Oakervee et al presented the initial sequential phase I/II study of PAD in newly diagnosed, transplant-eligible myeloma patients (n=21) in 2005.r In this study, the maximum administered dose of Doxorubicin was 9 mg/m2, which was subsequently adopted in a second cohort of patients in the long-term follow-up study by Popat et al,r and also used in the recently published randomised, multicentre phase III HOVON-65/GMMG-HD4 Trial.r
Patients in the Oakervee/Popat studies received four 21-day cycles of PAD prior to autologous stem cell transplantation (ASCT), while a cohort of patients in the Popat study (n=20) received a lower dose of twice-weekly bortezomib (1.0 mg/m2). Dexamethasone was administered on day 1 to 4 (plus days 8 to 11, 15 to 18 in cycle 1 only). There were no statistically significant differences in CR/nCR and >VGPR rates post-induction between PAD patients whom received 1.0 mg/m2 or 1.3 mg/m2 of twice-weekly bortezomib (CR 11%/nCR 5%/VGPR 26% versus CR 24%/nCR 5%/VGPR 33%, respectively).
The HOVON-65/GMMG-HD4 Trialr enrolled 833 patients with newly diagnosed, transplant-eligible myeloma patients. Patients were randomised to three cycles of VAD induction, ASCT, followed by thalidomide 50 mg maintenance for 2 years or three cycles of PAD induction (bortezomib 1.3 mg/m2 days 1, 4, 8, 11; doxorubicin 9 mg/m2 days 1 to 4; dexamethasone 40 mg days 1 to 4, 9 to 12, 17 to 20 in a 28-day cycle), followed by ASCT and subsequent IV bortezomib 1.3 mg/m2 every 2 weeks for 2 years. Of note, HOVON patients received single ASCT while GMMG patients received tandem ASCTs, as per institutional protocols. CR rates after induction were 24% with VAD vs. 36% with PAD (p=<0.001). Median PFS was 28 months for VAD arm vs. 35 months for PAD arm; in a multivariate analysis PAD induction is associated with superior PFS (HR 0.74; 95% CI 0.62-0.89; p=0.001). Median OS was not reached after 66 months of follow-up in either arm, with 5-year OS of 55% (VAD arm) vs. 61% (PAD arm), p=0.07. Of note, GMMG patients had better OS overall (HR 0.75; 95% CI 0.57 -0.97; p=0.03) but when VAD vs. PAD patients were analysed within the GMMG group, there was no statistical difference in OS.
A small, phase II single-arm study published by Lee et alr explored the use of short course (two cycles) PAD induction in transplant-eligible South Korean patients to minimize toxicity. 32 patients received two 21-day cycles of PAD with bortezomib 1.3 mg/m2 on days 1, 4, 8, 11; doxorubicin 9 mg/m2 on days 1 to 4; and IV dexamethasone 40 mg on days 1 to 4 and 8 to 11. Patients were then mobilised with G-CSF only, followed by ASCT. After induction, CR was achieved in 19%, VGPR in 16% of patients. Post-ASCT, CR was achieved in 47% and VGPR in 27% of patients.
The use of liposomal doxorubicin in “PAD” has also been reported in 4 studies in the frontline treatment of myeloma. Most of these studies are small phase II trials with around 40 enrolled patients, most of whom are transplant eligible. In three of the trials the patients received bortezomib 1.3 mg/m2 days 1, 4, 8, and 11; liposomal doxorubicin 30mg/m2 on day 4; dexamethasone 20 to 40 mg on days of, and day after bortezomib therapy in a 21-day cycle,rr (one trial administered 40 mg day 1-4 only).r Most of these trials have limited patient follow-up, with an observed ORR 81-86% and nCR/CR 20 to 37.5% after 3-8 cycles of liposomal PAD. Given the small size of these phase II studies, the results should be interpreted with caution.
The use of PAD during induction therapy resulted in CR rates of 19 to 36% after 2 or 4 cycles, respectively. The HOVON-65/GMMG-HD4 showed that PAD was superior to VAD induction in respect to post-induction CR rates and PFS (refer to graph below). Median OS was not reached after 66 months of follow-up in either arm post-ASCT, with 5-year OS of 55% (VAD arm) vs. 61% (PAD arm), p=0.07.
© J Clin Oncol 2012
© J Clin Oncol 2012