Background: Thalidomide (THAL), an immunomodulatory agent with antiangiogenic properties, has become standard of care for patients with refractory or relapsed multiple myeloma (MM). Zoledronic acid (ZOL) is effective in preventing skeletal complications from MM, has cytotoxic effects, and enhances dexamethasone and THAL cytotoxicity in vitro (

Ural A, et al.
Int J Hematol.
2003
;
78
:
443
–449
). However, reports have suggested that combining ZOL with THAL increases the risk of renal adverse events in MM patients. In the present study, the potential effect of this combination on renal function was investigated as part of a multicenter, randomized, phase III trial. The study design also allowed the investigation of a potential effect of THAL on serum PK of ZOL in a subgroup of patients.

Methods: Patients with nonprogressive MM who had previously undergone autologous stem cell transplantation were randomized to receive either THAL 200 mg od or no THAL. All patients received ZOL 4 mg via 15-minute infusion every 28 days and prednisolone 50 mg every other day. Total treatment and observation period was 12 months. Creatinine was determined in all pre-infusion serum samples. PK (Cmax and AUC) was determined from serum samples collected over 48 hours after the first 2 infusions of ZOL. The potential effect of THAL co-administration on serum creatinine and ZOL PK was investigated with a repeated measures analysis using a mixed model and paired t-tests. P < .05 was regarded as statistically significant.

Results: 243 patients have been randomized (114 to receive THAL, 129 without). Analysis has been completed on 171 patients (79/92) who have received a median of 11 and 9 doses of ZOL respectively. 6 patients had ZOL withheld because of a rise in serum creatinine (2 treated with THAL, 4 treated without THAL). There were no significant differences in creatinine levels between patients treated with or without THAL, over time (P = .58), although a small increase in mean creatinine levels was noted over time in both arms at 0.64 mmol/L per 4 week cycle. PK was investigated in a total of 24 patients equally distributed among the treatment arms. No statistically significant influence was found of THAL co-administration on the PK parameters of ZOL.

Conclusions: These results suggest that co-administration of THAL with ZOL does not result in an increased risk for nephrotoxicity. Serum PK of ZOL is not influenced by THAL. ZOL is safe and well tolerated in multiple myeloma patients when used in combination with THAL.

Topics:
hematopoietic stem cell transplantation, multiple myeloma, thalidomide, zoledronic acid, creatinine, creatinine tests, serum, infusion procedures, serum specimen, adverse event, angiogenesis inhibitors

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2005, The American Society of Hematology
2005
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