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Renal failure in multiple myeloma: a medical emergency

Abstract

Up to 50% of newly diagnosed plasma cell myeloma (PCM) patients can present with renal insufficiency, 20% with severe renal impairment and 10% requiring dialysis. PCM patients account for 2% of the dialysis population, adding 5000 new patients each year worldwide. Dialysis-dependent PCM patients have a 2.77 higher risk of death compared with other dialysis-dependent patients without this diagnosis. Renal failure and especially dialysis dependency is an independent poor prognostic factor in PCM, with the majority unable to achieve dialysis independence. Renal failure in PCM is a medical emergency with the need for rapid accurate diagnosis and prompt institution of supportive care and PCM-directed therapy, because reversal of renal impairment and recovery from dialysis dependency can occur in up to half the patients early in the course of disease and can lead to enormous survival benefits. Recently, the serum free light chain (SFLC) assay and serum β-2-microglobulin free heavy chain (SFHC) assay have been used to rapidly diagnose PCM in renal failure and provide prognostic information in the setting of renal failure where the Durie–Salmon and International Staging Systems do not. A renal biopsy early in the course of renal impairment can provide diagnostic and prognostic information. A new generation of dialyzers with larger pores than routine dialyzers can be used with extended hemodialysis to remove SFLC more efficiently than plasmapheresis, allowing for greater renal recovery. Novel chemotherapy agents such as bortezomib are associated with an improved renal response and have moved to the front line of therapy. Successful use of high-dose therapy and autologous hematopoietic cell transplantation (HCT) in PCM with renal failure and even dialysis dependency has been associated with late renal recovery and also allowed for the subsequent use of renal transplantation to provide even greater survival benefits. Combined non-myeloablative allogeneic HCT with renal transplant in PCM patients with end-stage renal disease on dialysis is now being studied in prospective trials.

Introduction

The incidence of plasma cell myeloma (PCM) in the United States is 4.3 per 100 000 people per year and has remained at this level over time.1 In Europe, the annual incidence of PCM is 3–4 per 100 000 people. Up to 50% of newly diagnosed PCM patients can present with renal insufficiency (serum creatinine >1.3 mg/dL), with 20% with severe renal impairment (serum creatinine >2–2.5 mg/dL) and 10% needing dialysis.2, 3 In elderly patients with reduced muscle mass, the serum creatinine underestimates the true incidence of renal failure. The Cockroft–Gault equation or the Modification of Diet in Renal Disease formula better defines renal failure in multiple myeloma (see Table 1).2, 3 The Modification of Diet in Renal Disease formula is recommended by the International Myeloma Working Group to define renal impairment in multiple myeloma with the Kidney Disease Improving Global Outcomes classification system to stage the kidney disease.7 PCM is the most common neoplasm causing end-stage renal disease (ESRD) and is the first malignancy that was an indication for dialysis.1 PCM patients account for 2% of the dialysis population adding 5000 new patients each year worldwide.7 Renal impairment and especially dialysis dependency is an independent poor prognostic factor for survival, with the majority of patients requiring dialysis unable to achieve renal recovery.1, 8, 9 Knudsen et al.3 found that PCM patients treated with chemotherapy who remained dialysis dependent had a median survival of 3.5 months. This is in contrast to a survival of over 5 years for PCM reported by many studies.10 PCM with renal failure should be regarded as a medical emergency with the need for accurate diagnosis and rapid institution of supportive care and PCM-directed therapy should be instituted because reversal of renal impairment and recovery from dialysis dependency can occur in up to half the patients early in the course of disease and can lead to enormous survival benefits.1, 3 This paper will explore the pathogenesis of renal failure in PCM and the role of supportive care, chemotherapy and transplantation (autologous HCT, allogeneic HCT and renal transplantation) in improving outcomes of PCM in renal failure.

Table 1 Definitions of renal impairment and renal response in plasma cell myeloma

Diagnosis of PCM in renal failure

The plasma cell clones secrete a unique monoclonal Ig idiotype, which is IgG in 50%, IgA in 20% and light chain only in 20% of cases. Less than 1% of cases have non-secretory PCM, but many of these have cytoplasmic Ig and these are seldom associated with renal impairment.11 Even rarer are PCM with the absence of even cytoplasmic Igs, but with typical plasma cell morphology, phenotype and gene expression signature. IgD, IgE and IgM secretion or production of more than one Ig class by the plasma cell clone is rarely seen. IgD PCM is associated with Bence Jones light chain proteinuria and renal failure in nearly all cases.12 The paraprotein band contains a complete Ig made up of two heavy Ig chains associated with two light chains, but even in this setting, the PCM cells can produce free unassociated light chains.12 Serum protein electrophoresis and immunofixation and 24-h urine protein electrophoresis and immunofixation have been used to diagnose and monitor disease, but these tests are not always reported promptly. A 24-h urine specimen is often difficult to collect in a patient with oliguric renal failure. Furthermore, in light chain-only PCM with renal failure and non-secretory disease, these tests are not helpful.13

Serum free light chain assay

The serum free light chain (SFLC) assay (Freelite; The Binding Site Group Ltd, Birmingham, UK) allows same-day analysis and recognizes previously hidden determinants of the light chain, allowing reclassification of non-secretory PCM in up to two-thirds of cases.13 An abnormal SFLC ratio is seen with the production of monoclonal FLC in the setting of light chain-only myeloma as well as with intact Ig PCM.14 The serum half-life of the light chains is 2–4 h compared with a half-life of 17–21 days for the heavy chains. The normal kidneys remove κ light chains preferentially accounting for the reference range κ/λ ratio of 0.26–1.65, with a median ratio of 0.6.15 In renal failure, the reticuloendothelial system accounts for the majority of the SFLC clearance, resulting in a similar half-life of κ and λ chains and the SFLC ratio reflects plasma cell production.16 As there are twice as many κ- as λ-producing cells, the SFLC ratio is 1.8 in renal failure.15 In 688 PCM patients with renal failure with normal serum protein electrophoresis and immunofixation, the SFLC ratio was 1.1, with a range of 0.37–3.1, which identified a 100% of cases.17 The serum protein electrophoresis and immunofixation and SFLC assay accurately diagnosed all myeloma patients without the need for urine collection.18 The long half-lives of the complete Ig molecules preclude their use as markers for early responsiveness to therapy in comparison to the SFLC assay owing to the shorter half-lives of the light chain.

The utility of screening assays lies in their specificity and sensitivity. A SFLC ratio of 0.26–1.65 provides 93% specificity in multiple myeloma patients with renal failure, but this was 99% with lower false positives when an extended SFLC ratio of 0.37–3.1 was used.19 SFLC assays are useful for diagnosis and management, and also provide prognostic information.20 The 5-year disease-free specific survival was 82 and 30% in patients with SFLC ratio lower than and equal to or greater than the median.20 High SFLC levels at baseline (reflecting more aggressive disease) and steeper reductions in SFLC after therapy were associated with inferior OS and EFS (indicative of PCM cells with high proliferative rate with rapid regrowth after chemotherapy).21

β-2-Microglobulin free heavy chain assay

β-2-Microglobulin (B2M) is the light chain of the HLA class 1 complex.22 B2M expression occurs on the surface of most nucleated cells, in which it is associated non-covalently with a 44 kDa polymorphic glycoprotein (heavy chain). B2M is increased in PCM according to the tumor load and a level more than 6 mg/L is associated with a poor prognosis.22 B2M is also elevated in renal failure and this is not a reflection of the PCM tumor load. Identification of the serum B2M free HLA class 1 heavy chain (SFHC) is correlated with the PCM tumor load and not affected by renal failure or the HLA allotype. SFHC can be detected by a moAb using a double determinant-based ELISA. The Durie–Salmon stage has not been correlated with prognosis in PCM. The International Staging System based on B2M and albumin at diagnosis has provided prognostic information, but in renal failure the elevation of B2M is not a reflection of the PCM tumor load, and this system loses its usefulness.22 The SFLC levels or polyclonal Igs, whose levels are reciprocally decreased in PCM, are not included in the International Staging System. Recently, Perosa et al.22 in a single center study of 149 PCM patients have formulated a staging system based on SFHC and IgM levels (Stage 1 IgM >31.5 mg/dL and SFHC 0.67 mg/L or less, Stage 2 IgM <31.5 mg/dL and SFHC 0.67 mg/L or less, Stage III with SFHC >0.67 mg/L), which was associated with a median survival of not yet reached, 41.5 months and 27.8 months for stage I, II and III, respectively. This staging system provided prognostic information in PCM with or without renal failure, but has to be validated in multicenter trials in a larger number of patients.

Pathogenesis of renal failure in plasma cell myeloma

Light chain-only clones account for up to 50% of PCM associated with renal impairment compared with 20% of all cases.19 The major reason for renal failure in PCM is the overproduction of nephrotoxic light chains. The degree of self-aggregation of light chains and the reduced lysosomal degradation by the proximal tubular cells determine the nephrotoxicity of the light chains, which is not always dependent on the concentration of light chains.23 Patients with large amounts of SFLC can have normal renal function and those with small concentrations of SFLC can present with renal failure. Injection of human light chains into mice produces the same renal pathology as in the donor and rarely (20% of cases) is light chain deposition disease (LCDD) associated with cast nephropathy attesting to the lesion specificity of light chains.24 Even before other related organ or tissue impairment, the nephrotoxic light chains can cause renal insufficiency as an early manifestation.25 Nephrotoxic light chains bind to a common site on Tamm–Horsfall protein (a 616-amino-acid glycoprotein produced by the medullary thick ascending loop of Henle) with differing affinities based on their hypervariable regions.26 In studies of PCM patients with renal impairment undergoing renal biopsies, the most common cause (Table 2) was cast nephropathy (40–63%), followed by LCDD (19–26%) and amyloidosis (7–30%).27 The λ light chain is more frequently associated with amyloid kidney and the κ light chain with LCDD, whereas cast nephropathy has not been found to be associated with a predominant light chain.26 Cast nephropathy usually presents in patients with more advanced stages of PCM, but this is not the case with amyloid light chain (AL)-amyloidosis or LCDD (see Table 2).27

Table 2 Renal disease in multiple myeloma

Cast nephropathy

Excess SFLC filtered through the glomerulus into the proximal tubule of the nephron binds the multiligand receptors, megalin and cubulin, resulting in endocytosis by the clathrin-dependent endosomal–lysosomal pathway in the proximal tubule cells, and if the concentration of the light chains overwhelms this lysosomal degradation pathway, then proximal tubular cell necrosis and apoptosis can occur.28, 29, 30 Renal failure in cast nephropathy (also known as myeloma kidney) is associated with the level of light chain.28 When the FLC exceed the endocytosis capacity of the proximal tubule cells, the FLC enter the distal tubule, in which they bind to a 9-amino acid-binding domain on the Tamm–Horsfall glycoprotein by the third complementarity determining region causing obstruction and reduction in glomerular filtration and interstitial blood flow and eventually interstitial nephritis from tubular rupture.31 Endocytosis of FLC in the proximal tubule cells activates nuclear factor (NF)-κB and mitogen-activated protein kinases leading to the induction of proinflammatory cytokines, ILs (IL-6, IL-8), TNF-α and monocyte chemoattractant protein-1, which result in interstitial fibrosis by the production of metalloproteinases and transforming growth factor-β.32 This accounts for the triad on renal biopsy of proximal tubular injury, hard waxy casts in the distal tubules and interstitial inflammation, and ultimately interstitial fibrosis. The glomerulus is spared leading to selective Bence Jones proteinuria. High concentrations of SFLC, urinary acidification, dehydration, furosemide, non-steroidal anti-inflammatory agents, i.v. contrast, hypercalcemia and nephrogenic diabetes insipidus potentiate PCM cast nephropathy.28 The degree of interstitial fibrosis correlates with the possibility of renal recovery.28 Cast nephropathy is potentially the most reversible of all the PCM renal diseases if treated early.

Light chains in proximal tubule cells can form crystalline inclusions interfering with membrane transporters such as sodium–potassium–ATPase, resulting in acquired adult Fanconi's syndrome, which has a predominant association with κ light chains. This causes amino aciduria, phosphaturia, bicarbonaturia, glucosuria and wasting of uric acid and is complicated by osteoporosis and renal failure.33, 34 The crystalline inclusions result from cathepsin B digestion of κ light chains that do not bind Tamm–Horsfall glycoprotein, hence Fanconi's syndrome is rarely found with cast nephropathy.35

Monoclonal Ig deposition disease

Monoclonal Ig deposition disease results from the production of monoclonal paraprotein and is associated with PCM in 65% of cases.36 This entity includes most commonly LCDD in 70% of cases and is associated with κ light chain in more than 70% of cases. Less frequently, heavy chain deposition disease (20%) and LCDD and heavy chain deposition disease (10%) is found.37 The monoclonal protein is non-fibrillar Congo Red stain negative and deposits along the glomerular and tubular basement membrane, mesangium and vessel walls, leading to nodular glomerular sclerosis resembling Kimmelstiel–Wilson lesions or membranoproliferative glomerulonephritis.37 These are detected by immunofluorescence showing the fixation of monoclonal light chain anti-sera along the basement membranes in 90% as linear deposits. Under EM, these are seen as granular deposits.37 In an analysis of LCDD, Pozzi et al.36 found that 35% of cases were associated with extrarenal manifestations involving the heart (21%) presenting as congestive heart failure and arrhythmias, and the liver (19%) that can lead to portal hypertension. The lung (pulmonary cystic disorder), gastrointestinal tract and neurological system are less frequently involved. LCDD associated with PCM presents with higher serum creatinine values and worse OS than LCDD not associated with PCM. LCDD is less likely to have renal recovery than PCM cast nephropathy. Because of glomerular involvement, the presentation is that of nephrotic syndrome with unselective proteinuria.38

Amyloidosis

Light chain AL-amyloidosis can be present in 30% of patients who have multiple myeloma. AL-amyloidosis is composed of the N-terminal fragments of the variable regions of the light chains (mainly λ light chain) in β pleated sheet of fibrils that deposit predominantly in the glomeruli causing nephrotic syndrome and progressive renal failure.39 Renal recovery is rare in this setting. In 10% of cases, the amyloid deposition is in the renal vasculature and tubulointerstitium causing renal failure without nephrotic syndrome. The amyloid deposits produce apple-green birefringence under polarized light when stained with Congo Red dye.39 The diagnosis of AL-amyloidos should be considered in patients with nephrotic syndrome, neuropathy, orthostatic hypotension, hepatomegaly, cardiomyopathy and requires demonstration of amyloid in tissue. An s.c. fat aspirate and BM biopsy can be diagnostic in 90% of cases.39 If these are negative and the patient has renal failure, then a renal biopsy can be diagnostic in 95% of cases.39

Management of renal failure in plasma cell myeloma

General measures

Non-steroidal anti-inflammatory agents, contrast dyes, furosemide, aminoglycosides, angiotensin-converting enzyme inhibitors and angiotensin II receptor inhibitors and other nephrotoxic agents should be avoided.28 Hydration combined with urinary alkalinization reduces the concentration of the light chains slightly and increases their solubility. Chemotherapy for PCM should be started as soon as possible with agents not excreted by the kidney. For hypercalcemia (which is the second most common cause of renal failure in PCM after cast nephropathy), hydration and calcitonin can reduce the calcium levels without the associated toxicity of bisphosphonates in the setting of renal failure. Bisphosphonates can be used when the renal failure improves.40 Loop diuretics such as furosemide increase cast formation in renal tubules and should be avoided in the treatment of hypercalcemia.41

Renal replacement therapy

Renal replacement therapy may be needed in oliguric patients who cannot tolerate hydration and who have no improvement in their renal function despite the general measures outlined above. Eighty-eight percent of PCM patients requiring dialysis receive hemodialysis and 12% have peritoneal dialysis and both are equally effective, although long-term peritoneal dialysis is associated with an increased risk of bacterial peritonitis.1 The most common causes of death in dialysis-dependent PCM patients were malignancy (36.1%), cardiovascular causes (17.2%) and infection (14.7%).1 PCM patients on dialysis had a 2.77 (95% confidence interval, 2.65–2.9) higher risk of death than other patients on dialysis and this translated to a lower survival of 0.91 years compared with 4.46 years in the European Renal Association-European Dialysis and Transplant Association registry data.1 This underlines the importance of renal recovery. Historically PCM patients on renal replacement therapy have been given reduced doses of chemotherapy and had autologous HCT withheld. However, Tables 3 and 4 delineate the improved outcomes with chemotherapy and subsequent autologous HCT even in PCM on renal replacement therapy, indicating that renal replacement therapy should be offered to PCM patients with renal failure.

Table 3 Results of chemotherapy in multiple myeloma patients with renal impairment
Table 4 Results of auto-SCT in multiple myeloma with renal impairment

Plasmapheresis

κ light chain (25 kDa) and λ light chain (50 kDa) are small molecules with a large volume of distribution and are present in similar concentrations in the intravascular and extravascular compartment. Plasma exchange over a 3-week period will only remove 25% of total FLCs. The intravascular compartment contains 20% of the total FLC, so plasma exchange has little impact in sustained removal of SFLC as shown in the largest randomized controlled trial of 104 PCM patients with acute renal failure who had no benefit with the addition of plasma exchange to chemotherapy in the improvement of the glomerular filtration rate, dialysis dependence or death.58 Recovery from dialysis occurred in 66% of the plasma exchange patients during the 6 months of this study and 50% of the control population (P=NS). This study provided no information on the renal histology or SFLC levels, making interpretation of the data difficult. Leung et al.59 reported on nine dialysis-dependent PCM patients with renal biopsy-proven cast nephropathy treated with plasma exchange and chemotherapy (mainly high-dose dexamethasone). Two of the nine patients had recovery from dialysis and these were patients with a 50% or more fall in SFLC indicating the importance of SFLC reduction in outcomes of cast nephropathy. However, there was no correlation between the number of plasma exchange sessions given and the SFLC reduction (P=0.9) or the renal recovery (P=0.28).59 Plasma exchange does have a role in reducing plasma viscosity when present, usually seen with IgM and IgA paraproteinemias.

SFLC removal by high cutoff dialyzers

A new generation of dialyzers with larger pores than routine dialyzers can be used with extended dialysis to remove the SFLC.60 The Gambro HCO 1100 dialyzer (Gambro Dialysatoren GmbH, Hechingen, Germany) has increased permeability to substances up to 60 kDa MW and a molecular cutoff similar to albumin (65 kDa), with albumin loss being the major side effect requiring replacement with 20% human albumin solution.60 Over a 3-week period, extended hemodialysis with a high cutoff dialyzer (HCO-HD) will remove 90% of total FLCs. In an elegant study by Hutchison et al.,60 two Gambro HCO 1100 dialyzers were connected in series to add a convective element and increase the surface area with doubling of the FLC removal with extended hemodialysis (>4 h). Seventy-four percent of patients had biopsy-proven PCM cast nephropathy. Fourteen of 19 patients who had extended HCO-HD and chemotherapy became hemodialysis independent at a median of 27 days (range 13–120 days) and had >50% reduction in SFLC and 11/14 had >75% reduction in SFLC. Those with renal recovery had improved survival. With reduced SFLC concentrations, new cast formation is halted and the existing casts are excreted and detected in the urine. Even with effective chemotherapy, SFLC concentrations can remain above the threshold required for the formation of casts for some weeks.60 After 1 month of obstruction by casts, irreversible damage to nephrons can occur.61 This suggests that the timing of SFLC removal is essential. Renal recovery was associated with reductions in SFLC concentrations of >50%.60 The Gambro 1100 HCO dialyzers are commercially available in the European Union and soon to gain orphan device status in the United States.

To fully assess the clinical benefits of HCO-HD in a multicenter randomized controlled trial, the EuLITE (European Trial of Free Light Chain Removal by Extended Hemodialysis in Cast Nephropathy) is recruiting 90 patients with newly diagnosed PCM and renal biopsy-proven cast nephropathy and renal failure on dialysis. Bortezomib-based chemotherapy will be given to all patients and patients will be randomized to FLC removal by HCO-HD or standard hemodialysis and assessed for dialysis independence at 3 months.62

Role of renal biopsy in PCM with renal failure

In another study of four patients with hemodialysis-dependent renal biopsy-proven PCM cast nephropathy treated with chemotherapy and HCO-HD, all patients remained dialysis dependent at 6 weeks at which time another renal biopsy was carried out.28 Three patients became dialysis independent at 51, 67 and 105 days from study entry. Areas of chronic damage were defined as sclerosed glomeruli, interstitial fibrosis, interstitial edema, atrophic tubules (defined as smaller than normal with thinned tubules including those that were cystic) and occluded arteries. The renal biopsies in all patients showed chronic damage with either no progression or accelerated progression to scarring from 10 to 42% despite a rapid and sustained fall in SFLC. In the three patients who became dialysis independent, there was a major reduction in intratubular cast numbers on the renal biopsy performed at 6 weeks.28 The fourth patient had no progression of chronic damage, but still had high cast numbers on renal biopsy and remained dialysis dependent. In this study, some patients with renal histology showing tubular atrophy and interstitial fibrosis still recovered late independent renal function and these were the patients with a reduction in cast numbers on the renal biopsy. A reduction in cast numbers on renal biopsy despite signs of chronic damage predicted renal recovery.28

Every effort should be made to perform a renal biopsy early in the course of renal impairment, especially when the creatinine rises above 30% of normal. Renal biopsies from PCM patients compared with a control population were not associated with a greater risk of hemorrhage (each 3.7%).63 In patients presenting with renal failure, renal histology may provide the initial diagnosis of PCM. The renal histology can guide therapy such as the use of rapid SFLC reduction with mechanical means with HCO-HD for cast nephropathy. Useful prognostic information is also provided by renal biopsies for the possibility of renal recovery, for example, by assessing the degree of interstitial fibrosis.28 Renal histology offers vital information for patients with regard to survival.27 In dialysis-dependent PCM patients treated with chemotherapy, Montseny et al.27 found that the median survival was 6, 18 and 48 months for cast nephropathy, LCDD and AL-amyloidosis, respectively. These renal disorders are difficult to differentiate clinically and the diagnosis relies on the renal biopsy.

Chemotherapy for PCM with renal impairment

Table 3 details the studies of chemotherapy in PCM with renal impairment. The studies can be subdivided into those using conventional agents (such as VAD, VMCP, melphalan prednisone), IMiD-based (immunomodulatory drugs) (thalidomide, lenalidomide with or without dexamethasone) or bortezomib-based therapies. Thalidomide undergoes spontaneous hydrolysis in plasma and its clearance is not based on renal function.64 Thalidomide is associated with hyperkalemia in renal failure, and for glomerular filtration rate (GFR) <50 mL/min, the recommended dose is 50–100 mg/day.64 Bortezomib's plasma elimination is also independent of renal function as it undergoes oxidative deboronation by the hepatic cytochrome P450 enzyme and requires no dose reduction even in dialysis patients. Bortezomib inhibits the transcription factor NF-κB, which is activated in renal tubular cells of proteinuric patients.65 Inhibition of NF-κB reduces inflammation and thereby interstitial fibrosis of the kidney. Lenalidomide undergoes renal clearance and causes myelosuppression necessitating dose reductions as follows: for GFR >50 mL/min give lenalidomide 25 mg/day; GFR 30–50 mL/min, use lenalidomide 10 mg/day; GFR <30 mL/min, use lenalidomide 15 mg every other day; and if on dialysis, give lenalidomide 5 mg after dialysis only.7 Caution needs to be exercised when using lenalidomide in PCM as there are case reports of potentiation of nephrotoxicity.66

Renal impairment and reversibility of renal failure is variably defined as shown in Table 3. However, recently, new criteria defining renal response have been proposed (Table 1).67 Using these criteria for renal response for 96 patients with newly diagnosed PCM with renal impairment defined as CrCl <50 mL/min, Roussou et al.48 found major renal response (CRrenal+PRrenal) of 59% in those patients given conventional chemotherapy vs 79% treated with IMiDs vs 94% in those given bortezomib-based regimens. The median time to renal response with conventional chemotherapy and IMiDs was 1.8 months, but was only 0.69 months with bortezomib, and this is important because rapid disease control is the aim for treatment of PCM with renal impairment. A CrCl >30 mL/min and bortezomib-based therapies were the only independent factors associated with a greater chance for renal response. Two dialysis patients treated with bortezomib achieved dialysis independence.48 Bortezomib with dexamethasone has emerged as the front-line therapy for PCM associated with renal failure.

Only one study by Montseny et al.27 reported on the survival of dialysis-dependent PCM patients treated with chemotherapy according to renal histology and found the median survival was 6, 18 and 48 months for cast nephropathy, LCDD and AL-amyloidosis, respectively. In multivariate analysis, only age <70 years, serum calcium <8.6 mg/dL and serum creatinine <3.4 mg/dL were associated with better OS.27 Cast nephropathy was associated with the highest mortality in the first 2 years of 24%.27 These data lend further support to the need for renal biopsy for diagnostic and prognostic purposes. The rate of reversal of dialysis dependency is low in the published studies with chemotherapy alone as shown in Table 2, despite the advent of novel agents such as bortezomib and the IMiDs. Knudsen et al.3 found a median survival of 43 months in PCM without renal impairment treated with chemotherapy in comparison to 31 months for reversible renal failure and 25 months for irreversible renal failure. The patients treated with chemotherapy who remained dialysis dependent had the worst median survival of 3.5 months.3

Autologous hematopoietic cell transplantation in PCM with renal impairment

Table 4 delineates the results of autologous HCT in PCM with renal impairment.49, 50, 51, 52, 53, 54, 55, 56, 57 Lee et al.52 found a 5-year OS of 36% and a median survival of 41 months for PCM patients on dialysis who underwent melphalan 200 mg/m2 conditioned autologous HCT compared with the 3.5-month survival reported by Knudsen et al.3 for dialysis-dependent PCM patients given chemotherapy alone. For those patients achieving CR or near CR (nCR), the 5-year OS was 58%. The CR+nCR rate improved from 46 to 51% with tandem autologous HCT. Twenty-four percent of patients achieved dialysis independence (eight of 54 patients after the first autologous HCT and five more patients after the tandem HCT).52 Patients with a 6-month or less duration on dialysis, CrCl of 10 mL/min or more, those with CR or nCR after autologous HCT and those with cast nephropathy rather than LCDD with diffuse mesangial nodular lesions or amyloid kidney had a greater chance of recovery from dialysis.52 In the study by Badros et al.,50 the CR rate improved from 26 to 38% with tandem autologous HCT; however, the EFS and OS) remained the same. This study did not report on the number of dialysis-dependent patients who benefited from renal recovery with a tandem autologous HCT, so firm recommendations with regard to the value of tandem autologous HCT in improving renal recovery are difficult to make as only one study (Lee et al.52) addresses this issue.50, 52 Raab et al.54 found that dialysis patients who did not proceed to autologous HCT had a median survival of 15 months with chemotherapy vs 36 months with autologous HCT. In a matched pair analysis with PCM patients with normal renal function undergoing autologous HCT, there were no differences in treatment-related mortality, EFS and OS in the cohort on dialysis.54 The Intergroupe Francophone du Myelome (IFM 90 trial) was the first to show that autologous HCT significantly improved the CR rate, EFS and OS compared with conventional chemotherapy for PCM, and the studies outlined in Table 4 convincingly confirm this is true also for PCM patients with renal failure and even those on dialysis.68

Stem cell mobilization

The quality of the PBSC collection and kinetics of engraftment were the same in PCM patients with renal impairment, including those on dialysis as those with normal renal function.49, 50, 51, 52, 53, 54, 55, 56, 57 For those patients failing neupogen mobilization, plerixafor, the selective antagonist of the CXC chemokine receptor 4, which reversibly inhibits the chemokine stromal cell-derived factor-1α, has been approved in the United States and European Union in multiple myeloma patients who have failed neupogen mobilization. The stem cell CXC chemokine receptor 4 binds stromal cell-derived factor-1α and thereby is anchored to the marrow matrix. The recommended dose of plerixafor is 240 μg/kg s.c. after 4 days of neupogen. Pharmacokinetic studies of plerixafor in varying levels of renal impairment recommend a reduced dose of plerixafor.69 The use of plerixafor in dialysis-dependent patients has been reported only in case reports.70 In a PCM dialysis-dependent patient, plerixafor at a reduced dose of 160 μg/kg/day was used with neupogen successfully for PBSC mobilization without adverse effects.70

Conditioning regimens

The optimal conditioning regimen for PCM with renal failure remains unknown. CY, BU and melphalan have been used in different studies.49, 50, 51, 52, 53, 54, 55, 56, 57 CY is excreted through the kidney in minor percentages of 1–14% indicating renal function independence.46 The liver is the major site of BU metabolism.49 A BU (1 mg/kg orally every 6 h for 16 doses) and CY (60 mg/kg i.v. for 2 consecutive days) conditioning regimen without any dose reductions was used in the study by Ballester et al.,49 including in three patients on dialysis. Although some studies have suggested that melphalan's pharmacokinetic parameters are related to creatinine clearance, other studies found spontaneous degradation to be the main route of melphalan's elimination.71 This may be due to the varying definitions of renal failure used. Therefore, as suggested in a study by Tricot et al.,71 using CrCl <40 mL/min (Cockroft–Gault formula), high-dose melphalan 200 mg/m2 would be an appropriate regimen even in multiple myeloma patients with renal failure. The half-life of melphalan and area under the curve are correlated with creatinine clearance, but renal impairment did not lead to a significant decrease in clearance of melphalan compared with inter-individual differences.71 Badros et al.,50 using serum creatinine >2 mg/dL to define renal failure, however, found no difference in response and survival in multiple myeloma patients with renal failure given melphalan 200 mg/m2 or melphalan 140 mg/m2, but the patients given melphalan 140 mg/m2 had less toxicity, specifically less mucositis. This is in contrast to Tricot et al.,71 who found that melphalan pharmacokinetics, even when administered at a dose of 200 mg/m2, were not adversely affected by impaired renal function and did not affect the incidence of mucositis. Furthermore, Sirohi et al.,72 using 51-chromium-labeled EDTA methodology to define renal failure, found that even though melphalan 200 mg/m2 was associated with greater toxicity (mainly hematological) in comparison to melphalan 140 mg/m2, there was a greater disease response as well as partial recovery of renal function in PCM patients on dialysis given melphalan 200 mg/m2. Parikh et al.,57 using serum creatinine >2 mg/dL to define renal failure, found that the TRM was not higher with melphalan 200 mg/m2 and that there was no significant difference in grade II–IV toxicity between dialysis-dependent and -independent patients. Adverse events included cardiac arrhythmias, pulmonary edema, hyperbilirubinemia, nausea, vomiting and diarrhea. Severe grade III or more mucositis occurred in 6% of patients and was not dependent on the stage of chronic kidney disease. Carlson,53 using iohexol clearance <30 mL/min to define renal failure, suggest that the melphalan dose be reduced to reduce toxicity given that the higher melphalan dose did not achieve a better survival. The International Myeloma Working Group guidelines recommend that a melphalan dose of 140 mg/m2 be used as conditioning for auto-SCT in multiple myeloma patients with renal failure with CrCl<60 mL/min and for those on dialysis.7

Renal transplantation

The extrarenal manifestations of LCDD are rarely improved by conventional chemotherapy alone and there can also be an inexorable progression to ESRD despite chemotherapy.36, 51 Royer et al.51 found that autologous HCT improved renal and extrarenal manifestations owing to LCDD and delayed their progression. Renal responses were seen in 4/11 patients, cardiac responses in 4/4 patients and hepatic responses in 2/2 patients.51 Three years after autologous HCT, while in CR one patient had nephrectomy and underwent renal transplantation, but developed LCDD in the transplanted kidney while still in remission.51 In the study by Hassoun et al.,56 two patients with LCDD achieved CR after autologous HCT and had renal transplantation from a living related donor accomplishing recovery from dialysis. Leung et al.73 recommended that CR has to be achieved, especially in LCDD, before renal transplantation, otherwise there can be relapse within 40 months, and in fact most transplant centers recommend CR of at least 3 years before renal transplantation. Successful use of autologous HCT in PCM dialysis-dependent patients in improving CR rates has allowed for the subsequent use of renal transplantation. In the registry of the European Renal Association-European Dialysis and Transplant Association, 1.4% of PCM patients on dialysis had renal transplant and a third of these patients had a living donor.1 Renal transplantation remains controversial in PCM owing to the role of immunosuppressive agents in PCM relapse and progression. Nonetheless, in the European Renal Association-European Dialysis and Transplant Association registry, the median survival of the PCM patients on dialysis who underwent renal transplant was 9.6 years.1

Allogeneic hematopoietic cell transplantation

PCM with high-risk cytogenetics such as t(4;14) has only an 8-month median time to progression after autologous HCT and ultimately all PCM patients will relapse because there is no plateau on the Kaplan–Meier survival curve after autologous HCT.74 Allogeneic HCT is the only curative therapy for myeloma based on the graft-versus-myeloma effect, but has rarely been used in myeloma with renal failure. Renal impairment before allogeneic HCT is a risk factor in the HCT co-morbidity index that predicts survival after HCT.75 Non-myeloablative HCT has broadened the inclusion criteria to allow patients with co-morbidities to undergo HCT. Kersting and Verdonck76 studied 13 patients with hematological malignancies, including one patient with PCM with LCDD, who had mild renal impairment (calculated by Modification of Diet in Renal Disease formula with a median GFR of 55 with a range of 35–59 mL/min/1.73 m2) undergoing non-myeloablative fludarabine 30 mg/m2/day for 3 days followed by 200 cGy TBI conditioned allogeneic HCT in a matched cohort analysis to patients with normal renal function. CYA and mycophenolate mofetil was used as GVHD prophylaxis. Remarkably, seven patients had improvement of GFR >60 mL/min/1.73 m2. No difference in the incidence of acute renal failure, GVHD, TRM or OS was seen in the two groups. No patient needed dialysis or developed ESRD. Similar doses and duration of CYA were used in both groups. This suggests that CYA can be used safely in patients with mild renal impairment with close monitoring of trough levels. However, this is a retrospective study with small numbers of patients and the results may not apply to other conditioning regimens or to other diseases. Nonetheless, allogeneic HCT is worth studying prospectively in patients with mild renal impairment, especially with the use of calineurin inhibitor-free GVHD prophylaxis with agents such as sirolimus and mycophenolate mofetil.

Recently, based on animal model studies where donor BM engraftment led to kidney graft tolerance, non-myeloablative conditioning (CY, antithymocyte globulin and thymic irradiation) before combined matched sibling donor BM transplant and renal transplant from the same donor was performed in six patients with ESRD on dialysis from stage II or greater PCM with the aim of curing the underlying PCM and enabling acceptance of the renal allograft.77 Before transplant, the patients had between 5 and 65% plasma cells in their BM. CYA was used for 2 months only for immunosuppression, followed by donor leukocyte infusions. All patients had long-term acceptance of their kidney allografts even off immunosuppression for 1.3 to more than 7 years. Three of the six patients achieved CR of the PCM at >2, >4 and >7 years, despite the loss of chimerism in two patients. One patient achieved PR and two patients had progressive disease. This approach is now being further explored in NCT00854139 (combined BMT and renal transplant in PCM with ESRD) trial, which has expanded the inclusion criteria to include 1/6 mismatched related donors (at HLA-A, -B or -DR) as well as matched related donors.78

Conclusions and future directions

Renal failure in PCM is a medical emergency with the need for rapid accurate diagnosis and prompt institution of supportive care and antimyeloma therapy because reversal of renal impairment and recovery from dialysis dependency can occur in up to half the patients early in the course of disease and can lead to substantial survival benefits. The SFLC and serum B2M-free HLA class 1 heavy chain assay can assist in diagnosing PCM associated with renal failure and provide prognostic information in the setting of renal failure where the Durie–Salmon and International Staging System do not.18, 19, 22 A renal biopsy should be performed early in the course of disease as this provides diagnostic and prognostic information, which can guide further therapy. Plasma exchange over a 3-week period will only remove 25% of total FLCs and a randomized controlled trial has not shown plasma exchange to provide any additional benefits over chemotherapy in recovery from dialysis dependency.58 Over a 3-week period, extended hemodialysis with an HCO-HD will remove 90% of total FLCs and shows promising results in the rate of recovery from dialysis in PCM cast nephropathy.60 Mechanical methods of efficient removal of the SFLCs with HCO-HD is being studied in a randomized prospective trial (NCT00700531 EuLITE) in combination with bortezomib chemotherapy for PCM with renal biopsy-proven cast nephropathy.62 Bortezomib and dexamethasone is the front-line chemotherapy for PCM with renal failure and is associated with a superior renal response than IMiDs or conventional chemotherapy.48 The IFM 90 trial has shown ASCT significantly improved the CR rate, EFS and OS compared with conventional chemotherapy for PCM and this is also true for PCM patients with renal failure and even in those on dialysis as shown in Table 4.68 Lee et al.52 found a 5-year OS of 36% and a median survival of 41 months for PCM patients on dialysis who had melphalan 200 mg/m2 conditioned auto-SCT compared with the 3.5-month survival reported by Knudsen et al.3 in PCM patients on dialysis given chemotherapy alone. Twenty-four percent of patients achieved dialysis independence with auto-HCT.52 Successful use of autologous HCT has allowed for the subsequent use of renal transplantation in ESRD, with a median survival of 9.6 years as shown in the European Renal Association-European Dialysis and Transplant Association registry.1

Whether induction chemotherapy with the novel agents bortezomib or the IMiDs with dexamethasone used in combination of three or more agents, followed by high-dose therapy with auto-HCT early in the course for maximum cytoreduction to halt renal damage would increase the possibility of renal function recovery should be evaluated in prospective trials. Ultimately, all PCM patients treated with autologous HCT will relapse as there is a lack of a plateau on the Kaplan–Meier survival curve. It is unknown if PCM with renal failure and ESRD is more commonly associated with adverse cytogenetics or a poor prognosis gene expression signature. Allogeneic HCT is the only curative therapy for myeloma based on the graft-versus-myeloma effect, but has rarely been used in myeloma with renal failure. Allogeneic HCT is worth studying prospectively in patients with mild renal impairment, especially with the use of calcineurin inhibitor-free GVHD prophylaxis with agents such as sirolimus and mycophenolate mofetil. Whether PCM patients with ESRD on dialysis represent a population who would achieve greatest survival benefit from allogeneic hematopoietic cell transplantation combined with renal transplant is now being explored in prospective trials.78

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Wirk, B. Renal failure in multiple myeloma: a medical emergency. Bone Marrow Transplant 46, 771–783 (2011). https://doi.org/10.1038/bmt.2011.8

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Keywords

  • multiple myeloma
  • renal failure
  • dialysis
  • auto-HCT

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