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