Bortezomib, Doxorubicin and Dexamethasone (PAD) Combination Therapy Followed by Thalidomide and Dexamethasone (TD) as a Salvage Treatment for Relapsed Multiple Myeloma (MM): Analysis of Efficacy and Safety

Introduction: PAD was reported to be highly effective regimen as an induction therapy before high dose therapy. TD is an another effective regimen with no cross resistance. We conducted a phase II study with PAD followed by TD in relapsed MM to test effectiveness of this combination.

Method: Patients were planned to receive 6 cycles of PAD, (bortezomib 1.3 mg/m² days 1, 4, 8 and 11, doxorubicin 4.5 mg/m² days 1–4, dexamethasone 40 mg days 1–4, every 21 days). Responders following 6 cylces of PAD received 12 cycles of TD (thalidomide 100 mg days 1–28 and dexamethasone 40 mg days 1–4, every 28 days). In patients with progression during PAD therapy, regimen was changed to 12 cycles of thalidomide 200 mg days 1–28 and dexamethasone 40 mg days 1–4, every 28 days. Response was assessed by EBMT criteria, with additional categories of nCR and VGPR. Adverse events were graded by the NCI-CTC, Version 3.0.

Result: This study aimed to enroll 40 patients till Oct 2007 and we are reporting the result with 40 patients. Efficacy could be assessed in 34 patients. After two cycles of PAD, 34 patients showed response with 6 CR. Overall response rate to 6 cylces of PAD was 90.9% with 36.4% CR. Seven of total 24 patients with TD showed further improvement of response status with 7 additional CR. Overall response to PAD followed by TD was 94%: CR 57.6%, nCR 15.2%, VGPR 6%, PR 15.2%, SD 3%, PD 3%. There was no prognostic factor for CR+nCR achieving in the univariate analysis. The median follow-up was 16.2 months with 2 year OS 54.5%. The median PFS time from study treatment was 18 mon (95% CI, 11.0~24.9 mon), median OS was not reached. The median OS time from first diagnosis was 112.9 mon (95% CI, 24.6~201.1 mon). One hundred seventy-eight PAD cycles (median 6, range 1–6) in 38 patients were assessable for safety. The most common hematologic toxicity was thrombocytopenia, with grade 3/4 in 39.5%. Grade 3/4 neutropenia was observed in 10.5%. Sensory neuropathy occurred with grade 2 in 26.3% and grade 3 in 13.2%. The median dose intensity was 1.35 mg/m²/week for bortezomib and 5.21 mg/m²/week for doxorubicin, which correspond 78% and 86.8% of the planned dose intensities, respectively. A total of 185 TD treatment cycles (median 2, range 0–12 cycles) was administered. One patient die by the pneumonia.

Conclusion: PAD followed by TD in patients with relapsed multiple myeloma is very active and tolerable.