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Original research
James R. Berenson MD
Abstract
Zoledronic acid, an intravenous (IV) bisphosphonate, is a standard treatment for multiple myeloma (MM) but may exacerbate preexisting renal dysfunction. The incidence of zoledronic acid–induced renal dysfunction may correlate with infusion duration. In this randomized, multicenter, open-label study, 176 patients with MM, at least one bone lesion, and stable renal function with a serum creatinine (SCr) level <3 mg/dL received zoledronic acid 4 mg (in 250 mL) as a 15- or 30-minute IV infusion every 3–4 weeks. At month 12, 20% (17 patients) in the 15-minute and 16% (13 patients) in the 30-minute arm experienced a clinically relevant but nonsignificant SCr-level increase (P = 0.44). By 24 months, the proportion of patients with a clinically relevant SCr-level increase was similar between arms (15-minute 28% [24 patients] vs 30-minute 27% [23 patients], P = 0.9014). Median zoledronic acid end-of-infusion concentrations were higher with the shorter infusion (15-minute 249 ng/mL vs 30-minute 172 ng/mL), and prolonging the infusion beyond 15 minutes did not influence adverse events related to zoledronic acid. For patients with MM, the safety profile of IV zoledronic acid is similar between those receiving a 15- or 30-minute infusion; therefore, determining the appropriate infusion duration of zoledronic acid should be based on individual patient considerations.
Article Outline
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 (Cmax) 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.
| NUMBER OF PATIENTS (%)a | ||
|---|---|---|
| CHARACTERISTIC | ZOLEDRONIC ACID 4 MG IV FOR 15 MINUTES (N = 88)b | ZOLEDRONIC ACID 4 MG IV FOR 30 MINUTES (N = 88)b |
| Age (years) | ||
| Mean (SD) | 64 | 64 |
| Median | 66 | 64 |
| Range | 37–91 | 27–86 |
| Age category (years) | ||
| <65 | 39 (44) | 47 (53) |
| ≥65 | 49 (56) | 41 (47) |
| Sex | ||
| Male | 56 (64) | 49 (56) |
| Female | 32 (36) | 39 (44) |
| Race | ||
| White | 70 (80) | 69 (78) |
| Black | 9 (10) | 13 (15) |
| Asian | 1 (1) | 1 (1) |
| Other | 8 (9) | 5 (6) |
| Time since diagnosis (months) | ||
| Mean (SD) | 12 (24) (n = 86) | 10 (14) (n = 87) |
| Median | 4 | 6 |
| Range | 0–186 | 0–98c |
| Prior bisphosphonate use | ||
| Naive | 28 (32) | 28 (32) |
| ≤1 year | 12 (14) | 14 (16) |
| >1 year | 48 (55) | 39 (44) |
| Missing | 0 (0) | 7 (8) |
| Calculated CrCl (mL/min) | ||
| Mean (SD) | 87 (33) | 89 (40) |
| Median | 84 | 83 |
| Range | 33–210 | 31–224 |
| Calculated CrCl category (mL/min) | ||
| CrCl ≥75 | 54 (61) | 49 (56) |
| 60 < CrCL < 75 | 13 (15) | 15 (17) |
| 30 < CrCl ≤ 60 | 21 (24) | 24 (27) |
| CrCl <30 | 0 (0) | 0 (0) |
CrCl = creatinine clearance; IV = intravenous; SD = standard deviation
a Unless otherwise notedb Safety populationc One patient had a screening visit date before the date of initial diagnosis
Protocol violations and/or deviations (n = 658) occurred during this study, affecting 139 patients. The types of protocol violations/deviations were related to protocol adherence (n = 404), timing of visits (n = 210), protocol adherence/timing of visits (n = 2), exclusion criteria (n = 22), inclusion criteria (n = 10), and informed consent (n = 1); 9 violations were unclassified. Notably, one protocol adherence deviation that occurred was incorrect infusion duration despite the patient having a stable SCr level. In the 15-minute treatment group, 15% of infusions administered were longer than 15 minutes. Among the longer infusions, 7% of the infusions correctly occurred per protocol following an SCr-level increase, whereas 7% of the prolonged infusions were 20 minutes or longer in the absence of an SCr-level increase. Similarly, in the 30-minute treatment group, 5% of patients received infusions lasting at least 35 minutes in the absence of an SCr-level increase.
Renal Safety
At 12 months, slightly fewer patients (n = 13 [16%]) in the 30-minute infusion group had a clinically relevant increase in SCr level than in the 15-minute infusion group (n = 17 [20%]); but this difference was not statistically significant, and for approximately 35% of patients in each group there were no SCr data available (Table 2). The median time to a clinically relevant increase in SCr by Kaplain-Meier was not reached in either group (data not shown). Neither previous bisphosphonate use nor baseline CrCl significantly affected the results (P = 0.5837 and P = 0.9371, respectively).
| NUMBER OF PATIENTS (%) | |||
|---|---|---|---|
| CLINICALLY RELEVANT INCREASE IN SCR | ZOLEDRONIC ACID 4 MG IV FOR 15 MINUTES (N = 85)a | ZOLEDRONIC ACID 4 MG IV FOR 30 MINUTES (N = 84)a | P VALUEb |
| 12 Months | 0.6892 | ||
| Yes | 17 (20) | 13 (16) | |
| No | 38 (45) | 42 (50) | |
| Unknown | 30 (35) | 29 (35) | |
| 24 Months | 0.9750 | ||
| Yes | 24 (28) | 23 (27) | |
| No | 22 (26) | 23 (27) | |
| Unknown | 39 (46) | 38 (45) | |
CI = confidence interval; IV = intravenous; SCr = serum creatinine
a Safety population, excluding patients with protocol violationsb P value calculated based on chi-squared test
After 24 months of treatment, the proportion of patients experiencing a clinically relevant increase in SCr level was similar between treatment groups, although for approximately 45% of patients in each group there were no SCr data available (see Table 2). Moreover, the difference in time to first clinically relevant increase in SCr level was not statistically significant between the two groups (P = 0.55) (Figure 1). However, among patients with a clinically significant rise in SCr level, the median time to SCr rise was slightly longer in the 30-minute group than in the 15-minute group (22 vs 24 weeks), but this was not statistically significant.
Increases in SCr relative to baseline led to treatment discontinuation in 20 patients (24%) receiving a 15-minute infusion and 14 patients (17%) receiving a 30-minute infusion. In these cases, the treating physician either considered the SCr level too high for continued treatment or the SCr level was persistently high despite treatment interruption.
Pharmacokinetics
Median zoledronic acid concentrations, as anticipated, were higher with the 15-minute infusion time at both sampling time points (during infusion: 15-minute group 231 ng/mL [at 10 minutes] vs 30-minute group 186 ng/mL [at 25 minutes]; end-of-infusion: 15-minute group, 249 ng/mL vs 30-minute group 172 ng/mL).
Adverse Events
Overall, the incidence and severity of AEs were as anticipated for MM patients. The most commonly reported AEs included fatigue, anemia, nausea, constipation, and back pain (Table 3). Although many AEs were reported more frequently in the 30-minute infusion group, the incidence rates of AEs suspected to be related to zoledronic acid were similar between the two groups. Toxicities were graded as mild, moderate, or severe; proportions of AEs categorized by these grades were comparable. Nonfatal serious AEs (SAEs) occurred in 26% of patients receiving the 15-minute infusion and 35% of patients receiving the 30-minute infusion; however, only one patient in the 15-minute group and two patients in the 30-minute group had SAEs suspected to be related to study medication.
| NUMBER OF PATIENTS (%) | |||
|---|---|---|---|
| TYPE OF AE | ZOLEDRONIC ACID 4 MG IV FOR 15 MINUTES (N = 85) | ZOLEDRONIC ACID 4 MG IV FOR 30 MINUTES (N = 84) | TOTAL (N = 169) |
| Blood and lymphatic system disorders | |||
| Anemia | 19 (22) | 27 (32) | 46 (27) |
| Neutropenia | 6 (7) | 12 (14) | 18 (11) |
| Gastrointestinal disorders | |||
| Constipation | 20 (24) | 21 (25) | 41 (24) |
| Diarrhea | 14 (17) | 20 (24) | 34 (20) |
| Nausea | 18 (21) | 27 (32) | 45 (27) |
| Vomiting | 10 (12) | 14 (17) | 24 (14) |
| General disorders | |||
| Fatigue | 30 (35) | 41 (49) | 71 (42) |
| Pain | 7 (8) | 10 (12) | 17 (10) |
| Pain in extremity | 14 (17) | 16 (19) | 30 (18) |
| Peripheral edema | 13 (15) | 20 (24) | 33 (20) |
| Pyrexia | 15 (18) | 19 (23) | 34 (20) |
| Infections and infestations | |||
| Pneumonia | 11 (13) | 7 (8) | 18 (11) |
| Upper respiratory tract infection | 13 (15) | 13 (16) | 26 (15) |
| Metabolism and nutrition disorders | |||
| Anorexia | 8 (9) | 9 (11) | 17 (10) |
| Hypokalemia | 12 (14) | 13 (15) | 25 (14) |
| Musculoskeletal and connective tissue disorders | |||
| Arthralgia | 10 (11) | 16 (19) | 26 (15) |
| Asthenia | 9 (10) | 13 (16) | 22 (13) |
| Back pain | 19 (22) | 20 (24) | 39 (23) |
| Bone pain | 10 (12) | 11 (13) | 21 (12) |
| Nervous system disorders | |||
| Dizziness | 11 (13) | 10 (12) | 21 (12) |
| Peripheral neuropathy | 7 (8) | 15 (18) | 22 (13) |
| Psychiatric disorders | |||
| Insomnia | 10 (12) | 14 (17) | 24 (14) |
| Respiratory, thoracic, and mediastinal disorders | |||
| Cough | 13 (15) | 15 (18) | 28 (17) |
| Dyspnea | 15 (18) | 17 (20) | 32 (19) |
| Skin and subcutaneous tissue disorders | |||
| Rash | 9 (11) | 12 (14) | 21 (12) |
AE = adverse event; IV = intravenous
a Safety population excluding patients with protocol violations
The numbers of deaths, trial discontinuations, and treatment interruptions due to AEs were similar between the two groups as well. Deaths (9 [10.6%] 15-minute group vs 6 [7.1%] 30-minute group) were not suspected to be related to zoledronic acid. Eight patients in each treatment group discontinued therapy because of an AE; events leading to treatment discontinuation that were suspected to be related to zoledronic acid occurred in two patients in the 15-minute group (skeletal pain and ONJ) and one patient in the 30-minute group (jaw pain). AEs that required treatment interruption occurred in eight and nine patients in the 15-minute and 30-minute groups, respectively.
AEs of special interest included those related to kidney dysfunction, cardiac arrhythmias, SREs, and ONJ. The number of patients reporting overall kidney and urinary disorders was the same in the two treatment groups (14 patients in each group); however, acute renal failure was reported more frequently in patients receiving the 15-minute infusion compared with the 30-minute infusion (four patients [5%] vs one patient [1%] in 30-minute group). Details of these five patients are presented in Table 4. AEs related to cardiac rhythm occurred in 20 patients while on study; however, only one case of bradycardia was suspected to be related to zoledronic acid therapy (in the 30-minute group). The incidence of SREs at 2 years was comparable in the two groups (19% in 15-minute group vs 21% in 30-minute group). The time to onset of SREs was longer in the 15-minute group (222 vs 158 days), but this was not statistically significant. A total of 10 patients with suspected ONJ were identified, with three patients in the 15-minute group (all moderate) and seven patients in the 30-minute group (mild [n = 5], moderate [n = 1], severe [n = 1]). Six of these patients received bisphosphonates before entering the study (four patients received no prior bisphosphonates), but the length of previous bisphosphonate therapy varied (0–30 months). Patients with suspected ONJ were assessed by clinicians and referred to dental professionals for further evaluation.
| PATIENT DEMOGRAPHICS | TYPE OF MM | MEDICAL HISTORY | CONCURRENT MEDICATIONSa | ACUTE RENAL FAILURE DETAILS | OUTCOME |
|---|---|---|---|---|---|
| Zoledronic acid 4 mg IV for 15 minutes | |||||
| 73-year-old female Caucasian | IgG | Anemia, cardiomyopathy, CHF, cholecystectomy, benign breast lump removal, CAD, DM, dyslipidemia, central venous catheterization, chronic renal failure, GERD, hypercholesterolemia, HTN, hysterectomy, mycobacterial infection, hemorrhoids, B-cell lymphoma, seborrheic keratosis, tonsillectomy | At start of study: aspirin, losartan, digoxin, hydrochlorothiazide/lorsartan, fluconazole, folic acid, atorvastatin, vitamins, warfarinDuring study: ethambutol dihydrochloride, moxifloxacin, rifabutin, fenofibrate, omeprazole, diuretics, nitroglycerin patch, angiotensin-converting enzyme inhibitors, hydroxyzine, loratadine, furosemide, vancomycin, pantoprozole, piperacillin/tazobactam, clarithromycin | Myeloma kidney mass consistent with myeloma kidney found during study; approximately 2 weeks later the patient developed severe infection that culminated in septic shock, with acute renal failure | Nephrologist considered renal insufficiency to be partly related to past history of large-cell lymphoma and chemotherapy; patient was discharged to hospice and died of acute renal failure secondary to myeloma |
| 71-year-old female Caucasian | IgA | Back pain, cholecystectomy, constipation, CAD, NIDDM, hypercholesterolemia, HTN, insomnia, left knee operation, neuralgia, obesity, osteoarthritis, hysterectomy, hypoacusis, seasonal allergies, urinary incontinence | At start of study: zolpidem, amitriptyline, loratidine, tolterodine l-tartrate, valsartan, metrotoprolol, furosemide, ibuprofen, clonazepam, gabapentin, liodcaine, hydrocodone/acetaminophen, quinine sulfate, simvastatin During study: calcium, multivitamins, lactulose, trazodone, hydromorphone, cyclobenzaprine, glipizide, macrogol, lorazepam, methadone, potassium, lisinopril, furosemide, meperidine, promethazine | Developed moderate acute renal failure on the day of her first dose; considered not associated with zoledronic acid | Renal ultrasound showed arterial stenosis; resolved approximately 1 month after diagnosis |
| 65-year-old male Caucasian | IgG | Oxycodone hypersensitivity, anemia, back pain, spine metastases, spinal compression fracture, depression, fatigue, inguinal hernia repair, spinal fusion (L1–L3) surgery, bilateral hip arthroplasty, pain, pneumonia, staphylococcal infection | At start of study: fluconazole, morphine sulfate, oxycodone/acetaminophen During study: naproxen, darbepoietin alfa, sodium ferrifluconate, calcium with vitamin D, cephalexin, dexamethasone, alginic acid, docusate, heparin, sodium polystyrene, levofloxacin, filgrastim, lansoprazole | After 5 doses of zoledronic acid, patient developed severe acute renal failure with elevated SCr; not suspected to be related to zoledronic acid | Resolved 9 days later following treatment with cephalexin and dexamethasone |
| 56-year-old female Caucasian | IgA | Osteolysis, cataract surgery, constipation, bone lesions, hypercholesterolemia, HTN, musculoskeletal pain, anorexia | At start of study: ibuprofen, oxycodone, propoxyphene/acetaminophen, hydrocodone/acetaminophen, valsartan, calcium/vitamin D, potassium chloride, docusate sodiumDuring study: vancomycin, acyclovir | Approximately 1 week after 9th zoledronic acid dose, patient developed acute renal failure with an increased SCr (12.5 mg/dL); not suspected to be related to zoledronic acid | Resulted from myeloma progression to plasma cell leukemia; emergency dialysis performed; catheter-related sepsis occurred approximately 1 month later, and patient died of sepsis and disease progression |
| Zoledronic acid 4 mg IV for 30 minutes | |||||
| 80-year-old male African American | IgG | Anemia, arteriosclerotic heart disease, bilateral ankle swelling/pain, degenerative joint disease, dyspnea on exertion, fatigue, GERD, HTN, neutropenia, shoulder pain, vasovagal syncope | At start of study: aspirin, atenolol, multivitamin, doxazosin, fosinopril, hydrochlorothiazide, amlodipine besylate, simvastatinDuring study: darbepoietin alfa, warfarin sodium, furosemide, omeprazole, calcium carbonate | Approximately 1 month after 2nd dose, patient experienced increased SCr (2.9 mg/dL, 53% increase from baseline); relationship to zoledronic acid unknown | Discontinued from study after 2nd dose, and SCr remained elevated for 2 months following discontinuation |
CAD = coronary artery disease; CHF = congestive heart failure; DM = diabetes mellitus; GERD = gastroesophageal reflux disease; HTN = hypertension; MM = multiple myeloma; NIDDM = non-insulin-dependent diabetes mellitus; SCr = serum creatinine
Discussion
During the past decade, bisphosphonate therapy has become an important adjunctive treatment to prevent the emergence, or worsening, of SREs in patients with MM involving the bone.15 Kidney failure is a common and severe complication of MM that may be exacerbated by chronic administration of zoledronic acid.7 A study evaluating zoledronic acid in patients with cancer and bone metastases suggests that increasing the infusion time decreases the Cmax, which may result in fewer renal AEs.[9] and [12] This study was designed to assess whether prolonging the infusion time of zoledronic acid from the recommended 15 to 30 minutes would improve kidney safety in MM patients, as evidenced by fewer rises in SCr levels. To our knowledge, this is the only trial that has been designed to evaluate the impact of infusion duration on renal effects in this population.
The 12-month results of this pilot study showed a trend toward improved renal safety with the longer infusion time, this difference not being statistically significant. By 24 months, however, there were no differences in SCr level elevations between the two groups. The clinically relevant SCr increases observed in our study, however, differ from those reported by Rosen and colleagues,[5] and [6] who first evaluated zoledronic acid for patients with MM. In that study, 4%–11% of patients experienced kidney function deterioration, manifested by SCr increases, which is much lower than the rate observed in our study. However, several differences exist between our trial and the Rosen study. The Rosen study included both breast cancer patients with at least one bone metastasis and Durie-Salmon stage 3 MM patients with at least one osteolytic lesion, whereas our study only included MM patients with at least one bone lesion. Additionally, the criteria for defining a clinically relevant SCr increase differ between the two studies; therefore, one cannot directly compare the incidence of kidney dysfunction between these two studies. Although in our study the sample size was small, confidence intervals were wide, and protocol deviations did not permit a robust comparison, the results of this pilot study suggest that the longer infusion time of 30 minutes every 3–4 weeks for 2 years for MM patients with bone disease is also safe and well-tolerated.
As expected, PK data showed that the median zoledronic acid concentrations were greater in the samples obtained from the 15-minute group compared to those from the 30-minute group. This effect was observed in samples obtained both 5 minutes before the end of infusion and at the end of infusion.
Increasing the infusion time did not significantly alter the AE profile and was not associated with any new or unexpected AEs. The incidence rates of deaths, SAEs, treatment-related AEs, and overall AEs were generally comparable between treatment groups. Overall, the incidence rates of reported SREs and ONJ were as expected for this patient population, which are important factors when considering zoledronic acid for patients with MM, where the goal of ongoing monthly IV bisphosphonate therapy is to prevent the development of new SREs without increasing the risk of AEs, such as ONJ.
Finally, the FDA-approved current labeling for zoledronic acid recommends decreasing the dose of this bisphosphonate based on baseline kidney function.7 Because these recommendations were not in place at the time that this study was designed, whether the implementation of these dosing guidelines for patients with MM along with varying infusion durations would have impacted the results observed in our study cannot be ascertained.
In summary, the results of this study suggest that the safety profile of IV zoledronic acid is similar regardless of a 15-minute or a 30-minute infusion duration. However, because the study was not powered to detect statistical significance and the current renal dosing guidelines for zoledronic acid were not used in this study, large randomized studies, using current dosing recommendations, will be required to further assess the effects on kidney safety of prolonging the infusion time of ongoing monthly IV zoledronic acid therapy for patients with MM.
Acknowledgments
The authors thank Syntaxx Communications, Inc., specifically, Kristin Hennenfent, PharmD, MBA, BCPS, and Lisa Holle, PharmD, BCOP, who provided manuscript development and medical writing services, and Holly Matthews, BS, who provided editorial services, with support from Novartis Pharmaceuticals Corporation. We also thank all participating patients and study personnel. Research support was provided by Novartis Pharmaceuticals Corporation (East Hanover, NJ).
References
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12 F. Saad, D.M. Gleason and R. Murray et al., A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma, J Natl Cancer Inst 94 (19) (2002), pp. 1458–1468. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (650)
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Appendix
The following ZMAX Trial principal investigators participated in this study: Bart Barlogie, MD, Myeloma Institute For Research and Therapy; James Berenson, MD, Oncotherapeutics; Robert Bloom, MD, Providence Cancer Center, Clinical Trials Department; Ralph Boccia, MD, Center for Cancer and Blood Disorders; Donald Brooks, MD, Arizona Clinical Research Center, Inc.; Robert Brouillard, MD, Robert P. Brouillard, MD, and Delvyn Case, MD, Maine Center for Cancer Medicine and Blood Disorders, Pharmacy; Veena Charu, MD, Pacific Cancer Medical Center; Naveed Chowhan, MD, Cancer Care Center, Inc; Robert Collins, MD, University of Texas Southwestern Medical Center at Dallas; Thomas Cosgriff, MD, Hematology and Oncology Specialists, LLC; Jose Cruz, MD, Joe Arrington Cancer Research and Treatment Center; Surrinder Dang, MD, Oncology Specialties; Sheldon Davidson, MD, North Valley H/O; Tracy Dobbs, MD, Baptist Regional Cancer Center; Luke Dreisbach, MD, Desert Hematology Oncology Medical Group; Isaac Esseesse, MD, Hematology Oncology Associates of Central Brevard, Laboratory; Mark Fesen, MD, Hutchinson Clinic, PA; George Geils, Jr., MD, Charleston Hematology Oncology Associates, PA; Michael Greenhawt, MD, South Florida Oncology-Hematology; Manuel Guerra, MD, ORA; Rita Gupta, MD, Oncology-Hematology Associates, PA; Vicram Gupta, MD, Saint Joseph Oncology; Alexandre Hageboutros, MD, Cancer Institute of New Jersey at Cooper Hospital; Vincent Hansen, MD, Utah Hematology Oncology; David Henry, MD, Pennsylvania Oncology Hematology Associates; Benjamin Himpler, MD, Syracuse Hematology/Oncology PC; Winston Ho, MD, Hematology/Oncology Group of Orange County; William Horvath, MD, Haematology Oncology Associates of Ohio and Michigan, PC; Paul Hyman, MD, Hematology Oncology Associates of Western Suffolk; Min Kang, MD, Western Washington Oncology; Mark Keaton, MD, Augusta Oncology Associates, PC; Howard Kesselheim, MD, The Center for Cancer and Hematologic Disease; Kapisthalam Kumar, MD, Pasco Hernando Oncology Associates, PA; Edward Lee, MD, Maryland Oncology-Hematology, PA; André Liem, MD, Pacific Shore Medical Group; Timothy Lopez, MD, New Mexico Cancer Care Associates, Cancer Institute of New Mexico; Paul Michael, MD, Comprehensive Cancer Centers of Nevada; Michael Milder, MD, Swedish Cancer Institute; Barry Mirtsching, MD, Center for Oncology Research & Treatment, PA; Ruben Niesvizky, MD, New York Presbyterian Hospital; Jorge Otoya, MD, Osceola Cancer Center; Joseph Pascuzzo, MD, California Oncology of the Central Valley; Ravi Patel, MD, Comprehensive Blood and Cancer Center Lab; Allen Patton, MD, Hematology Oncology Associates, PA; Kelly Pendergrass, MD, Kansas City Cancer Center, LLC; Anthony Phillips, MD, Fox Valley Hematolgy Oncology, SC; Robert Raju, MD, Dayton Oncology and Hematology, PA; Harry Ramsey, MD, Berks Hematology Oncology Associates; Ritesh Rathore, MD, Roger Williams Hospital Medical Center; Phillip Reid, MD, Central Jersey Oncology Center; Robert Robles, MD, Bay Area Cancer Research Group, LLC; Stephen Rosenoff, MD, Oncology and Hematology Associates of Southwest Virginia, Inc; Martin Rubenstein, MD, Southbay Oncology Hematology Partners; Mansoor Saleh, MD, Georgia Cancer Specialists; Sundaresan Sambandam, MD, Hematology and Oncology Associates of RI; Mukund Shah, MD, Antelope Valley Cancer Center; David Siegel, MD, Hackensack University Medical Center; Nelida Sjak-Shie, MD, The Center for Cancer Care and Research; Michael Stone, MD, Greeley Medical Clinic; Stefano Tarantolo, MD, Nebraska Methodist Hospital; Joseph Volk, MD, Palo Verde Hematology Oncology, Ltd; Mitchell Weisberg, MD, MetCare Oncology; Ann Wierman, MD, Nevada Cancer Center; Donald Woytowitz, Jr., MD, Florida Cancer Specialists; Peter Yu, MD, Camino Medical Group.
Original research
James R. Berenson MD
Abstract
Zoledronic acid, an intravenous (IV) bisphosphonate, is a standard treatment for multiple myeloma (MM) but may exacerbate preexisting renal dysfunction. The incidence of zoledronic acid–induced renal dysfunction may correlate with infusion duration. In this randomized, multicenter, open-label study, 176 patients with MM, at least one bone lesion, and stable renal function with a serum creatinine (SCr) level <3 mg/dL received zoledronic acid 4 mg (in 250 mL) as a 15- or 30-minute IV infusion every 3–4 weeks. At month 12, 20% (17 patients) in the 15-minute and 16% (13 patients) in the 30-minute arm experienced a clinically relevant but nonsignificant SCr-level increase (P = 0.44). By 24 months, the proportion of patients with a clinically relevant SCr-level increase was similar between arms (15-minute 28% [24 patients] vs 30-minute 27% [23 patients], P = 0.9014). Median zoledronic acid end-of-infusion concentrations were higher with the shorter infusion (15-minute 249 ng/mL vs 30-minute 172 ng/mL), and prolonging the infusion beyond 15 minutes did not influence adverse events related to zoledronic acid. For patients with MM, the safety profile of IV zoledronic acid is similar between those receiving a 15- or 30-minute infusion; therefore, determining the appropriate infusion duration of zoledronic acid should be based on individual patient considerations.
Article Outline
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 (Cmax) 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.
| NUMBER OF PATIENTS (%)a | ||
|---|---|---|
| CHARACTERISTIC | ZOLEDRONIC ACID 4 MG IV FOR 15 MINUTES (N = 88)b | ZOLEDRONIC ACID 4 MG IV FOR 30 MINUTES (N = 88)b |
| Age (years) | ||
| Mean (SD) | 64 | 64 |
| Median | 66 | 64 |
| Range | 37–91 | 27–86 |
| Age category (years) | ||
| <65 | 39 (44) | 47 (53) |
| ≥65 | 49 (56) | 41 (47) |
| Sex | ||
| Male | 56 (64) | 49 (56) |
| Female | 32 (36) | 39 (44) |
| Race | ||
| White | 70 (80) | 69 (78) |
| Black | 9 (10) | 13 (15) |
| Asian | 1 (1) | 1 (1) |
| Other | 8 (9) | 5 (6) |
| Time since diagnosis (months) | ||
| Mean (SD) | 12 (24) (n = 86) | 10 (14) (n = 87) |
| Median | 4 | 6 |
| Range | 0–186 | 0–98c |
| Prior bisphosphonate use | ||
| Naive | 28 (32) | 28 (32) |
| ≤1 year | 12 (14) | 14 (16) |
| >1 year | 48 (55) | 39 (44) |
| Missing | 0 (0) | 7 (8) |
| Calculated CrCl (mL/min) | ||
| Mean (SD) | 87 (33) | 89 (40) |
| Median | 84 | 83 |
| Range | 33–210 | 31–224 |
| Calculated CrCl category (mL/min) | ||
| CrCl ≥75 | 54 (61) | 49 (56) |
| 60 < CrCL < 75 | 13 (15) | 15 (17) |
| 30 < CrCl ≤ 60 | 21 (24) | 24 (27) |
| CrCl <30 | 0 (0) | 0 (0) |
CrCl = creatinine clearance; IV = intravenous; SD = standard deviation
a Unless otherwise notedb Safety populationc One patient had a screening visit date before the date of initial diagnosis
Protocol violations and/or deviations (n = 658) occurred during this study, affecting 139 patients. The types of protocol violations/deviations were related to protocol adherence (n = 404), timing of visits (n = 210), protocol adherence/timing of visits (n = 2), exclusion criteria (n = 22), inclusion criteria (n = 10), and informed consent (n = 1); 9 violations were unclassified. Notably, one protocol adherence deviation that occurred was incorrect infusion duration despite the patient having a stable SCr level. In the 15-minute treatment group, 15% of infusions administered were longer than 15 minutes. Among the longer infusions, 7% of the infusions correctly occurred per protocol following an SCr-level increase, whereas 7% of the prolonged infusions were 20 minutes or longer in the absence of an SCr-level increase. Similarly, in the 30-minute treatment group, 5% of patients received infusions lasting at least 35 minutes in the absence of an SCr-level increase.
Renal Safety
At 12 months, slightly fewer patients (n = 13 [16%]) in the 30-minute infusion group had a clinically relevant increase in SCr level than in the 15-minute infusion group (n = 17 [20%]); but this difference was not statistically significant, and for approximately 35% of patients in each group there were no SCr data available (Table 2). The median time to a clinically relevant increase in SCr by Kaplain-Meier was not reached in either group (data not shown). Neither previous bisphosphonate use nor baseline CrCl significantly affected the results (P = 0.5837 and P = 0.9371, respectively).
| NUMBER OF PATIENTS (%) | |||
|---|---|---|---|
| CLINICALLY RELEVANT INCREASE IN SCR | ZOLEDRONIC ACID 4 MG IV FOR 15 MINUTES (N = 85)a | ZOLEDRONIC ACID 4 MG IV FOR 30 MINUTES (N = 84)a | P VALUEb |
| 12 Months | 0.6892 | ||
| Yes | 17 (20) | 13 (16) | |
| No | 38 (45) | 42 (50) | |
| Unknown | 30 (35) | 29 (35) | |
| 24 Months | 0.9750 | ||
| Yes | 24 (28) | 23 (27) | |
| No | 22 (26) | 23 (27) | |
| Unknown | 39 (46) | 38 (45) | |
CI = confidence interval; IV = intravenous; SCr = serum creatinine
a Safety population, excluding patients with protocol violationsb P value calculated based on chi-squared test
After 24 months of treatment, the proportion of patients experiencing a clinically relevant increase in SCr level was similar between treatment groups, although for approximately 45% of patients in each group there were no SCr data available (see Table 2). Moreover, the difference in time to first clinically relevant increase in SCr level was not statistically significant between the two groups (P = 0.55) (Figure 1). However, among patients with a clinically significant rise in SCr level, the median time to SCr rise was slightly longer in the 30-minute group than in the 15-minute group (22 vs 24 weeks), but this was not statistically significant.
Increases in SCr relative to baseline led to treatment discontinuation in 20 patients (24%) receiving a 15-minute infusion and 14 patients (17%) receiving a 30-minute infusion. In these cases, the treating physician either considered the SCr level too high for continued treatment or the SCr level was persistently high despite treatment interruption.
Pharmacokinetics
Median zoledronic acid concentrations, as anticipated, were higher with the 15-minute infusion time at both sampling time points (during infusion: 15-minute group 231 ng/mL [at 10 minutes] vs 30-minute group 186 ng/mL [at 25 minutes]; end-of-infusion: 15-minute group, 249 ng/mL vs 30-minute group 172 ng/mL).
Adverse Events
Overall, the incidence and severity of AEs were as anticipated for MM patients. The most commonly reported AEs included fatigue, anemia, nausea, constipation, and back pain (Table 3). Although many AEs were reported more frequently in the 30-minute infusion group, the incidence rates of AEs suspected to be related to zoledronic acid were similar between the two groups. Toxicities were graded as mild, moderate, or severe; proportions of AEs categorized by these grades were comparable. Nonfatal serious AEs (SAEs) occurred in 26% of patients receiving the 15-minute infusion and 35% of patients receiving the 30-minute infusion; however, only one patient in the 15-minute group and two patients in the 30-minute group had SAEs suspected to be related to study medication.
| NUMBER OF PATIENTS (%) | |||
|---|---|---|---|
| TYPE OF AE | ZOLEDRONIC ACID 4 MG IV FOR 15 MINUTES (N = 85) | ZOLEDRONIC ACID 4 MG IV FOR 30 MINUTES (N = 84) | TOTAL (N = 169) |
| Blood and lymphatic system disorders | |||
| Anemia | 19 (22) | 27 (32) | 46 (27) |
| Neutropenia | 6 (7) | 12 (14) | 18 (11) |
| Gastrointestinal disorders | |||
| Constipation | 20 (24) | 21 (25) | 41 (24) |
| Diarrhea | 14 (17) | 20 (24) | 34 (20) |
| Nausea | 18 (21) | 27 (32) | 45 (27) |
| Vomiting | 10 (12) | 14 (17) | 24 (14) |
| General disorders | |||
| Fatigue | 30 (35) | 41 (49) | 71 (42) |
| Pain | 7 (8) | 10 (12) | 17 (10) |
| Pain in extremity | 14 (17) | 16 (19) | 30 (18) |
| Peripheral edema | 13 (15) | 20 (24) | 33 (20) |
| Pyrexia | 15 (18) | 19 (23) | 34 (20) |
| Infections and infestations | |||
| Pneumonia | 11 (13) | 7 (8) | 18 (11) |
| Upper respiratory tract infection | 13 (15) | 13 (16) | 26 (15) |
| Metabolism and nutrition disorders | |||
| Anorexia | 8 (9) | 9 (11) | 17 (10) |
| Hypokalemia | 12 (14) | 13 (15) | 25 (14) |
| Musculoskeletal and connective tissue disorders | |||
| Arthralgia | 10 (11) | 16 (19) | 26 (15) |
| Asthenia | 9 (10) | 13 (16) | 22 (13) |
| Back pain | 19 (22) | 20 (24) | 39 (23) |
| Bone pain | 10 (12) | 11 (13) | 21 (12) |
| Nervous system disorders | |||
| Dizziness | 11 (13) | 10 (12) | 21 (12) |
| Peripheral neuropathy | 7 (8) | 15 (18) | 22 (13) |
| Psychiatric disorders | |||
| Insomnia | 10 (12) | 14 (17) | 24 (14) |
| Respiratory, thoracic, and mediastinal disorders | |||
| Cough | 13 (15) | 15 (18) | 28 (17) |
| Dyspnea | 15 (18) | 17 (20) | 32 (19) |
| Skin and subcutaneous tissue disorders | |||
| Rash | 9 (11) | 12 (14) | 21 (12) |
AE = adverse event; IV = intravenous
a Safety population excluding patients with protocol violations
The numbers of deaths, trial discontinuations, and treatment interruptions due to AEs were similar between the two groups as well. Deaths (9 [10.6%] 15-minute group vs 6 [7.1%] 30-minute group) were not suspected to be related to zoledronic acid. Eight patients in each treatment group discontinued therapy because of an AE; events leading to treatment discontinuation that were suspected to be related to zoledronic acid occurred in two patients in the 15-minute group (skeletal pain and ONJ) and one patient in the 30-minute group (jaw pain). AEs that required treatment interruption occurred in eight and nine patients in the 15-minute and 30-minute groups, respectively.
AEs of special interest included those related to kidney dysfunction, cardiac arrhythmias, SREs, and ONJ. The number of patients reporting overall kidney and urinary disorders was the same in the two treatment groups (14 patients in each group); however, acute renal failure was reported more frequently in patients receiving the 15-minute infusion compared with the 30-minute infusion (four patients [5%] vs one patient [1%] in 30-minute group). Details of these five patients are presented in Table 4. AEs related to cardiac rhythm occurred in 20 patients while on study; however, only one case of bradycardia was suspected to be related to zoledronic acid therapy (in the 30-minute group). The incidence of SREs at 2 years was comparable in the two groups (19% in 15-minute group vs 21% in 30-minute group). The time to onset of SREs was longer in the 15-minute group (222 vs 158 days), but this was not statistically significant. A total of 10 patients with suspected ONJ were identified, with three patients in the 15-minute group (all moderate) and seven patients in the 30-minute group (mild [n = 5], moderate [n = 1], severe [n = 1]). Six of these patients received bisphosphonates before entering the study (four patients received no prior bisphosphonates), but the length of previous bisphosphonate therapy varied (0–30 months). Patients with suspected ONJ were assessed by clinicians and referred to dental professionals for further evaluation.
| PATIENT DEMOGRAPHICS | TYPE OF MM | MEDICAL HISTORY | CONCURRENT MEDICATIONSa | ACUTE RENAL FAILURE DETAILS | OUTCOME |
|---|---|---|---|---|---|
| Zoledronic acid 4 mg IV for 15 minutes | |||||
| 73-year-old female Caucasian | IgG | Anemia, cardiomyopathy, CHF, cholecystectomy, benign breast lump removal, CAD, DM, dyslipidemia, central venous catheterization, chronic renal failure, GERD, hypercholesterolemia, HTN, hysterectomy, mycobacterial infection, hemorrhoids, B-cell lymphoma, seborrheic keratosis, tonsillectomy | At start of study: aspirin, losartan, digoxin, hydrochlorothiazide/lorsartan, fluconazole, folic acid, atorvastatin, vitamins, warfarinDuring study: ethambutol dihydrochloride, moxifloxacin, rifabutin, fenofibrate, omeprazole, diuretics, nitroglycerin patch, angiotensin-converting enzyme inhibitors, hydroxyzine, loratadine, furosemide, vancomycin, pantoprozole, piperacillin/tazobactam, clarithromycin | Myeloma kidney mass consistent with myeloma kidney found during study; approximately 2 weeks later the patient developed severe infection that culminated in septic shock, with acute renal failure | Nephrologist considered renal insufficiency to be partly related to past history of large-cell lymphoma and chemotherapy; patient was discharged to hospice and died of acute renal failure secondary to myeloma |
| 71-year-old female Caucasian | IgA | Back pain, cholecystectomy, constipation, CAD, NIDDM, hypercholesterolemia, HTN, insomnia, left knee operation, neuralgia, obesity, osteoarthritis, hysterectomy, hypoacusis, seasonal allergies, urinary incontinence | At start of study: zolpidem, amitriptyline, loratidine, tolterodine l-tartrate, valsartan, metrotoprolol, furosemide, ibuprofen, clonazepam, gabapentin, liodcaine, hydrocodone/acetaminophen, quinine sulfate, simvastatin During study: calcium, multivitamins, lactulose, trazodone, hydromorphone, cyclobenzaprine, glipizide, macrogol, lorazepam, methadone, potassium, lisinopril, furosemide, meperidine, promethazine | Developed moderate acute renal failure on the day of her first dose; considered not associated with zoledronic acid | Renal ultrasound showed arterial stenosis; resolved approximately 1 month after diagnosis |
| 65-year-old male Caucasian | IgG | Oxycodone hypersensitivity, anemia, back pain, spine metastases, spinal compression fracture, depression, fatigue, inguinal hernia repair, spinal fusion (L1–L3) surgery, bilateral hip arthroplasty, pain, pneumonia, staphylococcal infection | At start of study: fluconazole, morphine sulfate, oxycodone/acetaminophen During study: naproxen, darbepoietin alfa, sodium ferrifluconate, calcium with vitamin D, cephalexin, dexamethasone, alginic acid, docusate, heparin, sodium polystyrene, levofloxacin, filgrastim, lansoprazole | After 5 doses of zoledronic acid, patient developed severe acute renal failure with elevated SCr; not suspected to be related to zoledronic acid | Resolved 9 days later following treatment with cephalexin and dexamethasone |
| 56-year-old female Caucasian | IgA | Osteolysis, cataract surgery, constipation, bone lesions, hypercholesterolemia, HTN, musculoskeletal pain, anorexia | At start of study: ibuprofen, oxycodone, propoxyphene/acetaminophen, hydrocodone/acetaminophen, valsartan, calcium/vitamin D, potassium chloride, docusate sodiumDuring study: vancomycin, acyclovir | Approximately 1 week after 9th zoledronic acid dose, patient developed acute renal failure with an increased SCr (12.5 mg/dL); not suspected to be related to zoledronic acid | Resulted from myeloma progression to plasma cell leukemia; emergency dialysis performed; catheter-related sepsis occurred approximately 1 month later, and patient died of sepsis and disease progression |
| Zoledronic acid 4 mg IV for 30 minutes | |||||
| 80-year-old male African American | IgG | Anemia, arteriosclerotic heart disease, bilateral ankle swelling/pain, degenerative joint disease, dyspnea on exertion, fatigue, GERD, HTN, neutropenia, shoulder pain, vasovagal syncope | At start of study: aspirin, atenolol, multivitamin, doxazosin, fosinopril, hydrochlorothiazide, amlodipine besylate, simvastatinDuring study: darbepoietin alfa, warfarin sodium, furosemide, omeprazole, calcium carbonate | Approximately 1 month after 2nd dose, patient experienced increased SCr (2.9 mg/dL, 53% increase from baseline); relationship to zoledronic acid unknown | Discontinued from study after 2nd dose, and SCr remained elevated for 2 months following discontinuation |
CAD = coronary artery disease; CHF = congestive heart failure; DM = diabetes mellitus; GERD = gastroesophageal reflux disease; HTN = hypertension; MM = multiple myeloma; NIDDM = non-insulin-dependent diabetes mellitus; SCr = serum creatinine
Discussion
During the past decade, bisphosphonate therapy has become an important adjunctive treatment to prevent the emergence, or worsening, of SREs in patients with MM involving the bone.15 Kidney failure is a common and severe complication of MM that may be exacerbated by chronic administration of zoledronic acid.7 A study evaluating zoledronic acid in patients with cancer and bone metastases suggests that increasing the infusion time decreases the Cmax, which may result in fewer renal AEs.[9] and [12] This study was designed to assess whether prolonging the infusion time of zoledronic acid from the recommended 15 to 30 minutes would improve kidney safety in MM patients, as evidenced by fewer rises in SCr levels. To our knowledge, this is the only trial that has been designed to evaluate the impact of infusion duration on renal effects in this population.
The 12-month results of this pilot study showed a trend toward improved renal safety with the longer infusion time, this difference not being statistically significant. By 24 months, however, there were no differences in SCr level elevations between the two groups. The clinically relevant SCr increases observed in our study, however, differ from those reported by Rosen and colleagues,[5] and [6] who first evaluated zoledronic acid for patients with MM. In that study, 4%–11% of patients experienced kidney function deterioration, manifested by SCr increases, which is much lower than the rate observed in our study. However, several differences exist between our trial and the Rosen study. The Rosen study included both breast cancer patients with at least one bone metastasis and Durie-Salmon stage 3 MM patients with at least one osteolytic lesion, whereas our study only included MM patients with at least one bone lesion. Additionally, the criteria for defining a clinically relevant SCr increase differ between the two studies; therefore, one cannot directly compare the incidence of kidney dysfunction between these two studies. Although in our study the sample size was small, confidence intervals were wide, and protocol deviations did not permit a robust comparison, the results of this pilot study suggest that the longer infusion time of 30 minutes every 3–4 weeks for 2 years for MM patients with bone disease is also safe and well-tolerated.
As expected, PK data showed that the median zoledronic acid concentrations were greater in the samples obtained from the 15-minute group compared to those from the 30-minute group. This effect was observed in samples obtained both 5 minutes before the end of infusion and at the end of infusion.
Increasing the infusion time did not significantly alter the AE profile and was not associated with any new or unexpected AEs. The incidence rates of deaths, SAEs, treatment-related AEs, and overall AEs were generally comparable between treatment groups. Overall, the incidence rates of reported SREs and ONJ were as expected for this patient population, which are important factors when considering zoledronic acid for patients with MM, where the goal of ongoing monthly IV bisphosphonate therapy is to prevent the development of new SREs without increasing the risk of AEs, such as ONJ.
Finally, the FDA-approved current labeling for zoledronic acid recommends decreasing the dose of this bisphosphonate based on baseline kidney function.7 Because these recommendations were not in place at the time that this study was designed, whether the implementation of these dosing guidelines for patients with MM along with varying infusion durations would have impacted the results observed in our study cannot be ascertained.
In summary, the results of this study suggest that the safety profile of IV zoledronic acid is similar regardless of a 15-minute or a 30-minute infusion duration. However, because the study was not powered to detect statistical significance and the current renal dosing guidelines for zoledronic acid were not used in this study, large randomized studies, using current dosing recommendations, will be required to further assess the effects on kidney safety of prolonging the infusion time of ongoing monthly IV zoledronic acid therapy for patients with MM.
Acknowledgments
The authors thank Syntaxx Communications, Inc., specifically, Kristin Hennenfent, PharmD, MBA, BCPS, and Lisa Holle, PharmD, BCOP, who provided manuscript development and medical writing services, and Holly Matthews, BS, who provided editorial services, with support from Novartis Pharmaceuticals Corporation. We also thank all participating patients and study personnel. Research support was provided by Novartis Pharmaceuticals Corporation (East Hanover, NJ).
References
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Appendix
The following ZMAX Trial principal investigators participated in this study: Bart Barlogie, MD, Myeloma Institute For Research and Therapy; James Berenson, MD, Oncotherapeutics; Robert Bloom, MD, Providence Cancer Center, Clinical Trials Department; Ralph Boccia, MD, Center for Cancer and Blood Disorders; Donald Brooks, MD, Arizona Clinical Research Center, Inc.; Robert Brouillard, MD, Robert P. Brouillard, MD, and Delvyn Case, MD, Maine Center for Cancer Medicine and Blood Disorders, Pharmacy; Veena Charu, MD, Pacific Cancer Medical Center; Naveed Chowhan, MD, Cancer Care Center, Inc; Robert Collins, MD, University of Texas Southwestern Medical Center at Dallas; Thomas Cosgriff, MD, Hematology and Oncology Specialists, LLC; Jose Cruz, MD, Joe Arrington Cancer Research and Treatment Center; Surrinder Dang, MD, Oncology Specialties; Sheldon Davidson, MD, North Valley H/O; Tracy Dobbs, MD, Baptist Regional Cancer Center; Luke Dreisbach, MD, Desert Hematology Oncology Medical Group; Isaac Esseesse, MD, Hematology Oncology Associates of Central Brevard, Laboratory; Mark Fesen, MD, Hutchinson Clinic, PA; George Geils, Jr., MD, Charleston Hematology Oncology Associates, PA; Michael Greenhawt, MD, South Florida Oncology-Hematology; Manuel Guerra, MD, ORA; Rita Gupta, MD, Oncology-Hematology Associates, PA; Vicram Gupta, MD, Saint Joseph Oncology; Alexandre Hageboutros, MD, Cancer Institute of New Jersey at Cooper Hospital; Vincent Hansen, MD, Utah Hematology Oncology; David Henry, MD, Pennsylvania Oncology Hematology Associates; Benjamin Himpler, MD, Syracuse Hematology/Oncology PC; Winston Ho, MD, Hematology/Oncology Group of Orange County; William Horvath, MD, Haematology Oncology Associates of Ohio and Michigan, PC; Paul Hyman, MD, Hematology Oncology Associates of Western Suffolk; Min Kang, MD, Western Washington Oncology; Mark Keaton, MD, Augusta Oncology Associates, PC; Howard Kesselheim, MD, The Center for Cancer and Hematologic Disease; Kapisthalam Kumar, MD, Pasco Hernando Oncology Associates, PA; Edward Lee, MD, Maryland Oncology-Hematology, PA; André Liem, MD, Pacific Shore Medical Group; Timothy Lopez, MD, New Mexico Cancer Care Associates, Cancer Institute of New Mexico; Paul Michael, MD, Comprehensive Cancer Centers of Nevada; Michael Milder, MD, Swedish Cancer Institute; Barry Mirtsching, MD, Center for Oncology Research & Treatment, PA; Ruben Niesvizky, MD, New York Presbyterian Hospital; Jorge Otoya, MD, Osceola Cancer Center; Joseph Pascuzzo, MD, California Oncology of the Central Valley; Ravi Patel, MD, Comprehensive Blood and Cancer Center Lab; Allen Patton, MD, Hematology Oncology Associates, PA; Kelly Pendergrass, MD, Kansas City Cancer Center, LLC; Anthony Phillips, MD, Fox Valley Hematolgy Oncology, SC; Robert Raju, MD, Dayton Oncology and Hematology, PA; Harry Ramsey, MD, Berks Hematology Oncology Associates; Ritesh Rathore, MD, Roger Williams Hospital Medical Center; Phillip Reid, MD, Central Jersey Oncology Center; Robert Robles, MD, Bay Area Cancer Research Group, LLC; Stephen Rosenoff, MD, Oncology and Hematology Associates of Southwest Virginia, Inc; Martin Rubenstein, MD, Southbay Oncology Hematology Partners; Mansoor Saleh, MD, Georgia Cancer Specialists; Sundaresan Sambandam, MD, Hematology and Oncology Associates of RI; Mukund Shah, MD, Antelope Valley Cancer Center; David Siegel, MD, Hackensack University Medical Center; Nelida Sjak-Shie, MD, The Center for Cancer Care and Research; Michael Stone, MD, Greeley Medical Clinic; Stefano Tarantolo, MD, Nebraska Methodist Hospital; Joseph Volk, MD, Palo Verde Hematology Oncology, Ltd; Mitchell Weisberg, MD, MetCare Oncology; Ann Wierman, MD, Nevada Cancer Center; Donald Woytowitz, Jr., MD, Florida Cancer Specialists; Peter Yu, MD, Camino Medical Group.
Original research
James R. Berenson MD
Abstract
Zoledronic acid, an intravenous (IV) bisphosphonate, is a standard treatment for multiple myeloma (MM) but may exacerbate preexisting renal dysfunction. The incidence of zoledronic acid–induced renal dysfunction may correlate with infusion duration. In this randomized, multicenter, open-label study, 176 patients with MM, at least one bone lesion, and stable renal function with a serum creatinine (SCr) level <3 mg/dL received zoledronic acid 4 mg (in 250 mL) as a 15- or 30-minute IV infusion every 3–4 weeks. At month 12, 20% (17 patients) in the 15-minute and 16% (13 patients) in the 30-minute arm experienced a clinically relevant but nonsignificant SCr-level increase (P = 0.44). By 24 months, the proportion of patients with a clinically relevant SCr-level increase was similar between arms (15-minute 28% [24 patients] vs 30-minute 27% [23 patients], P = 0.9014). Median zoledronic acid end-of-infusion concentrations were higher with the shorter infusion (15-minute 249 ng/mL vs 30-minute 172 ng/mL), and prolonging the infusion beyond 15 minutes did not influence adverse events related to zoledronic acid. For patients with MM, the safety profile of IV zoledronic acid is similar between those receiving a 15- or 30-minute infusion; therefore, determining the appropriate infusion duration of zoledronic acid should be based on individual patient considerations.
Article Outline
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 (Cmax) 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.
| NUMBER OF PATIENTS (%)a | ||
|---|---|---|
| CHARACTERISTIC | ZOLEDRONIC ACID 4 MG IV FOR 15 MINUTES (N = 88)b | ZOLEDRONIC ACID 4 MG IV FOR 30 MINUTES (N = 88)b |
| Age (years) | ||
| Mean (SD) | 64 | 64 |
| Median | 66 | 64 |
| Range | 37–91 | 27–86 |
| Age category (years) | ||
| <65 | 39 (44) | 47 (53) |
| ≥65 | 49 (56) | 41 (47) |
| Sex | ||
| Male | 56 (64) | 49 (56) |
| Female | 32 (36) | 39 (44) |
| Race | ||
| White | 70 (80) | 69 (78) |
| Black | 9 (10) | 13 (15) |
| Asian | 1 (1) | 1 (1) |
| Other | 8 (9) | 5 (6) |
| Time since diagnosis (months) | ||
| Mean (SD) | 12 (24) (n = 86) | 10 (14) (n = 87) |
| Median | 4 | 6 |
| Range | 0–186 | 0–98c |
| Prior bisphosphonate use | ||
| Naive | 28 (32) | 28 (32) |
| ≤1 year | 12 (14) | 14 (16) |
| >1 year | 48 (55) | 39 (44) |
| Missing | 0 (0) | 7 (8) |
| Calculated CrCl (mL/min) | ||
| Mean (SD) | 87 (33) | 89 (40) |
| Median | 84 | 83 |
| Range | 33–210 | 31–224 |
| Calculated CrCl category (mL/min) | ||
| CrCl ≥75 | 54 (61) | 49 (56) |
| 60 < CrCL < 75 | 13 (15) | 15 (17) |
| 30 < CrCl ≤ 60 | 21 (24) | 24 (27) |
| CrCl <30 | 0 (0) | 0 (0) |
CrCl = creatinine clearance; IV = intravenous; SD = standard deviation
a Unless otherwise notedb Safety populationc One patient had a screening visit date before the date of initial diagnosis
Protocol violations and/or deviations (n = 658) occurred during this study, affecting 139 patients. The types of protocol violations/deviations were related to protocol adherence (n = 404), timing of visits (n = 210), protocol adherence/timing of visits (n = 2), exclusion criteria (n = 22), inclusion criteria (n = 10), and informed consent (n = 1); 9 violations were unclassified. Notably, one protocol adherence deviation that occurred was incorrect infusion duration despite the patient having a stable SCr level. In the 15-minute treatment group, 15% of infusions administered were longer than 15 minutes. Among the longer infusions, 7% of the infusions correctly occurred per protocol following an SCr-level increase, whereas 7% of the prolonged infusions were 20 minutes or longer in the absence of an SCr-level increase. Similarly, in the 30-minute treatment group, 5% of patients received infusions lasting at least 35 minutes in the absence of an SCr-level increase.
Renal Safety
At 12 months, slightly fewer patients (n = 13 [16%]) in the 30-minute infusion group had a clinically relevant increase in SCr level than in the 15-minute infusion group (n = 17 [20%]); but this difference was not statistically significant, and for approximately 35% of patients in each group there were no SCr data available (Table 2). The median time to a clinically relevant increase in SCr by Kaplain-Meier was not reached in either group (data not shown). Neither previous bisphosphonate use nor baseline CrCl significantly affected the results (P = 0.5837 and P = 0.9371, respectively).
| NUMBER OF PATIENTS (%) | |||
|---|---|---|---|
| CLINICALLY RELEVANT INCREASE IN SCR | ZOLEDRONIC ACID 4 MG IV FOR 15 MINUTES (N = 85)a | ZOLEDRONIC ACID 4 MG IV FOR 30 MINUTES (N = 84)a | P VALUEb |
| 12 Months | 0.6892 | ||
| Yes | 17 (20) | 13 (16) | |
| No | 38 (45) | 42 (50) | |
| Unknown | 30 (35) | 29 (35) | |
| 24 Months | 0.9750 | ||
| Yes | 24 (28) | 23 (27) | |
| No | 22 (26) | 23 (27) | |
| Unknown | 39 (46) | 38 (45) | |
CI = confidence interval; IV = intravenous; SCr = serum creatinine
a Safety population, excluding patients with protocol violationsb P value calculated based on chi-squared test
After 24 months of treatment, the proportion of patients experiencing a clinically relevant increase in SCr level was similar between treatment groups, although for approximately 45% of patients in each group there were no SCr data available (see Table 2). Moreover, the difference in time to first clinically relevant increase in SCr level was not statistically significant between the two groups (P = 0.55) (Figure 1). However, among patients with a clinically significant rise in SCr level, the median time to SCr rise was slightly longer in the 30-minute group than in the 15-minute group (22 vs 24 weeks), but this was not statistically significant.
Increases in SCr relative to baseline led to treatment discontinuation in 20 patients (24%) receiving a 15-minute infusion and 14 patients (17%) receiving a 30-minute infusion. In these cases, the treating physician either considered the SCr level too high for continued treatment or the SCr level was persistently high despite treatment interruption.
Pharmacokinetics
Median zoledronic acid concentrations, as anticipated, were higher with the 15-minute infusion time at both sampling time points (during infusion: 15-minute group 231 ng/mL [at 10 minutes] vs 30-minute group 186 ng/mL [at 25 minutes]; end-of-infusion: 15-minute group, 249 ng/mL vs 30-minute group 172 ng/mL).
Adverse Events
Overall, the incidence and severity of AEs were as anticipated for MM patients. The most commonly reported AEs included fatigue, anemia, nausea, constipation, and back pain (Table 3). Although many AEs were reported more frequently in the 30-minute infusion group, the incidence rates of AEs suspected to be related to zoledronic acid were similar between the two groups. Toxicities were graded as mild, moderate, or severe; proportions of AEs categorized by these grades were comparable. Nonfatal serious AEs (SAEs) occurred in 26% of patients receiving the 15-minute infusion and 35% of patients receiving the 30-minute infusion; however, only one patient in the 15-minute group and two patients in the 30-minute group had SAEs suspected to be related to study medication.
| NUMBER OF PATIENTS (%) | |||
|---|---|---|---|
| TYPE OF AE | ZOLEDRONIC ACID 4 MG IV FOR 15 MINUTES (N = 85) | ZOLEDRONIC ACID 4 MG IV FOR 30 MINUTES (N = 84) | TOTAL (N = 169) |
| Blood and lymphatic system disorders | |||
| Anemia | 19 (22) | 27 (32) | 46 (27) |
| Neutropenia | 6 (7) | 12 (14) | 18 (11) |
| Gastrointestinal disorders | |||
| Constipation | 20 (24) | 21 (25) | 41 (24) |
| Diarrhea | 14 (17) | 20 (24) | 34 (20) |
| Nausea | 18 (21) | 27 (32) | 45 (27) |
| Vomiting | 10 (12) | 14 (17) | 24 (14) |
| General disorders | |||
| Fatigue | 30 (35) | 41 (49) | 71 (42) |
| Pain | 7 (8) | 10 (12) | 17 (10) |
| Pain in extremity | 14 (17) | 16 (19) | 30 (18) |
| Peripheral edema | 13 (15) | 20 (24) | 33 (20) |
| Pyrexia | 15 (18) | 19 (23) | 34 (20) |
| Infections and infestations | |||
| Pneumonia | 11 (13) | 7 (8) | 18 (11) |
| Upper respiratory tract infection | 13 (15) | 13 (16) | 26 (15) |
| Metabolism and nutrition disorders | |||
| Anorexia | 8 (9) | 9 (11) | 17 (10) |
| Hypokalemia | 12 (14) | 13 (15) | 25 (14) |
| Musculoskeletal and connective tissue disorders | |||
| Arthralgia | 10 (11) | 16 (19) | 26 (15) |
| Asthenia | 9 (10) | 13 (16) | 22 (13) |
| Back pain | 19 (22) | 20 (24) | 39 (23) |
| Bone pain | 10 (12) | 11 (13) | 21 (12) |
| Nervous system disorders | |||
| Dizziness | 11 (13) | 10 (12) | 21 (12) |
| Peripheral neuropathy | 7 (8) | 15 (18) | 22 (13) |
| Psychiatric disorders | |||
| Insomnia | 10 (12) | 14 (17) | 24 (14) |
| Respiratory, thoracic, and mediastinal disorders | |||
| Cough | 13 (15) | 15 (18) | 28 (17) |
| Dyspnea | 15 (18) | 17 (20) | 32 (19) |
| Skin and subcutaneous tissue disorders | |||
| Rash | 9 (11) | 12 (14) | 21 (12) |
AE = adverse event; IV = intravenous
a Safety population excluding patients with protocol violations
The numbers of deaths, trial discontinuations, and treatment interruptions due to AEs were similar between the two groups as well. Deaths (9 [10.6%] 15-minute group vs 6 [7.1%] 30-minute group) were not suspected to be related to zoledronic acid. Eight patients in each treatment group discontinued therapy because of an AE; events leading to treatment discontinuation that were suspected to be related to zoledronic acid occurred in two patients in the 15-minute group (skeletal pain and ONJ) and one patient in the 30-minute group (jaw pain). AEs that required treatment interruption occurred in eight and nine patients in the 15-minute and 30-minute groups, respectively.
AEs of special interest included those related to kidney dysfunction, cardiac arrhythmias, SREs, and ONJ. The number of patients reporting overall kidney and urinary disorders was the same in the two treatment groups (14 patients in each group); however, acute renal failure was reported more frequently in patients receiving the 15-minute infusion compared with the 30-minute infusion (four patients [5%] vs one patient [1%] in 30-minute group). Details of these five patients are presented in Table 4. AEs related to cardiac rhythm occurred in 20 patients while on study; however, only one case of bradycardia was suspected to be related to zoledronic acid therapy (in the 30-minute group). The incidence of SREs at 2 years was comparable in the two groups (19% in 15-minute group vs 21% in 30-minute group). The time to onset of SREs was longer in the 15-minute group (222 vs 158 days), but this was not statistically significant. A total of 10 patients with suspected ONJ were identified, with three patients in the 15-minute group (all moderate) and seven patients in the 30-minute group (mild [n = 5], moderate [n = 1], severe [n = 1]). Six of these patients received bisphosphonates before entering the study (four patients received no prior bisphosphonates), but the length of previous bisphosphonate therapy varied (0–30 months). Patients with suspected ONJ were assessed by clinicians and referred to dental professionals for further evaluation.
| PATIENT DEMOGRAPHICS | TYPE OF MM | MEDICAL HISTORY | CONCURRENT MEDICATIONSa | ACUTE RENAL FAILURE DETAILS | OUTCOME |
|---|---|---|---|---|---|
| Zoledronic acid 4 mg IV for 15 minutes | |||||
| 73-year-old female Caucasian | IgG | Anemia, cardiomyopathy, CHF, cholecystectomy, benign breast lump removal, CAD, DM, dyslipidemia, central venous catheterization, chronic renal failure, GERD, hypercholesterolemia, HTN, hysterectomy, mycobacterial infection, hemorrhoids, B-cell lymphoma, seborrheic keratosis, tonsillectomy | At start of study: aspirin, losartan, digoxin, hydrochlorothiazide/lorsartan, fluconazole, folic acid, atorvastatin, vitamins, warfarinDuring study: ethambutol dihydrochloride, moxifloxacin, rifabutin, fenofibrate, omeprazole, diuretics, nitroglycerin patch, angiotensin-converting enzyme inhibitors, hydroxyzine, loratadine, furosemide, vancomycin, pantoprozole, piperacillin/tazobactam, clarithromycin | Myeloma kidney mass consistent with myeloma kidney found during study; approximately 2 weeks later the patient developed severe infection that culminated in septic shock, with acute renal failure | Nephrologist considered renal insufficiency to be partly related to past history of large-cell lymphoma and chemotherapy; patient was discharged to hospice and died of acute renal failure secondary to myeloma |
| 71-year-old female Caucasian | IgA | Back pain, cholecystectomy, constipation, CAD, NIDDM, hypercholesterolemia, HTN, insomnia, left knee operation, neuralgia, obesity, osteoarthritis, hysterectomy, hypoacusis, seasonal allergies, urinary incontinence | At start of study: zolpidem, amitriptyline, loratidine, tolterodine l-tartrate, valsartan, metrotoprolol, furosemide, ibuprofen, clonazepam, gabapentin, liodcaine, hydrocodone/acetaminophen, quinine sulfate, simvastatin During study: calcium, multivitamins, lactulose, trazodone, hydromorphone, cyclobenzaprine, glipizide, macrogol, lorazepam, methadone, potassium, lisinopril, furosemide, meperidine, promethazine | Developed moderate acute renal failure on the day of her first dose; considered not associated with zoledronic acid | Renal ultrasound showed arterial stenosis; resolved approximately 1 month after diagnosis |
| 65-year-old male Caucasian | IgG | Oxycodone hypersensitivity, anemia, back pain, spine metastases, spinal compression fracture, depression, fatigue, inguinal hernia repair, spinal fusion (L1–L3) surgery, bilateral hip arthroplasty, pain, pneumonia, staphylococcal infection | At start of study: fluconazole, morphine sulfate, oxycodone/acetaminophen During study: naproxen, darbepoietin alfa, sodium ferrifluconate, calcium with vitamin D, cephalexin, dexamethasone, alginic acid, docusate, heparin, sodium polystyrene, levofloxacin, filgrastim, lansoprazole | After 5 doses of zoledronic acid, patient developed severe acute renal failure with elevated SCr; not suspected to be related to zoledronic acid | Resolved 9 days later following treatment with cephalexin and dexamethasone |
| 56-year-old female Caucasian | IgA | Osteolysis, cataract surgery, constipation, bone lesions, hypercholesterolemia, HTN, musculoskeletal pain, anorexia | At start of study: ibuprofen, oxycodone, propoxyphene/acetaminophen, hydrocodone/acetaminophen, valsartan, calcium/vitamin D, potassium chloride, docusate sodiumDuring study: vancomycin, acyclovir | Approximately 1 week after 9th zoledronic acid dose, patient developed acute renal failure with an increased SCr (12.5 mg/dL); not suspected to be related to zoledronic acid | Resulted from myeloma progression to plasma cell leukemia; emergency dialysis performed; catheter-related sepsis occurred approximately 1 month later, and patient died of sepsis and disease progression |
| Zoledronic acid 4 mg IV for 30 minutes | |||||
| 80-year-old male African American | IgG | Anemia, arteriosclerotic heart disease, bilateral ankle swelling/pain, degenerative joint disease, dyspnea on exertion, fatigue, GERD, HTN, neutropenia, shoulder pain, vasovagal syncope | At start of study: aspirin, atenolol, multivitamin, doxazosin, fosinopril, hydrochlorothiazide, amlodipine besylate, simvastatinDuring study: darbepoietin alfa, warfarin sodium, furosemide, omeprazole, calcium carbonate | Approximately 1 month after 2nd dose, patient experienced increased SCr (2.9 mg/dL, 53% increase from baseline); relationship to zoledronic acid unknown | Discontinued from study after 2nd dose, and SCr remained elevated for 2 months following discontinuation |
CAD = coronary artery disease; CHF = congestive heart failure; DM = diabetes mellitus; GERD = gastroesophageal reflux disease; HTN = hypertension; MM = multiple myeloma; NIDDM = non-insulin-dependent diabetes mellitus; SCr = serum creatinine
Discussion
During the past decade, bisphosphonate therapy has become an important adjunctive treatment to prevent the emergence, or worsening, of SREs in patients with MM involving the bone.15 Kidney failure is a common and severe complication of MM that may be exacerbated by chronic administration of zoledronic acid.7 A study evaluating zoledronic acid in patients with cancer and bone metastases suggests that increasing the infusion time decreases the Cmax, which may result in fewer renal AEs.[9] and [12] This study was designed to assess whether prolonging the infusion time of zoledronic acid from the recommended 15 to 30 minutes would improve kidney safety in MM patients, as evidenced by fewer rises in SCr levels. To our knowledge, this is the only trial that has been designed to evaluate the impact of infusion duration on renal effects in this population.
The 12-month results of this pilot study showed a trend toward improved renal safety with the longer infusion time, this difference not being statistically significant. By 24 months, however, there were no differences in SCr level elevations between the two groups. The clinically relevant SCr increases observed in our study, however, differ from those reported by Rosen and colleagues,[5] and [6] who first evaluated zoledronic acid for patients with MM. In that study, 4%–11% of patients experienced kidney function deterioration, manifested by SCr increases, which is much lower than the rate observed in our study. However, several differences exist between our trial and the Rosen study. The Rosen study included both breast cancer patients with at least one bone metastasis and Durie-Salmon stage 3 MM patients with at least one osteolytic lesion, whereas our study only included MM patients with at least one bone lesion. Additionally, the criteria for defining a clinically relevant SCr increase differ between the two studies; therefore, one cannot directly compare the incidence of kidney dysfunction between these two studies. Although in our study the sample size was small, confidence intervals were wide, and protocol deviations did not permit a robust comparison, the results of this pilot study suggest that the longer infusion time of 30 minutes every 3–4 weeks for 2 years for MM patients with bone disease is also safe and well-tolerated.
As expected, PK data showed that the median zoledronic acid concentrations were greater in the samples obtained from the 15-minute group compared to those from the 30-minute group. This effect was observed in samples obtained both 5 minutes before the end of infusion and at the end of infusion.
Increasing the infusion time did not significantly alter the AE profile and was not associated with any new or unexpected AEs. The incidence rates of deaths, SAEs, treatment-related AEs, and overall AEs were generally comparable between treatment groups. Overall, the incidence rates of reported SREs and ONJ were as expected for this patient population, which are important factors when considering zoledronic acid for patients with MM, where the goal of ongoing monthly IV bisphosphonate therapy is to prevent the development of new SREs without increasing the risk of AEs, such as ONJ.
Finally, the FDA-approved current labeling for zoledronic acid recommends decreasing the dose of this bisphosphonate based on baseline kidney function.7 Because these recommendations were not in place at the time that this study was designed, whether the implementation of these dosing guidelines for patients with MM along with varying infusion durations would have impacted the results observed in our study cannot be ascertained.
In summary, the results of this study suggest that the safety profile of IV zoledronic acid is similar regardless of a 15-minute or a 30-minute infusion duration. However, because the study was not powered to detect statistical significance and the current renal dosing guidelines for zoledronic acid were not used in this study, large randomized studies, using current dosing recommendations, will be required to further assess the effects on kidney safety of prolonging the infusion time of ongoing monthly IV zoledronic acid therapy for patients with MM.
Acknowledgments
The authors thank Syntaxx Communications, Inc., specifically, Kristin Hennenfent, PharmD, MBA, BCPS, and Lisa Holle, PharmD, BCOP, who provided manuscript development and medical writing services, and Holly Matthews, BS, who provided editorial services, with support from Novartis Pharmaceuticals Corporation. We also thank all participating patients and study personnel. Research support was provided by Novartis Pharmaceuticals Corporation (East Hanover, NJ).
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Appendix
The following ZMAX Trial principal investigators participated in this study: Bart Barlogie, MD, Myeloma Institute For Research and Therapy; James Berenson, MD, Oncotherapeutics; Robert Bloom, MD, Providence Cancer Center, Clinical Trials Department; Ralph Boccia, MD, Center for Cancer and Blood Disorders; Donald Brooks, MD, Arizona Clinical Research Center, Inc.; Robert Brouillard, MD, Robert P. Brouillard, MD, and Delvyn Case, MD, Maine Center for Cancer Medicine and Blood Disorders, Pharmacy; Veena Charu, MD, Pacific Cancer Medical Center; Naveed Chowhan, MD, Cancer Care Center, Inc; Robert Collins, MD, University of Texas Southwestern Medical Center at Dallas; Thomas Cosgriff, MD, Hematology and Oncology Specialists, LLC; Jose Cruz, MD, Joe Arrington Cancer Research and Treatment Center; Surrinder Dang, MD, Oncology Specialties; Sheldon Davidson, MD, North Valley H/O; Tracy Dobbs, MD, Baptist Regional Cancer Center; Luke Dreisbach, MD, Desert Hematology Oncology Medical Group; Isaac Esseesse, MD, Hematology Oncology Associates of Central Brevard, Laboratory; Mark Fesen, MD, Hutchinson Clinic, PA; George Geils, Jr., MD, Charleston Hematology Oncology Associates, PA; Michael Greenhawt, MD, South Florida Oncology-Hematology; Manuel Guerra, MD, ORA; Rita Gupta, MD, Oncology-Hematology Associates, PA; Vicram Gupta, MD, Saint Joseph Oncology; Alexandre Hageboutros, MD, Cancer Institute of New Jersey at Cooper Hospital; Vincent Hansen, MD, Utah Hematology Oncology; David Henry, MD, Pennsylvania Oncology Hematology Associates; Benjamin Himpler, MD, Syracuse Hematology/Oncology PC; Winston Ho, MD, Hematology/Oncology Group of Orange County; William Horvath, MD, Haematology Oncology Associates of Ohio and Michigan, PC; Paul Hyman, MD, Hematology Oncology Associates of Western Suffolk; Min Kang, MD, Western Washington Oncology; Mark Keaton, MD, Augusta Oncology Associates, PC; Howard Kesselheim, MD, The Center for Cancer and Hematologic Disease; Kapisthalam Kumar, MD, Pasco Hernando Oncology Associates, PA; Edward Lee, MD, Maryland Oncology-Hematology, PA; André Liem, MD, Pacific Shore Medical Group; Timothy Lopez, MD, New Mexico Cancer Care Associates, Cancer Institute of New Mexico; Paul Michael, MD, Comprehensive Cancer Centers of Nevada; Michael Milder, MD, Swedish Cancer Institute; Barry Mirtsching, MD, Center for Oncology Research & Treatment, PA; Ruben Niesvizky, MD, New York Presbyterian Hospital; Jorge Otoya, MD, Osceola Cancer Center; Joseph Pascuzzo, MD, California Oncology of the Central Valley; Ravi Patel, MD, Comprehensive Blood and Cancer Center Lab; Allen Patton, MD, Hematology Oncology Associates, PA; Kelly Pendergrass, MD, Kansas City Cancer Center, LLC; Anthony Phillips, MD, Fox Valley Hematolgy Oncology, SC; Robert Raju, MD, Dayton Oncology and Hematology, PA; Harry Ramsey, MD, Berks Hematology Oncology Associates; Ritesh Rathore, MD, Roger Williams Hospital Medical Center; Phillip Reid, MD, Central Jersey Oncology Center; Robert Robles, MD, Bay Area Cancer Research Group, LLC; Stephen Rosenoff, MD, Oncology and Hematology Associates of Southwest Virginia, Inc; Martin Rubenstein, MD, Southbay Oncology Hematology Partners; Mansoor Saleh, MD, Georgia Cancer Specialists; Sundaresan Sambandam, MD, Hematology and Oncology Associates of RI; Mukund Shah, MD, Antelope Valley Cancer Center; David Siegel, MD, Hackensack University Medical Center; Nelida Sjak-Shie, MD, The Center for Cancer Care and Research; Michael Stone, MD, Greeley Medical Clinic; Stefano Tarantolo, MD, Nebraska Methodist Hospital; Joseph Volk, MD, Palo Verde Hematology Oncology, Ltd; Mitchell Weisberg, MD, MetCare Oncology; Ann Wierman, MD, Nevada Cancer Center; Donald Woytowitz, Jr., MD, Florida Cancer Specialists; Peter Yu, MD, Camino Medical Group.