First Asia-Pacific Co-Operative Multicenter Multiple Myeloma Clinical Trial: Preliminary Results of the “dtZ”/“DAZZLE” Study.

Many physicians have anecdotally reported that Asian patients with multiple myeloma (MM) are frequently unable to tolerate full doses of dexamethasone (Dex) and/or thalidomide (Thal). Unfortunately, co-operative clinical studies from the Asia-Pacific countries are presently lacking and the effective dose of the Dex/Thal combination in Asians is unknown. Since higher doses of zoledronic acid (Zol) have been shown to exert an anti-MM effect in pre-clinical models of MM, we investigated whether higher frequency dosing of Zol combined with lower doses of Dex/Thal could be an effective and better tolerated regimen in Asian patients. Moreover, since attainment of very good partial response (VGPR), near complete response (nCR) or complete response (CR) prior to autologous hematopoietic stem cell transplantation (AHSCT) correlates with good outcome in MM, we wanted to determine if this lower-dose Dex/Thal with higher-frequency dosing Zol regimen could be a good preparative regimen in transplant-eligible patients.

In this international co-operative multicenter phase II non-randomized single arm study in previously untreated patients with MM (n=44), all patients received up to 6 cycles of three-weekly Dex/Thal/Zol (or “dtZ”). Doses of Dex ranged from 20 mg weekly to 20 mg four times a week; and doses of Thal ranged from 50 mg weekly to 100 mg every night. Zol 4 mg was given three-weekly. Response was graded using Blade's criteria.

The study population included 67.3% Oriental (Korean and Chinese), 30.8% Indian and 1.9% Malay patients. 15.4% of patients were ISS stage I, 61.5% stage II and 23.1% stage III prior to treatment. 39 (88.6%) patients demonstrated at least a partial response (PR); and 23 (52.3%) of patients achieved VGPR (18.2%), near nCR (15.9%) or CR (18.2%). The fastest time to VGPR/nCR/CR was 1 cycle. Most patients tolerated treatment very well and were managed in the outpatient clinic. Sepsis was the most frequently reported grade 3 or 4 toxicity – 8 (18.2%) patients developed bronchopneumonia, and 3 (6.8%) gastrointestinal or urinary tract infections. 1 (2.3%) patient was suspected of having pulmonary embolism. There were 4 (9.1%) deaths – 3 from severe sepsis and 1 from an unknown cause. Importantly, there were no reports of peripheral neuropathy, osteonecrosis of the jaw (ONJ) or end stage renal failure. In fact, there was an overall 2.4% improvement in the median creatinine clearance time (CCT). Finally, the percentage of CD34 stem cells was not adversely affected by treatment with dtZ.

The dtZ regimen appears to be an effective and well-tolerated treatment regimen for Asian patients with newly-diagnosed MM. The high rate of VGPR/nCR/CR will greatly facilitate AHSCT in transplant-eligible patients. Judicious use of low-dose Thal has abrogated the numerous side-effects associated with Thal and greatly improved patient tolerance. Even though Zol is administered at a higher frequency, it is not associated with worsening of renal function or ONJ. Infections are the most frequent and worrisome complications of treatment. These are likely to be related to the dose of Dex. Accordingly, it is probably wise to further lower the dose of Dex in future studies. (This study is registered with NIH PRS # 00263484.)

No relevant conflicts of interest to declare.