Bortezomib, Dexamethasone and Concomitant or Sequential Thalidomide (VTD): An Effective Combination for Relapsed/Refractory Multiple Myeloma Failing Thalidomide and Dexamethasone.

Twenty one relapsed/refractory myeloma patients who failed thalidomide and dexamethasone received VTD combination treatment at our institution. Median age was 57 years (range, 43–80) and median number of previous lines of therapy was 3. Ten had prior autologous SCT and one had reduced intensity allogeneic SCT. All patients had active and measurable disease. Treatment plan was as follows: bortezomib iv on 1st, 4th, 8th and 11th days of a 21-day cycle (up to 8 cycles), dexamethasone 40 mg iv before each bortezomib dose and thalidomide 100 mg each evening. Elderly (≥65 year-old, n=6, 4 of whom also had grade 1 peripheral neuropathy (PN)) and two younger patients with grade 1 PN received bortezomib 1.5 mg iv (low dose) and thalidomide 100 mg each evening only during 10 day rest periods after bortezomib treatments (sequential, n=8). All other patients received bortezomib 1.75 mg iv (higher dose) and thalidomide 100 mg each evening (concomitant, n=13). The patients received a median of 6 cycles of the treatment (range, 2–8 cycles). DVT prophylaxis was aspirin 100 mg po qd. All patients who had at least 2 cycles of the treatment were evaluable for response according to EBMT criteria and 16 (76%) were the responders: 4 CR, 9 PR (5 VGPR by IMWG criteria), 3 MR. Five were the progressive ones. Among these, 8 went on to receive autologous and 2 had reduced intensity allogeneic SCT immediately after planned VTD treatment. Median number of cycles to the best response was 6 cycles. Among responders who did not go on to transplant, duration of response lasted from 2 to 15 months. Three patients had pneumonia (14%), three had varicella zoster infection (14%). No case of DVT was recorded. No treatment related deaths occurred. Four patients had grade 3 toxicity (PN, n=2; fatigue, n=2; and pancytopenia, n=1). Thalidomide was discontiuned in two patients after 2 cycles and in one patient after 3 cycles owing to grade 3 toxicities of fatigue and/or PN that were down-graded and reversible after cessation of thalidomide. Bortezomib was temporarily discontinued in one patient owing to grade 3 pancytopenia and re-started at the dose of 1.5 mg iv. The most frequently observed adverse effects were as follows: PN, n=14 (67%); fatigue, n=13 (62%); anemia, n=13 (62%); thrombocytopenia, n=10 (48%); leucopenia, n=9 (43%); constipation, n=6 (28%); peripheral edema, n=5 (24%); insomnia, n=3 (14%). Elderly and the patients with low-grade PN who received low dose bortezomib and sequential thalidomide experienced less PN (no new cases except two patients with grade 1 PN were upgraded to grade 2 and 3) compared to the patients who received higher dose bortezomib and concomitant thalidomide treatment (newly developed PN in 8: grade 1, n=6; grade 2, n=1; grade 3, n=1). Response rates were comparable between two groups (concomitant, 77% versus sequential, 75%). We conclude that VTD combination may induce high quality responses with acceptable toxicity in a significant proportion of relapsed/refractory myeloma patients with progression after thalidomide, dexamethasone and transplantation. This may be explained by synergism and/or additive effect. Low dose bortezomib and sequential thalidomide are well tolerated with less PN by elderly and the patients with low-grade PN. Increased incidences of infections may justify antibacterial and antiviral prophylaxis.