Trial Information

A Randomized Controlled Trial of Plasma Exchange for Acute Renal Failure at the Onset of Myeloma

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.