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