Dramatic Results Seen in Phase III Front-Line Multiple Myeloma Trials of Bortezomib-Based Therapy

January 1, 2008

Millennium Pharmaceuticals, Inc, recently announced the presentation of results from three phase III investigations of bortezomib used in various combinations, for initial treatment of patients with multiple myeloma.

Millennium Pharmaceuticals, Inc, recently announced the presentation of results from three phase III investigations of bortezomib used in various combinations, for initial treatment of patients with multiple myeloma. Data from these trials were selected for oral presentations at the American Society of Hematology (ASH) 49th Annual Meeting in Atlanta, December 8–11, 2007.

VISTA Trial: Highest Reported Complete Remission Rate Achieved in Multiple Myeloma

The 682-patient, randomized, phase III VISTA trial (Velcade as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone). The trial compared VcMP (bortezomib [Velcade], melphalan [Alkeran], and prednisone) to MP (melphalan and prednisone) alone, a recognized standard of care in this treatment setting. Patients in the study had previously untreated multiple myeloma and were ineligible for stem cell transplantation.

"The goal of therapy is long-term survival, and complete remission is a well-known indicator for survival," said Professor Jesus San-Miguel, MD, Hematology Department Head, University Hospital of Salamanca and principal investigator of the trial. "Data from this rigorously controlled trial clearly show that Velcade-based therapy should be a standard of care for previously untreated patients who are not able to receive stem cell transplantation."

Data from the large international clinical trial were presented by Professor San-Miguel. Responses were evaluated by the commonly used M-protein levels measured in serum or urine by a centralized laboratory as well as the most stringent European Group for Blood and Marrow Transplantation (EBMT) criteria. Among the findings:

• Immunofixation-negative complete remission (CR) rate of 35% in the VcMP arm compared to 5% with MP (P < .000001); EBMT criteria showed a CR rate of 30% in the VcMP arm compared to 4% with MP.

• The median duration of response was 24 months for patients with CR in VcMP compared to 13 months with MP.

• Time-to-disease progression (TTP) in the VcMP arm of 24 months compared to 17 months with MP (P = .0000001)

• VcMP demonstrated statistical significance in overall survival, with a 40% reduction in risk of death (P = .0078); median survival was not reached despite a short follow-up of 16 months.

• The median treatment duration was 46 weeks, and a low rate of discontinuation due to adverse events was similar in both arms.

GIMEMA Trial: Fourfold Increase in CR Rates for Bortezomib Plus Commonly Used Regimen

An interim analysis of the first 256 patients evaluated in a multicenter, randomized phase III clinical trial compared VcTD (bortezomib, thalidomide [Thalomid], and dexamethasone) to TD (thalidomide and dexamethasone) alone, currently the most commonly used US regimen for patients with previously untreated multiple myeloma. The trial was conducted by the Italian Myeloma Network (GIMEMA) cooperative group.

"This Velcade-based induction regimen achieved a fourfold increase in the complete remission rate. Complete remission is widely recognized as a predictor for long-term survival," said Professor Michele Cavo, MD, Seragnoli Institute of Hematology, University of Bologna and principal investigator of the trial. "These exciting results demonstrated that adding Velcade to the standard induction therapy prior to stem cell transplantation improves the response rate dramatically."

Results from the large clinical trial were presented by Professor Cavo, and included the following:

• As induction therapy prior to stem cell transplantation, the VcTD arm demonstrated a CR (including immunofixation positive and negative) rate of 36% compared to 9% in the TD arm (P < .001).

• Following transplantation, the VcTD arm demonstrated a CR (including immunofixation positive and negative) rate of 57% compared to 28% in the TD arm (P < .001).

• Successful stem cell mobilization occurred in more than 90% of patients in both arms.

IFM Trial: Significant CR Rates Achieved Both Pre- and Posttransplantation

A 482-patient, multicenter, randomized phase III clinical trial, comparing VcD (bortezomib and dexamethasone) to VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone), was conducted by the Intergroupe Francophone du Myelome (IFM) cooperative group and CHU Nantes.

"The very high complete and near complete remission rate of 21% with this induction therapy significantly improved posttransplantation complete remission rates. This led to a decrease in patients requiring a second transplant," said Professor Jean-Luc Harousseau, MD, Hospital Hotel-Dieu Nantes and principal investigator of the trial. "Historically, regimens used as induction therapy prior to stem cell transplantation produced low complete remission rates and offered minimal incremental benefit posttransplantation."

Results from the large clinical trial presented by Professor Harousseau included the following:

• As induction therapy prior to stem cell transplant, the VcD arm demonstrated a CR (including immunofixation positive and negative) rate of 21% compared to 8% with VAD (P < .0001).

• Of the 404 patients who proceeded to stem cell transplant, the VcD arm demonstrated a posttransplantation CR (including immunofixation positive and negative) rate of 41% compared to 29% with VAD (P = .0089).

"Results from this trial build on the growing body of data showing that Velcade-based regimens deliver high CR rates that translate to increased posttransplantation benefits," said Nancy Simonian, MD, Chief Medical Officer, Millennium. "Since we know high CR rates lead to longer-term survival, we believe these data position Velcade-based therapy as a new standard of care for front-line patients."