Trial of Plasma Exchange for Acute Renal Failure at the Onset of Myeloma
Condition: Multiple Myeloma; Acute Renal Failure
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Renal Insufficiency; Acute Kidney Injury
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Plasma Exchange
Intervention type(s): Procedure
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Plasma Exchange; Myeloma; Acute renal failure; Light Chains; Bence Jones Proteins; Kidney Function