aEntered another randomized study comparing 2 bortezomib-based chemotherapeutic regimens (bortezomib and dexamethasone vs bortezomib, cyclophosphamide, and dexamethasone) for kidney outcome.
bRequired treatment with hemodialysis because of the presence of at least 1 of the following: hyperkalemia, metabolic acidosis, fluid overload, or symptoms of uremia.
cAllows efficient serum immunoglobulin light chain removal through very large membrane pores.
dIn accordance with the intention-to-treat principle, this patient was included in the analysis of the high-cutoff hemodialysis group.
A, The median follow-up (until hemodialysis independence or, if not, within the 12-month observation period) was 5.1 months (interquartile range [IQR], 1.3-12.1 months) in the high-cutoff hemodialysis group and 8.0 months (IQR, 1.8-12.1 months) in the conventional hemodialysis group. After 3 months, 9 patients in the high-cutoff hemodialysis group reached hemodialysis independence compared with 2 patients in the conventional hemodialysis group.
B, The short vertical bars on the curves indicate censored observations. The median duration of follow-up was 19.5 months (IQR, 12.0-30.8 months) in the high-cutoff hemodialysis group and 17.0 months (IQR, 10.9-27.5 months) in the conventional hemodialysis group.
Amended trial protocol
Statistical analysis plan
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Bridoux F, Carron P, Pegourie B, et al. Effect of High-Cutoff Hemodialysis vs Conventional Hemodialysis on Hemodialysis Independence Among Patients With Myeloma Cast Nephropathy: A Randomized Clinical Trial. JAMA. 2017;318(21):2099–2110. doi:10.1001/jama.2017.17924
Does high-cutoff hemodialysis (allowing efficient serum immunoglobulin light chain removal through very large membrane pores) improve kidney function in patients with myeloma cast nephropathy and severe acute kidney injury?
In this randomized clinical trial that included 98 patients, the hemodialysis independence rate at 3 months was 41% in the high-cutoff hemodialysis group and 33% in the conventional hemodialysis group, a difference that was not statistically significant but had a wide confidence interval.
Although this study found no significant difference in hemodialysis independence at 3 months, further research may be warranted.
Cast nephropathy is the main cause of acute kidney injury in multiple myeloma and persistent reduction in kidney function strongly affects prognosis. Strategies to rapidly remove nephrotoxic serum-free light chains combined with novel antimyeloma agents have not been evaluated prospectively.
To compare the hemodialysis independence rate among patients newly diagnosed with myeloma cast nephropathy treated with hemodialysis using a high-cutoff dialyzer (with very large membrane pores and high permeability to immunoglobulin light chains) or a conventional high-flux dialyzer (with small pores and lower permeability).
Design, Setting, and Participants
Randomized clinical trial involving 98 patients with biopsy-proven myeloma cast nephropathy requiring hemodialysis treated at 48 French centers between July 2011 and June 2016; the final date of follow-up was June 29, 2016.
Intensive hemodialysis (eight 5-hour sessions over 10 days) with either a high-cutoff dialyzer (46 patients) or a conventional high-flux dialyzer (48 patients). All patients received the same chemotherapy regimen of bortezomib and dexamethasone.
Main Outcomes and Measures
Primary end point was hemodialysis independence at 3 months; secondary end points: hemodialysis independence rates at 6 and 12 months, hemodialysis- and chemotherapy-related adverse events, and death.
Among 98 randomized patients, 94 (96%) (median age, 68.8 years [interquartile range, 61.2-75.3 years]; 45% women) were included in the modified intent-to-treat analysis. The hemodialysis independence rate at 3 months was 41.3% (n = 19) in the high-cutoff hemodialysis group vs 33.3% (n = 16) in the conventional hemodialysis group (between-group difference, 8.0% [95% CI, −12.0% to 27.9%], P = .42); at 6 months, the rate was 56.5% (n = 26) vs 35.4% (n = 17), respectively (between-group difference, 21.1% [95% CI, 0.9% to 41.3%], P = .04); and at 12 months, the rate was 60.9% (n = 28) vs 37.5% (n = 18) (between-group difference, 23.4% [95% CI, 3.2% to 43.5%], P = .02). The incidence of hemodialysis-related adverse events was 43% in the high-cutoff hemodialysis group vs 39% in the conventional hemodialysis group; chemotherapy-related serious adverse events, 39% vs 37%, respectively; and at 12 months, 9 patients vs 10 patients died.
Conclusions and Relevance
Among patients with myeloma cast nephropathy treated with a bortezomib-based chemotherapy regimen, the use of high-cutoff hemodialysis compared with conventional hemodialysis did not result in a statistically significant difference in hemodialysis independence at 3 months. However, the study may have been underpowered to identify an early clinically important difference.
clinicaltrials.gov Identifier: NCT01208818
Symptomatic multiple myeloma presents at diagnosis in about 30% of patients with acute kidney injury (AKI), a minority of whom require hemodialysis.1,2 Acute kidney injury is mostly related to myeloma cast nephropathy characterized by precipitation of monoclonal light chains with uromodulin in distal tubules of the kidneys. Cast nephropathy occurs in multiple myeloma with massive light chain secretion, and is favored by factors enhancing light chain precipitability, reducing tubular flow, or both.2 Persistent impairment of kidney function (particularly end-stage kidney disease) induces higher morbidity and mortality, strongly affects quality of life, and is associated with increased costs.1,3
Improvement of kidney function is achievable if a diagnosis is made early. Treatment of cast nephropathy addresses urgent symptomatic measures such as adequate fluid replacement, correction of precipitating factors, and administration of high-dose steroids. In addition, suppression of light chain production with chemotherapy is mandatory. The proteasome inhibitor bortezomib, which does not require dose adaptation to kidney function, is the current standard of care. However, because patients with severe AKI have been excluded from most randomized trials, these recommendations are based on retrospective studies.
The benefit of rapidly removing circulating monoclonal light chains by mechanical approaches has not been established. A randomized clinical trial,4 which was limited by a lack of histological confirmation of cast nephropathy, failed to demonstrate an advantage of plasma exchange. High-cutoff hemodialysis with new-generation membranes (allowing efficient light chain removal through their large pores) has been evaluated in retrospective studies5-11 in which hemodialysis independence was achieved in about 60% of patients. This compares favorably with the hemodialysis independence rate of around 30% reported in most cohorts of patients treated with conventional intermittent hemodialysis during the era of novel antimyeloma agents.12-15
With the objective of assessing the effect of high-cutoff hemodialysis on the hemodialysis independence (discontinuation) rate, this randomized clinical trial was designed to assess patients newly diagnosed with myeloma and severe AKI secondary to biopsy-proven cast nephropathy.
Signed informed consent was obtained from all patients at trial entry. Research was performed in accordance with the Declaration of Helsinki and good clinical practice guidelines and with approval from an institutional review board (Comité de Protection des Personnes, Ile-de-France VI, France).
The MYRE study was conducted between July 2011 and June 2016 within hematology and nephrology departments at 48 French centers. The study enrolled patients with cast nephropathy, who were classified by the severity of kidney impairment. Patients who did not require hemodialysis were enrolled in a part of the MYRE trial that compared 2 chemotherapy regimens and their data are not reported herein.
Patients with an indication for hemodialysis entered the part of the MYRE trial that evaluated high-cutoff hemodialysis compared with conventional hemodialysis. The study used a 2-group parallel randomized clinical trial design (Figure 1).
Patients were selected by investigators based on presence of previously untreated monoclonal gammopathy and AKI (defined according to the Acute Kidney Injury Network criteria16). The patients entered a 4- to 15-day screening period that involved correction of dehydration and other precipitating factors. Treatment of hypercalcemia with intravenous bisphosphonates was allowed. All patients received a 4-day oral course of 40 mg/d of dexamethasone or 400 mg/d of intravenous methylprednisolone. Multiple myeloma and cast nephropathy were diagnostically confirmed. In addition, histological confirmation of cast nephropathy17,18 was required.
After the screening period, patients with (1) a diagnosis of secreting multiple myeloma (according to criteria from the International Myeloma Working Group19), (2) biopsy-proven cast nephropathy, (3) clinical indication for hemodialysis, and (4) neutrophil counts of 1.0 × 109/L or greater and platelet counts of 70 × 109/L or greater were randomized by investigators.
Patients were excluded if they (1) had preexisting chronic kidney disease with an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 m2 for longer than 3 months (calculated using the simplified Modification of Diet in Renal Disease Study equation20), (2) received more than 1 previous course of chemotherapy for myeloma, (3) had an uncontrolled malignant disorder, infection, or peripheral neuropathy, or (4) had associated immunoglobulin light chain amyloidosis in the kidney or overt light chain deposition disease with nodular glomerulosclerosis.21,22
All patients were started on 21-day chemotherapy cycles with bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11) and dexamethasone (20 mg on days 1-2, 4-5, 8-9, and 11-12). After the first chemotherapy cycle, patients who were older than 70 years were continued on 28-day cycles of bortezomib (1.3 mg/m2 weekly) and dexamethasone. Bortezomib was administered after the hemodialysis session on dialysis days, and was initially administered intravenously. Six months after study initiation, the protocol was amended for using the subcutaneous route (the original trial protocol appears in Supplement 1 and the amended trial protocol appears in Supplement 2).
Bortezomib dose was adapted according to standard recommendations for patients who experienced hematologic and neurological toxic effects. Corticosteroid dose could be reduced at the individual investigator’s discretion. Supportive and prophylactic measures included antibiotic therapy with penicillin and combination trimethoprim and sulfamethoxazole. Chemotherapy was started immediately after randomization. After the third chemotherapy cycle, reinforcement with cyclophosphamide (750 mg/m2 administered intravenously on day 1) was recommended for patients without a hematologic response. After the sixth chemotherapy cycle, treatment was determined by the individual investigator. High-dose melphalan with autologous stem cell transplantation was recommended for patients who were younger than 65 years and had an eGFR of 40 mL/min/1.73 m2 or greater.
Initiation of hemodialysis was recommended if patients had hyperkalemia, metabolic acidosis, fluid overload, or symptoms of uremia.23 In both groups, 8 hemodialysis sessions (5-hour duration, blood flow ≥250 mL/min, dialysate flow ≥500 mL/min) were planned over the first 10 days. If needed, patients received 3 additional weekly hemodialysis sessions using the same dialyzer until completion of 3 cycles of chemotherapy. In the high-cutoff hemodialysis group, the 2.1-m2 Theralite dialyzer (Gambro) was used. In the conventional hemodialysis group, a polyacrylonitrile, polysulfone, or polymethylmethacrylate high-flux dialyzer (eg, ultrafiltration coefficient >14 mL/min and surface ≥1.8 m2) could be used. Other hemodialysis procedures were performed according to local practice. If serum albumin level was less than 25 g/L prior to dialysis, a postdialysis perfusion of 20 g of albumin was performed. Local monitoring of serum-free light chain levels was recommended before and after the first 3 hemodialysis sessions, then twice weekly until the predialysis level of involved serum-free light chain was less than 500 mg/L.
An interactive web-response system was used to randomize patients in a 1:1 allocation ratio. The randomization was stratified by center and age (<65 years vs ≥65 years), with prespecified lists that were computer-generated by the study statistician using R software version 3.3.2 (R Project for Statistical Computing), based on permuted block sizes of 4 that remained blinded to investigators. Randomization was intended to occur before the first hemodialysis session. Among patients requiring urgent hemodialysis, a maximum of 7 previous sessions was allowed.
The primary end point was the rate of hemodialysis independence at 3 months after randomization (defined by an eGFR ≥15 mL/min/1.73 m2 15 days after the last hemodialysis session). Individual investigators determined hemodialysis withdrawal. Secondary end points included the hemodialysis independence rate after the first chemotherapy cycle at 6 and 12 months; complete recovery of kidney function (defined by return to baseline level of serum creatinine or eGFR if known or by eGFR ≥60 mL/min/1.73 m2 after the first and third chemotherapy cycles at 6 months and 1 year); eGFR level after the first and third chemotherapy cycles at 6 and 12 months; hematologic response after the first and third chemotherapy cycles at 6 and 12 months; event-free survival, relapse-free survival (myeloma progression-free survival), time to next myeloma therapy, and overall survival; and tolerance to treatment (including hemodialysis-related adverse events). The final date of follow-up was June 29, 2016.
Hematologic response was assessed based on involved serum-free light chain level. Partial hematologic response was defined by a serum-free light chain level reduction of 50% or greater. A very good partial hematologic response was defined by a serum-free light chain level reduction of 90% or greater. Complete hematologic response was defined by a normal serum-free light chain level and a normal ratio of κ to λ with negative serum and urine immunofixation. Among patients who received hemodialysis, progression-free survival referred to the time until myeloma progression or death; progressive disease was defined by an increase of 25% or greater of involved serum-free light chain level from baseline (or entire serum monoclonal immunoglobulin level if present) or by any non–kidney myeloma-defining event. Otherwise, International Myeloma Working Group criteria were used.24 Adverse events (graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events) were systematically recorded. Data were periodically reviewed by an independent data and safety monitoring committee.
Based on experience17 and literature data,12-15 the hemodialysis independence rate was estimated at 30% at 3 months among patients with cast nephropathy and persistent severe AKI treated with bortezomib-containing chemotherapy regimens and hemodialysis with conventional high-flux dialyzers. Given the incidence of myeloma cast nephropathy, the potential risks, and the constraints of intensive hemodialysis, we determined that the minimal clinically important difference would be achievement of a 2-fold hemodialysis independence rate (ie, 60%) in the high-cutoff hemodialysis group. Such a difference was considered achievable because hemodialysis independence rates as high as 60% have been reported using high-cutoff hemodialysis.5-11 To detect a hemodialysis independence rate increase from 30% to 60% at 3 months after randomization, a sample size of 98 patients (49 in each group) was computed based on a 2-sided χ2 test (power of 80% and type I error rate of 5%). The statistical analysis plan appears in Supplement 3.
The analyses were performed on a modified intention-to-treat basis. Only patients without all eligible conditions or who withdrew consent (according to French regulations) were excluded. Summary statistics were reported as medians, interquartile ranges (IQRs), and percentages. Point estimates were computed with 95% CIs.
The χ2 test was used to compare hemodialysis independence at 3, 6, and 12 months and event-free survival (proportion of patients alive and still withdrawn from hemodialysis) at 12 months. Patients with missing data on kidney outcomes because of death were considered as treatment failures. Cumulative incidence of hemodialysis independence was estimated in a competing-risks framework because of deaths prior to hemodialysis independence, and then compared across randomized groups using the Gray test. A logistic regression model was used to provide effect size estimates based on odds ratios (ORs), and then adjust for the treatment comparisons based on potential prognostic factors selected by univariate analyses at the 10% level. In the regression model, missing values of serum-free light chain level reduction were imputed by the modal class.
Progression-free survival and overall survival from date of randomization were estimated using the Kaplan-Meier method and compared using the log-rank test, with treatment effect size measured by hazard ratios (HRs) estimated from Cox models. Proportional hazards assumptions were checked based on weighted residuals (P = .66).25 Safety was evaluated by the rates of reported severe adverse events.
A secondary analysis used a mixed-effects logistic model to account for potential center effects. For the post hoc analysis, a generalized estimating equation model for hemodialysis independence over the 12 months of follow-up was fitted to estimate the time × treatment interaction. Center effects were accounted for in the post hoc analysis using a random-effects estimator that compares the change in the odds for a treated patient vs a control patient from the same center.
All tests were 2-sided and 2-sided P values of <.05 were considered statistically significant. For the secondary end point analyses, there was no adjustment for multiple comparisons. Accordingly, these findings should be considered exploratory. Statistical analysis was performed using SAS version 9.3 (SAS Institute Inc) or R version 3.3.2. In addition, the R package geepack was used.26
Among 98 randomized patients, 94 (96%) (median age, 68.8 years [IQR, 61.2-75.3 years]; 45% women) were included in the modified intent-to-treat analysis. Fifty patients were randomized to the high-cutoff hemodialysis group and 48 patients were randomized to the conventional hemodialysis group (Figure 1). Four patients were excluded (3 because of incorrect diagnosis and 1 withdrew consent).
Baseline characteristics were similar in the 2 groups (Table 1). Light chain isotypes were equally distributed; 50% of patients in the high-cutoff hemodialysis group had light-chain multiple myeloma only compared with 46% of patients in the conventional hemodialysis group. All patients displayed high levels of serum-free light chain. After symptomatic measures were addressed such as fluid replacement, correction of precipitating factors, and administration of high-dose steroids, the median serum creatinine level was 6.4 mg/dL in the high-cutoff hemodialysis group and 7.3 mg/dL in the conventional hemodialysis group. At least 1 precipitating factor (most commonly use of nonsteroidal anti-inflammatory drugs) was recorded in 51% of the patients.
Urine protein electrophoresis (when available) invariably showed prominent light-chain proteinuria and the median albuminuria level was less than 10%. Kidney biopsy was complicated by severe bleeding in 2 patients, including 1 in the high-cutoff hemodialysis group who died 5 months later after multiple complications. Typical myeloma casts were observed in 92 patients and indirect lesions of cast nephropathy in 2 patients. Eighty-two patients had pure cast nephropathy, 2 had associated light chain crystals in proximal tubules, and 10 had concomitant light chain deposition disease without significant glomerular lesions by light microscopy.21,22
The hemodialysis independence rate at 3 months was 41.3% (n = 19) in the high-cutoff hemodialysis group vs 33.3% (n = 16) in the conventional hemodialysis group (between-group difference, 8.0% [95% CI, −12.0% to 27.9%], P = .42). The estimate in the post hoc secondary analysis accounting for center effects was similar (OR, 1.27 [95% CI, 0.50 to 3.27]; P = .62).
At 6 months, the hemodialysis independence rate in the high-cutoff hemodialysis group was 56.5% (n = 26) compared with 35.4% (n = 17) in the conventional hemodialysis group (between-group difference, 21.1% [95% CI, 0.9%-41.3%]; OR, 2.37 [95% CI, 1.03-5.44]; P = .04); at 12 months, it was 60.9% (n = 28) vs 37.5% (n = 18), respectively (between-group difference, 23.4% [95% CI, 3.2%-43.5%]; OR, 2.59 [95% CI, 1.13-5.96]; P = .02). Kidney recovery (hemodialysis independence) occurred after a median of 2 months in the high-cutoff hemodialysis group and after a median of 1 month in the conventional hemodialysis group (Table 2). The cumulative incidence of hemodialysis independence within 12 months after randomization appears in Figure 2A; the 12-month estimate was 60.9% (95% CI, 47.0%-74.8%) in the high-cutoff hemodialysis group and 38.4% (95% CI, 24.5%-52.2%) in the conventional hemodialysis group (P = .04).
At 12 months, among 75 patients, 41 were still alive and no longer receiving hemodialysis (24/37 [64.9%] in the high-cutoff hemodialysis group and 17/38 [44.7%] in the conventional hemodialysis group; between-group difference, 20.2% [95% CI, −2.6% to 42.9%]; OR, 2.28 [95% CI, 0.90 to 5.77]; P = .15) (Table 2) and had median eGFR values of 36 mL/min/1.73 m2 (IQR, 25 to 63 mL/min/1.73 m2) and 39 mL/min/1.73 m2 (IQR, 27 to 53 mL/min/1.73 m2), respectively. One patient in each group was restarted on hemodialysis (at 22 months in the high-cutoff hemodialysis group and at 13 months in the conventional hemodialysis group).
At 12 months, 19 patients had died (9 [20%] in the high-cutoff hemodialysis group and 10 [21%] in the conventional hemodialysis group). Of these 19 patients, 9 had been withdrawn from hemodialysis (5 in the high-cutoff hemodialysis group and 4 in the conventional hemodialysis group). Within a median follow-up of 17.5 months (IQR, 12.0-30.0 months), 29 patients had died (13 in the high-cutoff hemodialysis group and 16 in the conventional hemodialysis group; HR, 0.76 [95% CI, 0.36-1.58]; log-rank test P = .46; Figure 2B). Causes of death were myeloma progression (n = 15; 9 in the high-cutoff hemodialysis group and 6 in the conventional hemodialysis group), infections (n = 7; 1 and 6, respectively), cardiovascular (n = 3; all in the conventional hemodialysis group), hemorrhage (n = 1 in the high-cutoff hemodialysis group), and other or unknown (n = 3; 2 in the high-cutoff hemodialysis group and 1 in the conventional hemodialysis group).
The median time from diagnosis of AKI to initiation of bortezomib was 8.0 days (IQR, 5.0-12.0 days) in the high-cutoff hemodialysis group and 9.0 days (IQR, 5.5-13.0 days) in the conventional hemodialysis group. Forty patients in each group received at least 3 courses of bortezomib and dexamethasone. Cyclophosphamide was added for 13 patients (28%) in the high-cutoff hemodialysis group after a mean of 4.4 months (SD, 1.0 month) and for 11 patients (23%) in the conventional hemodialysis group after a mean of 4.2 months (SD, 0.6 months).
Chemotherapy was prematurely discontinued because of toxic effects in 5 patients (3 in the high-cutoff hemodialysis group and 2 in the conventional hemodialysis group). The incidence of grade 3 or greater cytopenia and infectious complications was not significantly different. Grade 3 or greater peripheral neuropathy was observed in 1 patient in the high-cutoff hemodialysis group and in 4 patients in the conventional hemodialysis group. At least 1 serious adverse event was recorded in 39% of the patients in the high-cutoff hemodialysis group and in 37% of the patients in the conventional hemodialysis group.
At 3 months, the rate of hematologic response (partial response, very good partial response, and complete response) was 89.1% (n = 41) in the high-cutoff hemodialysis group and 62.5% (n = 30) in the conventional hemodialysis group (between-group difference, 26.6% [95% CI, 9.8% to 43.4%]; OR, 4.9 [95% CI, 1.6 to 14.7]; P = .003; Table 2). At 3 months, the rate of very good partial or complete hematologic response was 60.9% (n = 28) in the high-cutoff hemodialysis group and 43.7% (n = 21) in the conventional hemodialysis group (between-group difference, 17.2% [95% CI, −3.3% to 37.5%]; OR, 2.00 [95% CI, 0.88 to 4.55]; P = .22).
After the first cycle of bortezomib and dexamethasone, the median reduction rate in involved serum-free light chain level was 89% (95% CI, 61% to 99%) in the high-cutoff hemodialysis group and 71% (95% CI, 22% to 91%) in the conventional hemodialysis group (P = .02). Twenty patients (43.5%) in the high-cutoff hemodialysis group achieved a serum-free light chain level of less than 500 mg/L compared with 15 patients (31.2%) in the conventional hemodialysis group (between-group difference, 12.3% [95% CI, −7.7% to 32.1%]; OR, 1.69 [95% CI, 0.59 to 3.94]; P = .29) (Table 2).
Autologous stem cell transplantation was performed in 13 patients in the high-cutoff hemodialysis group and in 6 patients in the conventional hemodialysis group. Of these patients, 4 in the high-cutoff hemodialysis group and 1 in the conventional hemodialysis group still required hemodialysis and none achieved subsequent kidney response.
The median progression-free survival was 35 months (95% CI, 26 months-not available) in the high-cutoff hemodialysis group and 20 months (95% CI, 17-31 months) in the conventional hemodialysis group (HR, 0.57 [95% CI, 0.33-0.99]; P = .046).
Compared with standard membranes used in hemodialysis, the membrane used for patients in the high-cutoff hemodialysis group produced a significantly higher reduction of both κ and λ light chain levels after the first and third hemodialysis session (P < .001; Table 2). Incidence of hemodialysis-related adverse events of any grade was 43% in the high-cutoff hemodialysis group and 39% in the conventional hemodialysis group (P = .83). One patient in the high-cutoff hemodialysis group discontinued the procedure because of intolerance. A postdialysis perfusion of 20 g of albumin was required for 41% of the high-cutoff hemodialysis sessions and 4% of the conventional hemodialysis sessions because the predialysis albumin level was less than 25 g/L.
The bivariable analysis of the variables associated with hemodialysis independence within 12 months appears in Table 3. In the multivariable analysis, the main variables were whole immunoglobulin–secreting myeloma, involved serum-free light chain level of 500 mg/L or less after 1 cycle of chemotherapy, and randomization to the high-cutoff hemodialysis group. After adjusting on myeloma subtype (whole immunoglobulin or myeloma-secreting light chain only) and serum-free light chain level reduction of 500 mg/L or less, randomization to the high-cutoff hemodialysis group was still associated with an increased occurrence of hemodialysis independence within 12 months (OR, 2.78 [95% CI, 1.13-6.80]; P = .03). Post hoc analysis based on the generalized estimating equation model showed that there was a significant time × treatment interaction for the evolution of response during the 12 months of follow-up (P = .03).
In this randomized clinical trial that included patients newly diagnosed with cast nephropathy treated with a bortezomib-based regimen, the primary outcome of an increase in hemodialysis independence rate from 30% to 60% at 3 months with high-cutoff hemodialysis was not reached. However, the study may have lacked power to detect such a difference at this early end point.
Randomization occurred after appropriate symptomatic measures were addressed such as adequate fluid replacement, correction of precipitating factors, and administration of high-dose steroids among patients with established AKI who still required hemodialysis. All patients received the same bortezomib-based regimen and hemodialysis intensity to specifically assess the effect of the 2.1-m2 high-cutoff dialyzer on kidney outcome. In both groups, the intensive hemodialysis schedule resulted in a good tolerance profile and acceptable feasibility in standard nephrology facilities. Higher albumin loss27 in the high-cutoff hemodialysis group did not result in more frequent complications with the postdialysis perfusion. High-cutoff hemodialysis allowed higher clearance of both κ and λ light chains.
In all participants, the diagnosis of myeloma cast nephropathy was histologically confirmed. The study highlights the characteristic features of cast nephropathy, including high serum-free light chain levels, predominant light chain proteinuria, and the frequency of precipitating factors, particularly nonsteroidal anti-inflammatory drugs. In routine practice, the risk-benefit ratio of kidney biopsy remains questionable because of the potential for hemorrhagic complications; therefore, biopsy should be primarily considered in patients with atypical features such as significant albuminuria.21,22
Results of this trial are in keeping with most retrospective studies that evaluated patients treated with high-cutoff dialyzers5-11 and conventional dialyzers.12-15 Preliminary results of another unpublished randomized trial that addressed intensive high-cutoff hemodialysis in myeloma cast nephropathy28 showed a kidney function recovery rate of 60% in the high-cutoff group. A similar high hemodialysis independence rate was observed in that study’s control group. In contrast with the current study, randomization occurred without a screening period, allowing inclusion of patients who might have lost indication for hemodialysis after symptomatic measures were addressed. In addition, frontline use of a bortezomib-based triplet and differences in hemodialysis schedule (daily 8-hour hemodialysis sessions using two 1.1-m2 high-cutoff dialyzers vs 3 weekly 4-hour sessions in the conventional hemodialysis group) resulted in a high incidence of infections and decreased overall survival in the high-cutoff hemodialysis group.
This trial reinforces literature supporting the importance of rapid and deep serum-free light chain response for subsequent kidney outcome.6,8,29,30 An independent predictive factor of hemodialysis independence at 12 months was the achievement of a predialysis serum-free light chain level below 500 mg/L after the first cycle of chemotherapy, a value considered a threshold for cast formation.2 Baseline serum-free light chain level was not predictive, presumably because of limitations of the nephelometric assay for high serum-free light chain values.31 However, light chain only multiple myeloma, which is the most frequent cause of cast nephropathy through the high production rate of nephrotoxic light chains,17 was associated with a lower probability of kidney recovery. To remove nephrotoxic serum-free light chains in patients with severe AKI, the use of plasma exchange also has been advocated.29,30 High-cutoff hemodialysis may be preferred because it carries a lower risk of adverse effects and allows higher serum-free light chain removal with less rebound effect.27
Additional studies are required to optimize the modalities of light chain removal in cast nephropathy. Because the cost of high-cutoff dialyzers is a concern, evaluation of global financial weight, taking into account the duration of hemodialysis support, is desirable.11 Future studies may include patients with AKI at the time of myeloma relapse, which is an increasingly observed situation for which the probability of a profound and swift serum-free light chain response with chemotherapy is less predictable than among patients with newly diagnosed myeloma.
This study has several limitations. First, the expected increase in hemodialysis independence rate from 30% to 60% at 3 months used in the sample size computation was arbitrarily chosen from retrospective studies. A smaller difference in the kidney recovery rate may have been of clinical significance; therefore, this study could be considered underpowered. Second, although the trial showed significantly higher kidney recovery rates at 6 and 12 months in the high-cutoff hemodialysis group, these were secondary end points and need to be interpreted as exploratory because of the potential for type I error. It was not anticipated that high-cutoff hemodialysis would allow delayed kidney function response (Figure 2A) because this type of response was rarely reported.32,33 Delayed improvement of kidney function may reflect selection of patients with severe AKI because of the screening period before randomization, which presumably eliminated patients for whom supportive care and steroids alone led to kidney recovery.
Third, another potential limitation was the use of a bortezomib-dexamethasone doublet instead of a triplet because frontline bortezomib-based triplets are increasingly used in the treatment of myeloma to produce rapid tumor mass reduction.34 However, available data do not suggest a superiority of triplet combinations in AKI,12-15 except for a retrospective study35 of 31 patients, in which hemodialysis independence was higher among the 13 patients who received different triplets. The benefit-risk ratio of intensified chemotherapy (particularly regarding infectious complications) warrants careful investigation among frail patients with severe AKI who sometimes require referral to intensive care units at diagnosis (required by 16% of patients in the current study). Moreover, the potential nephrotoxicity of certain novel agents36 and the increased risk of tumor lysis syndrome with more effective antimyeloma combinations37 should be considered. In this trial, chemotherapy was reinforced with cyclophosphamide in cases of insufficient hematologic response. Chemotherapy was similarly delivered in both groups, and both groups had high hematologic response rates and good tolerance profiles. The achievement of more frequent partial response at 3 months in the high-cutoff hemodialysis group (Table 2) was likely caused by better serum-free light chain removal through hemodialysis.
Fourth, although the primary outcome was not achieved, the trial showed significantly higher kidney recovery rates at 6 and 12 months in the high-cutoff hemodialysis group. Nevertheless, those results should be considered exploratory given the potential inflation of the type I error rate because of the numerous secondary and post hoc analyses.
Among patients with myeloma cast nephropathy treated with a bortezomib-based chemotherapy regimen, the use of high-cutoff hemodialysis compared with conventional hemodialysis did not result in a statistically significant difference in hemodialysis independence at 3 months. However, the study may have been underpowered to identify an early clinically important difference.
Corresponding Author: Frank Bridoux, MD, PhD, Department of Nephrology, Centre Hospitalier Universitaire, 2 Rue de la Milétrie, 86021 Poitiers, France (email@example.com).
Accepted for Publication: November 6, 2017.
Author Contributions: Drs Bridoux and Fermand had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Bridoux, Arnulf, Combe, Jaccard, Moulin, Chevret, Fermand.
Acquisition, analysis, or interpretation of data: Bridoux, Carron, Pegourie, Alamartine, Augeul-Meunier, Karras, Joly, Peraldi, Arnulf, Vigneau, Lamy, Wynckel, Kolb, Royer, Rabot, Benboubker, Jaccard, Moulin, Knebelmann, Chevret, Fermand.
Drafting of the manuscript: Bridoux, Chevret, Fermand.
Critical revision of the manuscript for important intellectual content: Bridoux, Carron, Pegourie, Alamartine, Augeul-Meunier, Karras, Joly, Peraldi, Arnulf, Vigneau, Lamy, Wynckel, Kolb, Royer, Rabot, Benboubker, Combe, Jaccard, Moulin, Knebelmann.
Statistical analysis: Chevret.
Obtained funding: Bridoux, Combe, Fermand.
Administrative, technical, or material support: Bridoux, Chevret, Fermand.
Supervision: Bridoux, Chevret, Fermand.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bridoux reported receiving lecture fees from Amgen, Baxter, Celgene, and Janssen. No other disclosures were reported.
Funding/Support: The study was funded by the Programme Hospitalier de Recherche Clinique-Cancer 2009 grant from the French Ministry of Health, French National Hospital Program for Clinical Research Cancer, 2009. Gambro Dialyzatoren provided the high-cutoff dialyzers used in the study. Janssen France provided bortezomib. The Binding Site company provided kits for measurement of serum-free light chains.
Role of the Funder/Sponsor: The French Ministry of Health, Gambro Dialyzatoren, Janssen France, and Binding Site had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Group Information: The MYRE Study Group members are Gabriel Choukroun, Maité Jaureguy, Caroline Lecaque, Laurent Ghandi Damaj, Bérangère Gruson, Raifah Makdassi, Jean-Pierre Marolleau, Lavinia Merlusca, and Ioana Vaida (Centre Hospitalier Universitaire, Amiens, France); Jean-François Augusto, Virginie Besson, Maud Cousin, Mamoun Dib, Céline Onno, Johnny Sayegh, Amélie Simon, Jean-François Subra, and Florence Villemain (Centre Hospitalier Universitaire, Angers, France); Jérémie Diolez and Myriam Pujo (Centre Hospitalier, Angoulême, France); Pierre Gobert and Borhane Slama (Centre Hospitalier, Avignon, France); Jean-Marc Chalopin, Adrien Chauchet, Eric Deconinck, Philippe Delaby, Didier Ducloux, Jean Fontan, Marian Heczko, Philippe Helias, Marie-Thérèse Rubio, and Jacqueline Vuillier (Centre Hospitalier Universitaire, Besançon, France); Yahsou Delmas, Axelle Lascaux, Gérald Marit, Claire Rigothier, and Sophie Salazar-Dimicoli (Centre Hospitalier Universitaire, Bordeaux, France); Pierre Bataille, Bachra Choufi-Belghoul, Maite Daroux, and Rafik Mesbah (Centre Hospitalier, Boulogne-sur-Mer, France); Firas Easy, Abdallah Maakaroun, Imad Mahfouz, Edward Maksour, Alain Nony, and Khair Rifard (Centre Hospitalier, Bourges, France); Christian Berthou, Emilie Cornec-Le Gall, Jean-Richard Eveillard, Morgane Gosselin, Catherine Hantorel-Saliou, Jean-Christophe Ianotto, Yannick Le Meur, and Isabelle Segalen (Centre Hospitalier Universitaire, Brest, France); Hyacinthe Atchroué, Khaled Benabed, Cindy Castrale, Sylvie Chantepie, Valérie Chatelet, Stéphane Cheze, Maxence Ficheux, Patrick Henri, Michel Leporrier, Thierry Lobbedez, Margaret Macro, and Oumédaly Reman (Centre Hospitalier Universitaire, Caen, France); Jacques-Olivier Bay, Carine Chaleteix, Cyril Garrouste, Anne-Elisabeth Heng, Martin Soubrier, Aurélien Tiple, and Marie-Pierre Valli (Centre Hospitalier Universitaire, Clermont-Ferrand, France); Selwa Bouledroua, Valérie Caudwell, Sophie Cereja, Alain Devidas, Catherine Gaudry, Stéphanie Haiat, Agathe Pardon, Charlotte Petitdidier, and Célia Salanoubat (Centre Hospitalier, Corbeil-Essones, France); Jean-Noël Bastie, René-Olivier Casasnovas, Denis Caillot, Emmanuelle Ferrant, Ingrid Lafon, Christiane Mousson, Jean Michel Rebibou, and Gilbert Zanetta (Centre Hospitalier Universitaire, Dijon, France); Claude Eric Bulabois, Jean-Yves Cahn, Stéphane Courby, Fréderic Garban, Remy Gressin, Jocelyne Maurizi-Balzan, Lysiane Molina, Rachel Tetaz, Anne Thiebaut-Bertrand, and Philippe Zaoui (Centre Hospitalier Universitaire, Grenoble, France); Antoine Durrbach, Hélène Francois, and Xavier Mariette (Centre Hospitalier Universitaire, Kremlin Bicêtre, Assistance Publique Hôpitaux de Paris, Paris, France); Sebastien Delbes, Emmanuel Fleck, Fannie Leroy, François Pourreau, and Carole Sarfati (Centre Hospitalier, La Rochelle, France); Thierry Chatellier, Mohamed Diab Mahmoud, Tifenn L’Haridon, Hervé Maisonneuve, Jean-Noël Ottavioli, Frank Priou, Mourad Tiab, and Bruno Villemagne (Centre Hospitalier, La Roche-sur-Yon, France); Evelyne Mac-Namara, Pierre Morel, and Daniela Robu (Centre Hospitalier, Lens, France); Manuel Cliquennois, Charlotte Dujardin, Thierry Facon, Maxime Hoffmann, Xavier Leleu, Nasser Nandini, Laurent Pascal, Géraldine Robitaille, Christian Rose, and Elisabeth Semtem (Centre Hospitalier Universitaire, Lille, France); Dominique Bordessoule, Marie Essig, Stéphane Girault, Marie-Pierre Gourin, and Pascal Turlure (Centre Hospitalier Universitaire, Limoges, France); Deborah Chaintreuil, Fitsum Guebre, Laurent Juillard, Emilie Karbacher, Sandrine Lemoine, and Solenne Pelletier (Hôpital Édouard Herriot, Lyon, France); Marie Bouteloup, Bertrand Coiffier, Anne Danielou-Lazareth, Sophie Dupire, Daniel Espinouse, Denis Fouque, Fadhéla Hind, Lionel Karlin, Anne-Sophie Michallet, Gilles Salles, and Bouafia Sauvy (Centre Hospitalier Universitaire, Lyon Sud, France); Stéphane Burtey, Régis Costello, Laure Farnault, Noémie Jourde-Chiche, and Cédric Mercier (Centre Hospitalier Universitaire Conception, Marseille, France); Xavier Belenfant, Martine Lenoble, and Mélanie Roland (Centre Hospitalier, Montfermeil-Montreuil, France); Stéphanie Bourry, Thanh Cao-Huu, Joelle Cridlig, Luc Frimat, Cyrille Hulin, Marc Ladriere, Nicolas Peters, and Julien Santini (Centre Hospitalier Universitaire, Nancy, France); Nicolas Blin, Aline Clavert, Grégoire Couvrat-Desvergnes, Catherine Delcroix, Viviane Dubreuil, Fadi Fakhouri, Thomas Gastinne, Maryvonne Hourmant, Frédéric Lavainne, Steven Le Gouill, Marie Lino Daniel, Béatrice Mahe, Aurélie Meurette, Philippe Moreau, and Virginie Roland (Centre Hospitalier Universitaire, Nantes, France); Vincent Esnault, Guillaume Favre, Jean-Gabriel Fuzibet, Olivier Moranne, Frederick Sanderson, and Nathalie Tieulie (Centre Hospitalier Universitaire, Nice, France); Alexandra Colombo, Delphine Labatut, Carine Motard, Eric Moumas, Anne Sechet, and Cathy Verove (Centre Hospitalier, Niort, France); Didier Bouscary (Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France); Sophie Chauvet, Christian D’Auzac, Elsa Guiard, Christian Jacquot, Charlene Levi, Mélanie Roland, Eric Thervet, and Claire Trivin (Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France); Caroline Algrin, Sylvain Choquet, Corinne Isnard-Bagnis, Véronique Leblond, Lucile Mercadal, Damien Roos-Weil, Dorota Szumilak, and Marcia Venditto (Hôpital La Pitié-Salpétrière, Assistance Publique Hôpitaux de Paris, Paris, France); Richard Delarue, Khalil El Karoui, Bruno Guery, Aurélie Hummel, Aude Servais, Felipe Suarez, Thomas Stehle, and Nathalie Vittoz (Hôpital Necker, Assistance Publique Hôpitaux de Paris, Paris, France); Marine Baron, Stéphanie Harel, and Marguerite Vignon (Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France); Marc Bauwens, Simohamed Belmouaz, Estelle Desport, Laure Ecotière, François Guilhot-Gaudefroy, Antoine Thierry, Guy Touchard, and Vincent Javaugue (Centre Hospitalier Universitaire, Poitiers, France); Alexandre Debrumetz, Alain Delmer, Chantal Himberlain, Quoc Hung Le, Natacha Noel, and Philippe Rieu (Centre Hospitalier Universitaire, Reims, France); Marc Bernard, Xavier Cahu, Charles Dauriac, Olivier Decaux, Thibault Dolley-Hitze, Martine Escoffre-Barbe, Thierry Frouget, Morgane Gosselin, Atman Hadj Elmerabet, Roch Houot, Marie-Pascale Morin, Stanislas Nimubona, and Joseph Rivalan (Centre Hospitalier Universitaire, Rennes, France); Denis Guyotat, Jérôme Jaubert, Nicolas Maillard, Christophe Mariat, Manolie Mehdi, and Damien Thibaudin (Centre Hospitalier Universitaire, Saint-Etienne, France); Ana Berceanu, Karim Bilger, Laura Braun, Sophie Caillard, Cécile Fohrer, Raoul Herbrecht, Bruno Lioure, Kun-Lun Liu, Shanti Natarajan-Ame, and Peggy Perrin (Centre Hospitalier Universitaire, Strasbourg, France); Michel Delahousse, Sylvie Glaisner, Gaelle Pelle, and Leila Tricot (Hôpital Foch, Suresnes, France); Jean-Jacques Boffa, Alexandre Cez, Géraldine D’Ythurbide, Alexandre Hertig, Anne Kolko-Labadens, Fabrice Mihout, Julie Peltier, Christophe Ridel, Pierre Ronco, and Eric Rondeau (Hôpital Tenon, Assistance Publique Hôpitaux de Paris, Paris, France); Béatrice Birmele, Matthias Büchler, Anne Fournier, Maud François, Philippe Gataut, Jean-Michel Halimi, Prisca Mutinelli-Szymanski, Martine Pelain, and Benedicte Sautenet (Centre Hospitalier Universitaire, Tours, France); and Jean-Louis Bacri, Dominique Fleury, Mary-Jane Guerry, Nathalie Housieaux, Jean-Paul Pollet, Thomas Quemeneur, Laurence Vrigneaud, and Philippe Vanhille (Centre Hospitalier, Valenciennes, France).
Additional Contributions: We are grateful to the following clinical research associates for their help in collecting data: Patricia Allenou-Lemaire, CRA, and Elise Chikhi, CRA (both with Department of Nephrology, Centre Hospitalier Universitaire, Poitiers, France); and Dalila Gherab, CRA, Amélie Marouane, CRA, Fabienne Prieur, CRA, and Malika Yahmi, CRA (all with Department of Biostatistics and Medical Information, Centre Hospitalier Universitaire Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France). None of these persons received compensation for their role in the study.
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