Two Cycles of PAD Combination (PS-341/Bortezomib, Adriamycin and Dexamethasone) Followed by Autologous Hematopoietic Cell Transplantation (AHCT) in Newly Diagnosed Multiple Myeloma (MM) Patients.

Clinical trials have demonstrated that various combinations including Bortezomib (PS-341) are effective in newly diagnosed MM patients. We investigated the effectiveness of PAD (PS-341/Bortezomib, Adriamycin and Dexamethasone) and the feasibility of harvesting peripheral blood stem cells (PBSC) and performing AHCT after 2 cycles of PAD in newly diagnosed MM. Patients and Methods: Patients received two 21-day cycles of PAD consisting of bortezomib 1.3 mg/m² on days 1, 4, 8, and 11; adriamycin 9 mg/m² on days 1-4; and dexamethasone 40 mg on days 1-4 and 8-11. For mobilization of PBSC, G-CSF 10 mcg/kg was given subcutaneously for 4 days starting on day 12 of the second cycle of PAD. Following PBSC harvesting, AHCT was performed with a conditioning therapy of high-dose melphalan. Thalidomide 100-200 mg/d was given following AHCT. Results: Between April 2005 and October 2008, a total of 32 previously untreated patients, 18 males and 14 females, with symptomatic MM were enrolled into this study. Median age was 58.5 years (range, 44-69). Durie-Salmon stage was 1A in 3 (9.4%), 2A in 7 (21.9%), 3A in 19 (59.4%), and 3B in 3 (9.4%), while SWOG stage was I in 4 (12.5%), II in 18 (56.3%), III in 6 (18.8%), IV in 2 (6.3%), and unknown in 2 (6.3%). Of 31 patients who completed 2 planned cycles of PAD chemotherapy, 25 (80.6%) showed PR or better responses: CR in 6 (19.4%), VGPR in 5 (16.1%), and PR in 14 (45.2%). Severe (grade 3 or 4) non-hematologic toxicities after PAD were uncommon and included transient elevation of AST/ALT (3.2%), while severe hematologic toxicities were common (anemia, 4.8%; neutropenia, 38.1%; thrombocytopenia, 47.6%). All but two patients, who were removed from the study before PBSC collection, successfully mobilized PBSC with G-CSF for a median collection number of 3 (range, 2-7). The second attempt of PBSC collection was needed in 7 patients. Median number of collected CD34+ cells was 9.2 × 10⁶/kg (range, 4.4-30.1). Thirty patients underwent AHCT on a median day of 73 (range, 50-126) from the first cycle of PAD. Tandem AHCT was performed in one patient. Median number of infused CD34+ cells was 7.6 × 10⁶/kg (range, 4.4-18.5). Melphalan dose for conditioning therapy was 200 mg/m² in 26 patients, 140 mg/m² in one, and 120 mg/m² in three. All patients showed adequate hematologic recovery after AHCT with a median day of 12 (range, 11-38) for neutrophils > 500/mcL and a median day of 17 (range, 10-54) for platelets > 20,000/mcL. Response after AHCT was CR in 14 (46.7%), VGPR in 8 (26.7%), PR in 6 (20.0%), SD in 1 (3.1%), and PD in 1 (3.1%). Thalidomide was given to 24 patients after AHCT as maintenance therapy. The median interval to starting thalidomide from AHCT was 61 days (range, 32-206) and the median duration of thalidomide administration was 283.5 days (range, 2-741). Nine patients showed better response after thalidomide (VGPR → CR in 4, PR → CR in 1, SD → CR in 1, PR → VGPR in 3, and PD → PR in 1), thus after all, 20 patients (66.7%) achieved CR. With a median follow-up duration of 736 days (range, 178-1398) among surviving patients, 14 patients progressed and 6 died. Probabilities of overall and progression-free survival (PFS) were 62.5% and 32.7% at 3 years, respectively. PFS was significantly longer in patients receiving thalidomide after AHCT compared to those not receiving thalidomide (41.5% vs. 0% at 3 years, P & 0.001). Conclusion: Our study results confirmed excellent activity of PAD in newly diagnosed MM patients and showed that adequate harvesting and autografting of PBSC after 2 cycles of PAD chemotherapy was feasible. Post-transplant maintenance of thalidomide appears to be beneficial in preventing disease progression after AHCT.

No relevant conflicts of interest to declare.