating rapidly. Serum-free light chains have been used for the assessment of those with light chain amyloidosis as well as patients with oligosecretory disease.40 It is our experience that patients with high serum levels of light chains by FREELITE assay have an increased probability of myeloma-associated renal failure. In patients with renal impairment, both kappa and lambda light chains increase, but an abnormal ratio may help interpret the results of the assay. However, further studies are needed to assess the role of this assay in the management of patients with myeloma-associated renal failure.

Management of renal impairment/failure

Supportive care

Adequate hydration is a key component of supportive care and should be ensured in all patients presenting with renal impairment. Although it has been reported that renal failure could be reverted by high fluid intake alone, hydration alone will at best only slightly reduce the concentration of the pathogenic light chains. Hydration should be combined with antimyeloma treatment, which includes agents that are not excreted by the kidneys. Additional supportive care measures include urine alkalinization and management of hypercalcemia. Bisphosphonates are very effective for the management of malignancy-related hypercalcemia; however, myeloma patients presenting with acute renal failure are at risk for complications such as renal toxicity and subsequent hypocalcemia when bisphosphonates are administered.41 Thus, close monitoring is needed in these patients, whereas mild asymptomatic hypercalcemia should preferably be managed with conservative measures such as hydration. For moderate or severe hypercalcemia, the prompt initiation of antimyeloma therapy, which includes steroids, is indicated. Calcitonin may moderately reduce calcium levels without causing severe hypocalcemia and without the risk of renal toxicity. When creatinine levels start to improve, bisphosphonates, in doses adjusted for renal impairment, may be administered. The use of furosemide to treat hypercalcemia is discouraged owing to the adverse impact of loop diuretics in the formation of casts in the renal tubule. Effective supportive care also includes the prompt treatment of infections and the avoidance of agents that contribute to renal damage, such as non-steroidal anti-inflammatory drugs, aminoglycoside antibiotiocs and contrast dyes.42

Mechanical means

Plasma exchange

A rapid removal of nephrotoxic light chains with plasma exchange, in combination with antimyeloma therapy, could prevent irreversible renal failure by avoiding further renal damage. Two studies suggested that plasma exchange was of benefit;43, 44 however, a prospective comparison of forced diuresis and chemotherapy (10 patients) versus forced diuresis, chemotherapy and plasma exchange (11 patients) found only a trend in favor of the plasma exchange group.45 On the other hand, a large randomized trial showed no conclusive evidence that plasma exchange improved the outcome in patients with MM and acute renal failure.46 However, in this study, patients did not need to have kidney biopsies performed, so patients with amyloidosis, LCDD or Fanconi's may have been included, thus underestimating the benefit of plasma exchange. Because free light chain measurement was not available in this study, the possibility that a subgroup of patients might benefit from plasma exchange cannot be ruled out. In the experience of Bladé et al.,17 patients with renal failure severe enough to require dialysis do not benefit from plasma exchange. This is in agreement with older findings that associated the severity of myeloma cast formation with the irreversibility of renal failure, even in patients undergoing plasma exchange.43, 45 However, we believe that in some patients with non-oliguric renal insufficiency, an early plasma exchange program along with forced diuresis and chemotherapy may be of some benefit. In these patients, plasma exchange can be performed with 5% albumin in saline solution with a total volume of about 5 l in each session. It is important to measure the M-protein in serum and urine before and after each plasma exchange. It is our practice to repeat a plasma exchange procedure every 2 or 3 days to a maximum of 4 or 5 sessions. With this approach, replacement with coagulation factors is generally not necessary. Considering the background immunoglobulin removal with plasma exchange, it is important to administer intravenous immunoglobulins after each plasma exchange to avoid bacterial infections in these high-risk patients.

Free-light chain removal with dialysis filters

The removal of free-light chains with dialysis is another alternative approach, and a new hemodialysis membrane that removes the circulating light chains more efficiently has been recently developed. A small study investigating hemodialysis with a protein-leaking dialyzer indicated that large reductions in the concentration of serum-free light chains could be obtained.47 The same group also investigated the use of high cutoff hemodialysis in combination with systemic treatments and found that 13 of 18 patients with renal failure became dialysis-independent.48 Renal recovery was also associated with improved survival (P<0.02). Although promising, these results need further confirmation in larger studies.

Renal replacement with dialysis

Despite the improvements in recent years, the mortality rate among patients with MM and dialysis-dependent renal failure during the first two months from diagnosis is about 30%.6 The response rate to chemotherapy in patients with MM on the long-term dialysis program ranges from 40 to 60%.6, 49, 50, 51 Thus, it seems that the presence of renal failure does not have per se a negative impact on the response to chemotherapy. On the other hand, if patients who die within the first two months from diagnosis are excluded, the median survival of patients with MM and non-reversible end-stage renal failure is almost 2 years and 30% of them survive for more than 3 years.6, 52 This suggests that the need for long-term dialysis does not adversely affect survival. Another important aspect is the quality of life of this population of patients. In two series, the average of hospitalization days was 12 and 19 days per patient-year, respectively.6, 52 In one of these studies, patients who survived for more than 1 year spent less than 10 days per year in hospital, a figure similar to that observed in patients on chronic hemodialysis, because of diabetic nephropathy.6 Apparently, there are no long-term differences between chronic peritoneal dialysis and hemodialysis, although patients on chronic peritoneal dialysis are at a higher risk of developing bacterial peritonitis.53 In summary, long-term dialysis is a worthwhile treatment for patients with MM and end-stage renal failure.

Antimyeloma treatment

Conventional chemotherapy

When defining the reversibility of renal impairment as a decrease in the serum creatinine level to less than 1.5 mg per 100 ml the recovery rate has ranged from 20 to 73%.1, 2, 5, 38, 46 Conventional chemotherapy with alkylating agents, such as melphalan prednisone (MP), results in moderate rates of renal function recovery, whereas it is complicated by the need for dose adjustment, which may in turn result in suboptimal treatment.54 In the study of Alexanian et al.,1 after administration of chemotherapy with alkylating agents, doxorubicin and steroids, 51% of patients recovered renal function (defined as a sustained decrease of creatinine <1.4 mg per 100 ml) within a median of 1.2 months. Light chain only myeloma (24 vs 63%, P=0.002) and creatinine level above 3.1 mg per 100 ml were associated with a lower probability of renal failure reversal. Response to chemotherapy was not associated with a higher probability of renal failure reversal, whereas the outcome of patients with restoration of renal function was similar to that of patients who did not reverse renal failure or to that of patients who did not have renal failure at presentation (P=0.36). In the series reported by Bladé et al.2 renal function was recovered in 26% and median survival for these patients was 28.3 months, compared with 3.8 months for those with irreversible renal failure. Median time to renal function recovery was 1.6 months. High creatinine level (>4 mg/l) at presentation (P=0.001) and Bence Jones proteinuria >1 g per 24 h (P=0.02) were associated with a lower probability of renal recovery, whereas hypercalcemia was associated with increased probability of reversal (P=0.02). There was no significant difference in the survival of patients who restored renal function compared to those patients who had normal renal function (P=0.97). Response to chemotherapy was found to be significantly lower in patients with renal failure, compared to those with normal renal function (39 vs 56%, P<0.001), and survival was 8.6 months in patients with renal failure vs 34.5 months (P<0.001) for patients with normal renal function. However, when patients who died during the first 2 months of treatment were excluded, the response to therapy was similar irrespective of renal function. This difference was due to high rates of early mortality in patients presenting with renal failure, with 30% of them dying within the first 2 months as compared to 7% in patients with normal renal function. Combination chemotherapy was more effective than MP or cyclophosphamide and prednisone, resulting in response rates of 50 vs 24% (P=0.03) among patients who presented with renal failure; however, survival was similar between these two groups (median 12.9 vs 14.2 months). In another series,5 renal failure defined as a creatinine >1.5 mg per 100 ml was observed in 29% of patients at the time of diagnosis. Treatment with alkylating agents and standard dose steroids resulted in reversal of renal failure (defined as reduction of creatinine <1.5 mg per 100 ml) in 58% of patients, whereas among patients with a creatinine >2.3 mg per 100 ml, 40% achieved a normal renal function. Renal improvement was evident within the first three months of treatment. Again, there was no difference in the probability of reversal among patients who responded and those who did not respond to chemotherapy, but in this series the reversal of renal failure (P=0.03) but not response to chemotherapy (P=0.07) was associated with improvement in survival.

High-dose dexamethasone-based regimens

High-dose dexamethasone-based regimens are associated with rapid responses with a median time to response in newly diagnosed patients of about 1–1.5 months. Thus, such regimens are useful in patients with acute renal failure who need rapid reduction of light chain production. Since their introduction in the 1980s, many physicians use regimens, such as vincristine doxorubicin dexamethasone (VAD), in patients who present with renal failure. In a single center retrospective series, newly diagnosed myeloma patients presenting with acute renal failure were treated with such regimens resulting in a reversal rate of 73%.38 This rate is higher compared to other series, which included alkylating-based regimens containing standard dose steroids.1, 2 Patients were divided into two groups who received VAD, VAD-like regimens, melphalan plus high-dose dexamethasone or high-dose dexamethasone alone (group A) or high-dose dexamethasone plus thalidomide and/or bortezomib (group B). Median time to reversal was 1.9 months with 8 out of 10 patients initially requiring dialysis becoming dialysis-independent. The probability of reversal of renal failure was similar in groups A and B (69 vs 80%, P=0.453), but the time to renal recovery was significantly shorter in patients receiving high-dose dexamethasone plus thalidomide and/or bortezomib (0.8 vs 2 months, P=0.005). Patients who presented with light chain only myeloma or with Bence Jones proteinuria 2 g per day or creatinine 4 mg per 100 ml or had no response of myeloma to primary treatment had a lower probability of renal failure reversal. However, in multivariate, there was a trend only for Bence Jones proteinuria 2 gr/day to be associated with lower probability of renal failure reversal (P=0.075).

Importantly, improvement in renal function was also observed in patients with poor-risk features for reversal, such as severe renal insufficiency, light-chain only myeloma and heavy proteinuria. There was no significant difference in median survival between patients in whom renal failure was reversed, compared with those with persistent renal failure (23.5 vs 21 months). An updated figure of reversal of renal failure according to the type of antimyeloma treatment is shown in Figure 2.

Figure 2
figure2

Time to reversal of renal function in 53 newly diagnosed patients treated with high-dose dexamethasone (……) or novel agent-based therapies (————).

Novel agents

Thalidomide

Thalidomide is an oral agent that is only minimally excreted through the kidneys. In patients with renal failure, the kinetics of the metabolites of the drug are not different than in patients with normal renal function.55 However, data are limited regarding the activity of this agent in patients with MM and renal failure. The data available suggest that this agent is an appropriate treatment, with response rates and tolerability similar to those observed in patients with normal renal function. In a series of 20 patients with relapsing myeloma who received thalidomide with or without dexamethasone, renal function was recovered in 12 out of 15 responding patients, but no improvement was observed in patients who were refractory to thalidomide with or without dexamethasone therapy.56 Kastritis et al.38 also observed reversal of renal failure with thalidomide, in combination with high-dose dexamethasone with or without bortezomib, in 80% of previously untreated patients. Although in most series the toxicity of thalidomide is not different among patients with different levels of renal function, a recent report indicates that severe neuropathy, constipation, lethargy and bradycardia are more frequent in patients with a serum creatinine 3 mg per 100 ml.57 Furthermore, there are some case reports suggesting that thalidomide may be associated with severe hyperkalemia in patients with renal failure58 or that it may enhance the nephrotoxicity of aminoglycoside antibiotics in patients with MM.59

Bortezomib

Bortezomib is a proteasome inhibitor with activity in the treatment of both relapsed/refractory and newly diagnosed MM.60, 61, 62 The pharmacokinetics of bortezomib are independent of renal clearance and are not influenced by the degree of renal impairment; dose adjustments are not required for patients with renal insufficiency, but in patients undergoing dialysis, bortezomib should be administered after dialysis. Adverse events in patients undergoing dialysis are largely similar to those observed in controls and in those with mild-to-severe impairment, with the exception of renal and metabolic adverse events, which were found to be more common in patients undergoing dialysis.63, 64 Bortezomib-based therapy is also associated with rapid responses typically occurring within the first two cycles of treatment.60, 61, 62 In the SUMMIT and CREST trials, bortezomib treatment was found to lead to an overall response rate of 25 and 30% in patients with moderate and severe renal impairment, respectively,65 whereas the toxicity was comparable to that of patients without renal impairment. In a subanalysis of the APEX trial, bortezomib was effective in patients with renal impairment, including those with severe renal impairment,66 with response rates and time to response similar across all subgroups of patients with varying degrees of renal function. Time to progression and overall survival were not substantially affected in patients with severe to moderate renal impairment compared to those with no or mild renal impairment or to the overall APEX population. Similarly, patients treated with bortezomib-based therapies experienced similar clinical benefit irrespective of renal function status in another retrospective series.67 In a multicenter retrospective analysis, 24 MM patients requiring dialysis were treated with bortezomib68 and 30% achieved a complete (CR) or near CR (nCR) with partial responses seen in 45%. Toxicity was mild to moderate and comparable in both frequency and severity to that observed in patients with normal renal function. Furthermore, renal function improved in four patients who no longer required dialysis.

Reversal of renal failure was observed in five of eight patients (seven newly diagnosed, one previously treated) with acute myeloma-induced renal failure who were treated with bortezomib-based therapy. It was suggested that bortezomib may improve kidney function not only through rapid reduction of toxic monoclonal light chains, but also through its action on nuclear factor-kappa B: bortezomib may reduce inflammation in myeloma kidney disease through its inhibitory effect on nuclear factor-kappa B, which has been shown to be activated in renal tubular cells of proteinuric patients.69 On the basis of the positive results of this pilot study, a phase 2 study investigated bortezomib in combination with doxorubicin and dexamethasone in patients with acute renal failure.70 The study included newly diagnosed and pretreated patients. Of 51 patients enrolled, 32 were evaluable at the time of reporting. Response rate was 75% (CR+PR+MR) with a 56% CR+very good partial response (VGPR) rate. In 14 patients (43%), there was reversal of renal failure to a GFR of >50 ml/min, and in six additional patients (19%), a greater than 200% increase in GFR to levels of 30–50 ml/min was observed. Improvements in renal function were noted preferentially in patients with a significant antimyeloma response to bortezomib. However, in patients with very low GFR (<10 ml/min), reversal of renal failure was less likely, suggesting that treatment should be initiated as soon as possible to prevent deterioration of kidney function. Although overall toxicity appears to be slightly higher in patients with renal failure than in those with normal renal function, tolerance is improved in patients whose disease responds to treatment and whose renal function improves to the extent that tolerability is comparable to that in patients with normal renal function. In another retrospective analysis, reversal of renal failure was observed in 40% of patients with newly diagnosed or relapsed/refractory disease treated with bortezomib-based regimens, within a median time of 17 days. In addition, 10 patients had >50% decrease in serum creatinine with a median time to decrease of 35 days (updated results of the study are depicted in Figure 3). The overall response rate was 65% and the toxicity profile was comparable to that observed in patients without renal failure.71

Figure 3
figure3

Median serum creatinine in 24 patients at each cycle of treatment with bortezomib-based regimens.

These data provide evidence for the activity and safety of bortezomib in this specific subset of patients. Response to bortezomib is independent of renal function and tolerability is comparable to that seen in patients with normal renal function, whereas response is rapid, a factor that is crucial in patients with deteriorating renal function.

Lenalidomide

Lenalidomide, a thalidomide analogue, is the first of the second-generation immunomodulatory drugs (IMiDs). Lenalidomide has efficacy in patients with relapsed/refractory myeloma, especially in combination with dexamethasone or with chemotherapy. Ongoing trials show that lenalidomide is also very active in newly diagnosed patients with either low or high dose dexamethasone or in combination with MP.72, 73 However, lenalidomide is mainly excreted through the kidneys.74 There is limited experience with the use of lenalidomide in patients with severe renal impairment, as serum creatinine >2.5 mg per 100 ml was an exclusion criterion in lenalidomide trials, whereas in patients with creatinine rising above 2.5 mg per 100 ml the drug was discontinued or withheld. However, data from MM-009 and MM-010 showed that patients with mild renal impairment could receive lenalidomide, although they developed thrombocytopenia more frequently than patients with creatinine clearance >50 ml/min.75 Another report in relapsed myeloma patients who received lenalidomide with or without corticosteroids showed that patients who had mild renal impairment, defined as a serum creatinine 1.0–2.5 mg per 100 ml for females and 1.2–2.5 mg per 100 ml for males, had similar response rates to patients with normal renal function, again at the expense of higher rates of thrombocytopenia.76 However, in this report, only five patients had a serum creatinine >2 mg per 100 ml. Another study investigating the combination of lenalidomide with clarithromycin and dexamethasone showed that patients with a baseline creatinine clearance <40 ml/min were 8.4 times more likely to require lenalidomide dose reduction due to grade 3 or grade 4 myelosuppression,77, 78 thus indicating the need for lenalidomide dose adjustments according to renal function. Recommendations for lenalidomide use in patients with renal impairment have been formulated on the basis of a pharmacokinetic study in 30 patients with various degrees of renal impairment. Patients were stratified into various groups on the basis of their creatinine clearance. Total and renal clearance of lenalidomide were strongly correlated with creatinine clearance (R>0.9, P<0.01) and as a result the area under the curve (AUC) increased with decreasing creatinine clearance. On the basis of these data, the following dose modifications for lenalidomide are recommended according to renal function: no dose reduction for creatinine clearance 50 ml/min; reduce dose to 10 mg per day for creatinine clearance 30–50 ml/min; 15 mg every other day for patients with creatinine clearance <30 ml/min but not on dialysis; and 15 mg thrice per week after each dialysis in patients requiring dialysis.79 However, more safety data are needed for lenalidomide in patients with moderate or severe renal failure before definite recommendations are made.

High-dose therapy with autologous stem cell transplantation

High-dose therapy with autologous stem cell transplantation (ASCT) has been associated with improved progression-free survival in several studies. In patients with renal impairment, the use of ASCT is limited because of increased toxicity.80, 81 A small prospective study indicated that impaired renal function did not affect the pharmacokinetics of melphalan and that stem cell collection or post-transplant engraftment was not impaired.81 Furthermore, an additional small series showed that ASCT is feasible in patients with renal failure and that it may result in the recovery of renal function.80, 82, 83, 84 Response to therapy and progression-free survival are independent of renal function; however, treatment-related mortality is significantly higher in patients with renal failure. Overall survival is adversely affected by the degree of renal impairment. Recovery of renal function is reported in 34–43% of patients; whereas some patients may become84 dialysis-independent after ASCT. Another series85 of ASCT with melphalan 200 mg/m2 or melphalan 140 mg/m2 in 81 patients with renal failure was associated with transplant-related mortality of six and 13% after single or double transplant, respectively. The nonhematologic toxicity, especially in dialysis-dependent patients who received melphalan 200mg/m2, was high, consisting of severe bacterial infections, atrial arrhythmias and encephalopathy. Thus, the authors recommended a dose of melphalan of 140 mg/m2. A recent retrospective analysis of patients who underwent ASCT found that response rate and time to progression were independent of creatinine level but that mortality rate post-transplant was increased and overall survival was shorter in patients with a creatinine >2 mg/ml before transplant.86 In addition, platelet engraftment was significantly delayed in patients with renal insufficiency. In view of the above data and because we now have more treatment options for patients with myeloma and renal failure, it is likely that the application of high-dose therapy to such patients will decrease.

Conclusion

Myeloma-induced renal failure is associated with significant morbidity and increased early mortality. Rapid intervention to reverse renal insufficiency is critical. Supportive care measures are essential and antimyeloma therapy should be initiated as soon as possible. High-dose dexamethasone-based regimens remain the cornerstone in the treatment of these patients, owing to their rapid antimyeloma activity. The addition of novel agents can further increase the rapidity of response and perhaps the probability of restoring renal function. The limited experience with thalidomide indicates that this agent can be administered in patients with renal failure. Bortezomib can be safely administered to patients presenting with renal failure, and the combination of bortezomib with high-dose dexamethasone may be the treatment of choice for such patients. Prospective trials will define the role of lenalidomide in patients with serum creatinine >2.5 mg per 100 ml, although recommendations have been made. In patients with persistent renal failure, high-dose therapy with ASCT should be limited to patients with chemosensitive disease and intensive treatment should probably consist of melphalan 140 mg/m2.

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Dimopoulos, M., Kastritis, E., Rosinol, L. et al. Pathogenesis and treatment of renal failure in multiple myeloma. Leukemia 22, 1485–1493 (2008). https://doi.org/10.1038/leu.2008.131

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Keywords

  • multiple myeloma
  • renal failure
  • light chains
  • renal recovery
  • bortezomib
  • thalidomide
  • lenalidomide

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