Higher Frequency Zoledronic Acid in the Treatment of Multiple Myeloma (dtZ)

An International, Multicenter, Non-Randomized, Open-Labeled Study to Evaluate the Efficacy of Lower Dose Dexamethasone/Thalidomide and Higher Frequency ZOMETA(TM) in the Treatment of Previously Untreated Patients With Multiple Myeloma

Singapore General Hospital, National Cancer Centre, Singapore, Tan Tock Seng Hospital, Seoul National University Hospital, Asan Medical Center, Samsung Medical Center, Chonnam National University Hospital, Christian Medical College, Vellore, India, Tata Memorial Hospital

The purpose of this study is to determine whether lower than conventional doses of dexamethasone and thalidomide; and a higher dosing frequency of zoledronic acid are effective in the treatment of newly-diagnosed multiple myeloma.

Patients with newly-diagnosed multiple myeloma (MM) may be treated using monthly cycles of dexamethasone plus thalidomide (DT). Unfortunately, the use of conventional doses of DT is associated with significant treatment-related morbidity and mortality, which is comparable to that observed with conventional chemotherapy. Hence, for safety reasons, patients frequently receive lower than conventional doses of DT (i.e. dt), and potentially experience a poorer anti-MM effect. The highly-potent aminobisphosphonate, zoledronic acid (Z), has been shown in pre-clinical mouse models to exhibit an impressive anti-MM effect. It is therefore possible to combined dt with Z (i.e. dtZ) to enhance the efficacy of (lower dose) dt. In addition, the anti-tumor effect of dtZ may potentially be augmented by using Z at a higher (three-weekly) dosing frequency.

20 mg, PO (orally) on days 1-4, 8-11 and 15-18 of each 21 day cycle. 6 Cycles: until progression or unacceptable toxicity develops.

100 mg, PO (orally) on days 1-21 of each 21 day cycle. 6 Cycles: until progression or unacceptable toxicity develops.

4 mg, IV (in the vein) on day 1 of each 21 day cycle. 6 Cycles: until progression or unacceptable toxicity develops.

1. To determine response rates (RR) and disease progression rates in all MM patients treated with dtZ regimen.

Inclusion Criteria: Age at or above 21 years Clinical diagnosis of MM Active MM with measurable disease Signed written informed consent Signed consent for drug safety program for thalidomide Exclusion Criteria: Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS) Patients with Indolent MM (IMM), or Smouldering MM (SMM) Known hypersensitivity (including severe cutaneous reactions) to d, t or Z Fulminant sepsis Females in the reproductive age group who refuse contraception Pregnancy 24 hr urinary creatinine clearance time (CCT) <30 ml/min Previous renal transplantation Severe peripheral neuropathy Recurrent DVT or PE Severe arrhythmias and cardiac conduction disorders Liver dysfunction of active viral hepatitis Osteonecrosis of the jaws (ONJ)

Yaccoby S, Pearse RN, Johnson CL, Barlogie B, Choi Y, Epstein J. Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity. Br J Haematol. 2002 Feb;116(2):278-90. doi: 10.1046/j.1365-2141.2002.03257.x.

Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, Apffelstaedt J, Hussein MA, Coleman RE, Reitsma DJ, Chen BL, Seaman JJ. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 2003 Oct 15;98(8):1735-44. doi: 10.1002/cncr.11701.

Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, Geyer S, Iturria N, Fonseca R, Lust JA, Kyle RA, Witzig TE. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol. 2002 Nov 1;20(21):4319-23. doi: 10.1200/JCO.2002.02.116.

Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. doi: 10.1200/JCO.2003.03.139.