Results of a Multicenter Open-Label Randomized Trial Evaluating Infusion Duration of Zoledronic Acid in Multiple Myeloma Patients (the ZMAX Trial)

Multiple myeloma (MM) is a malignant plasma cell disorder that accounts for 10% of all hematologic malignancies diagnosed in the United States. In 2010, approximately 20,000 new cases and almost 11,000 deaths are expected.¹ Osteolytic bone destruction leads to many of the clinical manifestations observed in patients with MM.² In a series of more than 1,000 patients, osteolytic lesions were present in approximately 67% of newly diagnosed MM patients, and an additional 17% of patients developed skeletal lesions during the course of their disease.² Many already had skeletal complications at diagnosis: 58% had bone pain, 26% had pathologic fractures, and 22% had compression fractures.² Furthermore, renal failure is present in nearly 20% of newly diagnosed MM patients and occurs in almost 50% of patients during the course of their disease.³ Hypercalcemia of malignancy (HCM) and precipitation of monoclonal light chains in the renal tubules are the major causes of renal failure in this patient population.⁴

Considerable research has focused on preventive and/or treatment strategies to reduce bone complications in MM patients. In a large, international, randomized, phase III trial of MM patients with at least one osteolytic bone lesion, zoledronic acid (Zometa), a potent intravenous (IV) bisphosphonate that inhibits osteoclast-mediated bone resorption, reduced the overall risk of developing skeletally related events (SREs) including HCM by 16% (P = 0.03) compared with standard-dose pamidronate 90 mg (Aredia), another less potent IV bisphosphonate.^{[5] and [6]} As a result of this study and others, monthly infusion of zoledronic acid at 4 mg over at least 15 minutes has become a common treatment for MM patients with bone involvement.

The U.S. Food and Drug Administration (FDA) has approved zoledronic acid use for patients with MM, documented bone metastases from solid tumors, or HCM.^{[5], [6], [7] and [8]} The FDA-approved dose for MM patients is 4 mg administered as an IV infusion over at least 15 minutes every 3–4 weeks for patients with a creatinine clearance (CrCl) of >60 mL/min; when treating HCM, zoledronic acid 4 mg is administered as a single IV infusion.^{[5], [6], [7] and [8]}

Zoledronic acid is primarily excreted intact through the kidney.⁹ Preexisting kidney disease and receipt of multiple cycles of bisphosphonate therapy are risk factors for subsequent kidney injury.⁷ In animal studies, IV bisphosphonates have been shown by histology to precipitate renal tubular injury when administered as a single high dose or when administered more frequently at lower doses.^{[10] and [11]} Additionally, renal dysfunction, as evidenced by increased serum creatinine (SCr) levels, was reported among patients treated at a dose of 4 mg with an infusion time of 5 minutes.^{[7] and [12]} When 4 mg zoledronic acid was administered with a longer infusion time of 15 minutes in large randomized trials, no significant difference between the renal safety profiles of zoledronic acid and pamidronate was reported.⁶

One hypothesis about the development of kidney injury associated with zoledronic acid is that it may be related to the peak plasma concentration as determined by infusion time. Results of a study evaluating patients with MM or other cancer types and bone metastases demonstrated that prolonging the infusion time of zoledronic acid reduced the end-of-infusion peak plasma concentration (C_max) by 35%.⁹ Another theory about the development of kidney dysfunction is that insoluble precipitates may form when the blood is exposed to high concentrations of bisphosphonates as this has been shown to occur in vitro.^{[9] and [13]} Therefore, the current management of renal adverse events (AEs) related to IV bisphosphonates is based on these theories so that reducing the peak plasma concentration of zoledronic acid may prevent the possible formation of insoluble precipitates through (1) lowering the dose, (2) slowing the infusion rate, or (3) increasing the volume of infusate.^{[5], [12] and [14]}

Because MM patients are predisposed to experience deterioration of renal function, it is critical to ensure that zoledronic acid does not contribute to, or exacerbate, a decline in kidney function. To determine if increasing the duration of zoledronic acid infusion further results in improved renal safety, a multicenter, open-label, randomized study was designed to compare a 15-minute vs a 30-minute infusion time with an increased volume of infusate from 100 to 250 mL administered every 3–4 weeks to MM patients with osteolytic bone disease.

Patients and Methods

Patient Population

Men and women (≥18 years of age) with a diagnosis of MM, at least one bone lesion on plain film radiographs, stable kidney function (defined as two SCr level determinations of <3 mg/dL obtained at least 7 days apart during the screening period), calculated CrCl of at least 30 mL/min, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less, and a life expectancy of at least 9 months were eligible. The study excluded patients with prolonged IV bisphosphonate use (defined as use of zoledronic acid longer than 3 years or pamidronate longer than 1 year [total bisphosphonate duration could not exceed 3 years]), corrected serum calcium level at first visit of <8 or ≥12 mg/dL, or diagnosis of amyloidosis. Additionally, patients who had known hypersensitivity to zoledronic acid or other bisphosphonates; were pregnant or lactating; had uncontrolled cardiovascular disease, hypertension, or type 2 diabetes mellitus; or had a history of noncompliance with medical regimens were not eligible.

Study Design

This open-label, randomized pilot study was conducted at 45 centers in the United States. Before randomization, patients were stratified based on length of time of prior bisphosphonate treatment (bisphosphonate-naive vs ≤1 year prior bisphosphonate therapy vs >1 year prior bisphosphonate therapy) and baseline calculated CrCl (>75 vs >60–75 vs ≥30–≤60 mL/min).

Treatment and Evaluation

Patients were randomized to receive zoledronic acid 4 mg as either a 15- or a 30-minute IV infusion. The volume of infusate was increased from the standard 100 to 250 mL to provide additional hydration; infusions were administered every 3–4 weeks for up to 24 months. At the time this study was developed, the 4 mg dose was used because the dose adjustments for renal dysfunction in the current FDA labeling for zoledronic acid were not yet available.⁷ Patients were required to take a calcium supplement containing 500 mg of calcium and a multivitamin containing 400–500 IU of vitamin D, orally, once daily, for the duration of zoledronic acid therapy.

HCM during the trial was defined as a corrected serum calcium level ≥12 mg/dL or a lower level of hypercalcemia accompanied by symptoms and/or requiring active treatment other than rehydration. If HCM occurred more than 14 days after a zoledronic acid infusion, patients could receive a zoledronic acid infusion as treatment for HCM, even if this required administration before the next scheduled dose. Patients were allowed to remain in the study provided that HCM did not persist or recur. However, zoledronic acid treatment was immediately discontinued if patients developed HCM ≤14 days after study drug infusion; these patients received HCM treatment at the discretion of their treating physician. Also, patients experiencing HCM discontinued calcium and vitamin D supplements.

Within 2 weeks before each dose, enrolled patients were assessed for increase in SCr levels. For patients experiencing a clinically relevant increase in SCr level (defined as a rise of 0.5 mg/dL or more or a doubling of baseline SCr levels), administration of zoledronic acid was suspended until the SCr level fell to within 10% of the baseline value. During the delay, SCr levels were monitored at each regularly scheduled study visit (every 3–4 weeks) or more frequently if deemed necessary by the investigator. If the SCr level fell to within 10% of the baseline value within the subsequent 12 weeks, zoledronic acid was restarted with an infusion time that was increased by 15 minutes over the starting duration. If the rise in SCr level did not resolve within 12 weeks or if the patient experienced a second clinically relevant increase in SCr level after modification of the infusion time, treatment was permanently discontinued. Otherwise, patients were followed for 24 months. A final safety assessment, including a full hematology and chemistry profile, was performed 28 days after the last infusion.

A pretreatment dental examination with appropriate preventive dentistry was suggested for all patients with known risk factors for the development of osteonecrosis of the jaw (ONJ) (eg, cancer chemotherapy, corticosteroids, poor oral hygiene, dental extraction, or dental implants). Throughout the study, patients reporting symptoms that could be consistent with ONJ were referred to a dental professional for assessment; if exposed bone was noted on dental examination, the patient was referred to an oral surgeon for further evaluation, diagnosis, and treatment. A diagnosis of ONJ required cessation of zoledronic acid therapy and study discontinuation.

Pharmacokinetic Sampling

At the first infusion visit (visit 2), pharmacokinetic (PK) parameters were measured. If PK samples were not obtained at visit 2, they could be obtained at visit 3 (otherwise, they were recorded as not done). All blood samples for PK analysis were drawn from the contralateral arm. For patients receiving the 15-minute zoledronic acid infusion, the protocol specified that PK samples were to be drawn at exactly 10 and 15 minutes from the start of the infusion; patients receiving the 30-minute zoledronic acid infusion were to have blood samples drawn at exactly 25 and 30 minutes from the start of the infusion. The second blood sample for PK analysis was taken before the study drug infusion was stopped in both groups. PK analysis was performed by Novartis Pharmaceuticals Corporation Drug Metabolism and Pharmacokinetics France (Rueil-Malmaison, France) and SGS Cephac (Geneva Switzerland), using a competitive radioimmunoassay that has a lower limit of quantification of 0.04 ng/mL and an upper limit of quantification of 40 ng/mL.

Statistical Analysis

The primary study end point was the proportion of patients with a clinically relevant increase in SCr level at 12 months. Descriptive statistics were used to summarize the primary end point; in addition, an exploratory analysis with a logistic regression model, using treatment group, prior bisphosphonate therapy, and baseline CrCl, was performed.

Additional secondary safety end points included the proportion of patients with a clinically relevant increase in SCr level at 24 months, time to first clinically relevant increase in SCr level, and the PK profile of zoledronic acid. The proportion of patients with a clinically relevant increase in SCr level at 24 months was summarized using descriptive statistics. Time to first clinically relevant increase in SCr level was analyzed using the Kaplan-Meier method at the time of the primary analysis (12 months) and at 24 months. Plasma concentration data were evaluated by treatment group and baseline kidney function using descriptive statistics. Continuous variables of baseline and demographic characteristics between treatment groups were compared using a two-sample t-test; between-group differences in discrete variables were analyzed using Pearson's chi-squared test.

The primary analysis included all randomized patients who received at least one zoledronic acid infusion and who had valid postbaseline data for assessment. All study subjects who had evaluable PK parameters were included in a secondary PK analysis. Efficacy assessments were not included in this trial.

This pilot trial was designed to obtain additional preliminary data to support the hypothesis that a longer infusion is associated with less kidney dysfunction than a shorter infusion; therefore, a sample size of 90 patients per treatment group was selected. All statistical tests employed a significance level of 0.05 against a two-sided alternative hypothesis.

The institutional review boards of participating institutions approved the study, and all patients provided written informed consent before study entry.

Results

Study Population

Between October 2004 and October 2007, 179 MM patients with SCr <3 mg/dL were randomized to receive either a 15- or a 30-minute infusion of zoledronic acid. Of these, 176 patients (88 in each group) received at least one dose of study drug. Because of protocol violations, postbaseline data from one site were excluded from analyses, leaving 85 assessable patients in the 15-minute group and 84 patients in the 30-minute group.

Overall, the study groups were representative of a general population with MM. About two-thirds of patients had received prior bisphosphonate therapy; the duration of therapy was greater than 1 year for most of these patients (Table 1). The most common concomitant therapies included dexamethasone, thalidomide, and melphalan. Although the median age, proportion of patients who were 65 years of age or older, and ratio of men to women were greater in the 15-minute infusion group, none of the differences in baseline demographics was statistically significant. All other baseline demographics and disease characteristics, including prior bisphosphonate use and baseline CrCl values, were similar between the two groups (see Table 1). During the study, six patients in the 15-minute treatment group and one patient in the 30-minute treatment group experienced HCM. Three of the six patients in the 15-minute treatment group and one patient in the 30-minute treatment group discontinued the study as a result of HCM.