A Phase II Study of Bortezomib (Velcade®), Cylophosphamide (Cytoxan®), Thalidomide (Thalomid^®) and Dexamethasone as First-Line Therapy for Multiple Myeloma.

Background: A phase II trial evaluating the response rate with sequential administration of Bortezomib, cyclophosphamide, and dexamethasone (3 cycles) followed by Bortezomib, Thalidomide, and dexamethasone (3 cycles). The primary endpoints are overall response, achievement of ≥ very good partial response (VGPR), as well as assessment of safety and tolerability. This report provides results for 25 of 43 planned eligible pts.

Methods: Pts with newly diagnosed, untreated symptomatic myeloma were eligible. Treatment consisted of three 21-day cycles of Bortezomib 1.3mg/m² days 1, 4, 8, and 11, Cyclophosphamide 300mg/m² IV days 1 and 8 and dexamethasone 40mg po or IV days 1, 2, 4, 5, 8, 9, 11, 12; followed by three 21-day cycles of Bortezomib 1.0 mg/m² days 1, 4, 8, and 11; Thalidomide 100 mg po daily and dexamethasone as before. Pts received thrombosis prophylaxis with ASA cycles 4–6. Upon completion of the 6 courses, pts proceeded to stem cell harvest and/or maintenance therapy. Responses were assessed by International Response Criteria.

Results: As of August 2007, 25 pts have been enrolled: median age 60 years; 65% male; 75% Stage III (D/S); IgG 66%, IgA 16%; 17% light chain only. All pts fully evaluable for response thus far (13/13 [100%]) have achieved at least PR. Of these, 7/13 (54%) have achieved ≥VGPR (with nCR/CR in 31%). The median time to PR was 2 cycles or 42 days. Maximum response occurred by cycle 4 for 12/13 (92%)pts. Overall, both components of the sequential regimen were very well tolerated. One pt had a ruptured colonic diverticulum related to dexamethasone, but recovered well and achieved nCR on trial. There have been 24 therapy attributed toxicity events ≥Grade 2 of which 11 have required drug/schedule adjustments: 3 each for cyclophosphamide (neutropenia), dexamethasone (hyperglycemia, pneumonia, perforated viscus) and Thalidomide (neuro related) plus 2 for Bortezomib (neuropathy). No deep vein thromboses (DVT) have occurred in the study. 3 pts have already proceeded to successful stem cell harvest with transplant planned.

Conclusion: The addition of cyclophosphamide and Thalidomide to Bortezomib/dexamethasone combination has improved the depth of response with ≥VGPR (54%) and CR/nCR (31%) compared to our previous 2-drug experience which produced ≥VGPR (38%). This very well tolerated new regimen is potentially an important step forward with further results and confirmation available by December 2007.