Trial of Plasma Exchange for Acute Renal Failure at the Onset of Myeloma
Trial of Plasma Exchange for Acute Renal Failure at the Onset of Myeloma
Background:Plasma exchange has been suggested to be of theoretical benefit in the treatment
 of acute renal failure at the onset of multiple myeloma. Two small-randomized trials provide
 conflicting evidence.

 Objective: To assess the effect of 5 to 7 plasma exchanges in the treatment of acute renal
 failure at the onset of multiple myeloma.

 Design: Randomized controlled trial with 4 strata (chemotherapy and dialysis dependence) from
 1998 to 2004.

 Setting: Hospital plasma exchange units in 14 major Canadian medical centers.

 Participants: 92 voluntary patients between the ages of 18 to 81 with acute renal failure at
 the onset of myeloma after volume repletion and hypercalcemia.

 Intervention: 5 to 7 plasma exchanges of 50 ml/Kgm of 5% Human Serum Albumin in first 10 days
 plus conventional therapy versus conventional therapy alone.

 Measurements: The primary outcome is a composite measure of death, dialysis dependence or
 Modification of Diet in Renal Disease Study glomerular filtration rate (MDRD GFR) <
 30mg/min/1.73 meter squared at 6 months.
Hypothesis: 5 to 7 plasma exchanges in addition to conventional therapy at onset of myeloma
 with acute renal failure, reduces the composite outcome of death, dialysis dependence or a
 GFR < 30 ml/min/1.73 meter squared at 6 months.

 Entry Criteria: The inclusion criteria are a new diagnosis of multiple myeloma and
 progressive acute kidney failure. The former is defined as a bone marrow aspirate with > 10%
 plasma cells and a monoclonal light chain in the urine, plasma or renal tissue. The latter is
 defined as a serum creatinine > 200 mmol/L with a rise > 50 mmol/L in the preceding two weeks
 despite correction of hypercalcemia, hypovolemia and metabolic acidosis as required in a
 patient with a normal sized kidney on renal ultrasound.

 Exclusion criteria are age < 18 or > 81 years, obstruction on renal ultrasound (required
 examination), use of intravenous contrast or non-steroidal anti-inflammatory drugs during the
 previous 2 weeks, prior treatment for myeloma, pregnancy or inability to provide informed
 consent.

 Research Design: This is a 14 centre randomized clinical trial. Patients who fulfill the
 entry criteria are referred by their oncologist or nephrologist to the apheresis physician at
 their centre who will explain the nature of the study via a human ethics approved letter of
 information. An informed consent is requested and if obtained the participants will be
 randomized centrally by telephone, using a random numbers generator, to either receive or not
 receive plasma exchange. Recruiting physicians are unaware of the treatment allocation prior
 to study entry and subsequent randomization, which is stratified by four strata (Vincristine,
 Adriamycin and Dexamethasone (VAD)/no VAD + on/not on acute hemodialysis with 28 possible
 allocations per strata for each centre). Following random blinded allocation, participants
 are treated in an unblinded manner. Patients are followed with standard forms which indicate
 their serum creatinine, dialysis and survival status at 10 days, 1 month and 6 months.
 Participants are enrolled from September 1998 to October 2003. The study is conducted after
 approval from the institutional ethics review boards of the 14 Canadian sites.

 Treatment: Patients, who are randomized to receive plasma exchange, undergo 5-7 plasma
 exchange procedures within the first 10 days of study entry, concurrent with the initiation
 of chemotherapy. They receive a routine plasma exchange of 50 ml/kg with acid citrate
 dextrose as the anticoagulant via a Gambro BCT, Spectra cell separator using 5% human serum
 albumin and normal saline as the replacement solutions. Chemotherapy will be either Melphalan
 and prednisone taken daily for 4 days every 28 days for up to 12 cycles or with 4 days of
 slow intravenous infusion of Vincristine and Adriamycin coupled with Dexamethasone (VAD)
 given on days 1 to 4, 9 to 12 and 17 to 20 for 28 day cycles up to 6 cycles. Those allocated
 to plasma exchange, have the VAD stopped 1.5 hours before the plasma exchange and no VAD will
 be given during the plasma exchange. Following the exchange, subjects receive a bolus volume
 of VAD that would have been the amount infused during this time period.

 Measurements: Blood and urine testing is performed at the time of study entry at 1 and 6
 months for serum creatinine, serum calcium, serum albumin, 24-hour urine for protein.
 Subjects are classified for severity of multiple myeloma presentation by Durie-Salmon staging
 and GFR is estimated using the Modified Diet in Renal Disease Equation (MDRD).

 Outcome Measurements: Following blinded random allocation to plasma exchange or control, the
 treating physicians who report the primary outcome will be aware of treatment assignment. The
 composite outcome includes death, dialysis dependence and a MDRD GFR calculated from a serum
 creatinine at 6 months follow-up. The addition of a GFR <30ml/min/1.73m2 to our negative
 composite outcome reflects a significant increased risk of death, cardiovascular events and
 hospitalization associated with this degree of kidney impairment.

 Statistical Analysis: All statistical analyses will be conducted using the Statistical
 Package for the Social Sciences (SPSS), Version 12.0 for Windows Release 12.0.0 Chicago:SPSS
 Inc, 2003. All significance testing utilizes two-tailed tests, reflecting the open-ended
 research hypothesis.

 Sample Size: There are few data in the literature on which to base a sample size calculation
 for the composite outcome selected. Based on historical data, which indicated an event rate >
 50%, we calculated a sample size designed to detect an effect of plasma exchange on dialysis
 dependence, without informative censoring from death, at 6 months. In order to detect a
 difference of 50% in that outcome with a type 1 error of 0.05 (two-sided) and a type 2 error
 probability of 0.20, the sample size requirement was 46 per group. We will use this
 historical based power analysis to provide a conservative estimate of sample size to detect a
 statistically significant difference in the composite outcome of death, dialysis dependence
 or a GFR of < 30ml/min/1.73m2 in our future study.

 Comparison of Baseline Characteristics: Pearson's Chi-square with the Yates continuity
 correction will be used to test for statistically significant differences between treatment
 groups on categorical variables in two by two tables. The Mann-Whitney U was employed with
 continuous variables with skewed frequency distributions, while an independent sample t-Test
 was used with normally distributed continuous variables.

 Interim Analysis: An interim analysis will be conducted by the Safety Subcommittee when the
 50th participant had completed the 6-month follow-up to prevent some patients from
 unnecessarily receiving a less effective treatment.

 Outcome Differences: Differences between the plasma exchange and control groups, with respect
 to the primary composite and secondary outcomes at 6 months, will be evaluated by Pearson's
 Chi-square. The time to death by treatment groups will be evaluated by Kaplan-Meier survival
 analysis using a log rank test for differences between groups. Uni- and multi-variate
 modeling of the primary composite outcome will be conducted by means of logistic regression,
 to determine for plasma exchange the unadjusted and adjusted odd ratios for the selected
 baseline determinants of chemotherapy, dialysis, age, urine protein, serum albumin and
 Durie-Salmon stage.
Inclusion Criteria:

 -  New diagnosis of multiple myeloma and progressive acute kidney failure. The former is
 defined as a bone marrow aspirate with > 10% plasma cells and a monoclonal light chain
 in the urine, plasma or renal tissue. The latter is defined as a serum Creatinine >
 200 umol/L with a rise > 50 umol/L in the preceding 2 weeks despite correction of
 hypercalcemia , hypovolemia and metabolic acidosis as required in a patient with a
 normal size kidney on ultrasound.

 Exclusion Criteria:

 -  <18 or > 81 years of age

 -  Obstruction on renal ultrasound (examination required)

 -  Use of intravenous contrast or non-steroidal anti-inflammatory drugs during the
 previous 2 weeks

 -  Prior treatment for myeloma

 -  Pregnancy

 -  Inability to sign informed consent