Phase III study results show that addition of the proteosome inhibitor bortezomib (Velcade) to standard chemotherapy significantly improves outcomes in patients with newly diagnosed multiple myeloma who are not eligible for high-dose chemotherapy and stem-cell transplantation (SCT).
ATLANTA-Phase III study results show that addition of the proteosome inhibitor bortezomib (Velcade) to standard chemotherapy significantly improves outcomes in patients with newly diagnosed multiple myeloma who are not eligible for high-dose chemotherapy and stem-cell transplantation (SCT).
Jess San Miguel, MD, of the Hematology Service, Hospital Universitario de Salamanca, Spain, presented results at ASH 2007 (abstract 73) showing complete response rates previously seen only in younger patients after intensive chemotherapy and SCT.
In the first-line setting, standard therapy for multiple myeloma patients who are not candidates for stem-cell transplantation has consisted of melphalan plus prednisone (MP). Recent results indicate that the addition of a third agent, such as thalidomide (Thalomid), further improves outcomes in this patient population (Palumbo A et al: Lancet 367:825-831, 2006; Facon T et al: Lancet 370:1209-1218, 2007).
Bortezomib has also been found to be effective as first-line therapy. In a recent phase I-II trial in elderly myeloma patients, the combination of bortezomib and MP resulted in a complete or near-complete response rate (CR/nCR) of 43%, including 32% CRs (Mateos MV et al: Blood 108:2165-2172, 2006).
The present study, known as VISTA (Velcade as initial standard therapy in multiple myeloma: Assessment with melphalan and prednisone), was designed to confirm and extend these results.
VISTA was a multicenter, international phase III trial of bortezomib plus MP (VMP) vs MP alone in patients with newly diagnosed, symptomatic myeloma who were not eligible for high-dose chemotherapy with SCT.
In this trial, 682 patients from 151 centers across 22 countries were randomized to VMP or MP. Patients were stratified based on baseline beta-2-microglobulin and albumin levels and geographic region.
The VMP regimen consisted of intravenous bortezomib 1.3 mg/m2 twice weekly (on weeks 1, 2, 4, 5) for four
6-week cycles (8 doses per cycle), then once weekly (on weeks 1, 2, 4, 5) for five 6-week cycles (4 doses per cycle), in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1 to 4 of each cycle, Dr. San Miguel explained.
In the MP arm, patients received nine 6-week cycles of MP once daily on days 1 to 4. Treatment in both arms was continued for up to nine cycles or the occurrence of disease progression or unacceptable treatment-related toxicity.
The study population included a high proportion of patients with advanced disease and high-risk factors, Dr. San Miguel said.
Median age was 71 years, and 30% of patients were at least 75 years old. Half were male and 88% were Caucasian. The median Karnofsky performance status was 80%, with one-third of patients having a status of 70% or less.
Of the 682 study patients, 63% had IgG myeloma, 25% had IgA myeloma, and 8% had light-chain disease.
Bone involvement with more than 10 lytic bone lesions occurred in 27% of patients, while 33% had beta-2-microglobulin more than 5.5 mg/L and 60% had albumin less than 35 g/L.
Median OS not reached
According to Dr. San Miguel, compared with MP alone, the addition of bortezomib to MP resulted in significant increases in CR (35% vs 5%), median duration of response (24 months vs 13 months), and time to progression, with a 40% decrease in risk of death.
Time to progression (the primary study endpoint) was 24 months on the VMP arm vs 17 months on the MP arm (P < .0000001). With a 16-month follow-up, median overall survival has not yet been reached.
The sevenfold increase in CR rate and the survival benefit observed with the VMP combination confirm the high clinical activity of this regimen in newly diagnosed multiple myeloma patients and the superiority of this triplet, compared with standard MP, he said.
In particular, Dr. San Miguel said, VMP may be a good therapeutic option for patients with poor prognostic factors, including high-risk cytogenetics, age at least 75 years, and impairment of renal function.
Paul Richardson, MD, of the Dana-Farber Cancer Institute, who was the senior investigator on the VISTA trial, noted that the study is the largest of its kind in this patient population, with global participation.
“The VMP combination constitutes yet another milestone in treatment, with bortezomib-based therapy providing a quality, depth, and duration of response that is unprecedented in this population,” Dr. Richardson said. “For older multiple myeloma patients, this represents a major therapeutic advance that is widely available and, as the number of study sites involved reflects, can now be utilized for patients across the world.”
FDA has granted priority review status for Millennium Pharmaceuticals’ supplemental New Drug Application for Velcade in patients with newly diagnosed multiple myeloma, based on data from the VISTA trial.
“Priority review designation puts us on track for a potential label expansion decision by June 20, 2008,” said Nancy Simonian, MD, chief medical officer at Millennium.