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

Background: This phase II trial evaluated the response rate of sequential bortezomib (VELCADE^®), cyclophosphamide (Cytoxan^®), and dexamethasone ([VCD]; 3 cycles) followed by bortezomib, thalidomide (Thalomid^®), and dexamethasone ([VTD]; 3 cycles) as first-line therapy for patients with multiple myeloma. The primary endpoints were overall response, achievement of „d very good partial response (VGPR), as well as assessment of safety and tolerability.

Methods: Patients 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 p.o. or IV days 1, 2, 4, 5, 8, 9, 11, 12; followed by three 21-day cycles of bortezomib 1.0mg/m² days 1, 4, 8, and 11; thalidomide 100 mg p.o. daily and dexamethasone same as cycles 1–3. Patients received thrombosis prophylaxis with ASA 325mg daily during cycles 4–6. Upon completion of the 6 cycles, patients proceeded to autologous stem cell harvest, transplant and/or maintenance therapy. Responses were defined as a decrease in serum and/or urine monoclonal (M) protein by 50% or greater. VGPR and other responses were as per the International Response Criteria.

Results: This report provides results for all 44 eligible patients: median age 59 years; 68% male; 61% Stage III (D/S); documented ISS Stage II/III 59%; IgG 66%, IgA 17%; 17% light chain only. To date the first 30 patients are fully evaluable for response with 28-day post therapy follow up. The overall response rate (ORR; ≥PR) is 90% with 18/30 (60%) achieving CR + VGPR (CR 33%); 9/30 (30%) PR and 3/30 (10%) stable disease or not evaluable. Overall, both components of the sequential regimen were very well tolerated. One patient had a ruptured colonic diverticulum possibly related to dexamethasone, but recovered well and achieved VGPR on trial. There have been 49 therapy attributed toxicity events which have required drug/schedule adjustments. Of these, 9 events were Gd 3/4: 3 attributed to cyclophosphamide, 3 to dexamethasone, 2 attributed to bortezomib and 1 to thalidomide. DVT occurred in one patient who was at high risk because of prior bilateral hip surgery. Fourteen patients have proceeded to successful stem cell harvest and autologous transplant. Post transplant follow up as well as response information for all 44 patients will be presented.

Conclusion: This bortezomib/cyclophosphamide/dexamethasone (VCD) based combination induction therapy followed by VTD is a promising addition to the treatment armamentarium for previously untreated patients. The response rates: ORR 90%; □ VGPR (60%) and CR (33%) are extremely encouraging and improve over our bortezomib/dexamethasone 2-drug experience which produced 90% □ PR and 38% □ VGPR. This very well tolerated new regimen is potentially an important step forward in induction therapy with presentation of more mature data.

Supported by the Aptium Oncology Research Network and a research grant from Millennium Pharmaceuticals, Inc.