PHILADELPHIATwo phase II clinical trials presented at the 44th Annual
Meeting of the American Society of Hematology (ASH) have established the
activity of the investigational proteasome inhibitor bortezomib (Velcade,
also known as PS-341, Millennium Pharmaceuticals) in relapsed or refractory
Both trials used similar bortezomib regimens, with dexamethasone added
after several cycles to produce additional responses. The SUMMIT trial
(abstract 385) reported an overall major response rate of 27% in 202
patients. The smaller CREST trial (abstract 3207), which evaluated two
different doses, demonstrated similar response rates, which were dose
Bortezomib is a first-in-class protea-some inhibitor that blocks NF-kB-mediated
transcription of cytokines, adhesion molecules, angiogenesis factors,
antiapoptotic factors, and other sub-stances that contribute to tumor growth
(see drawing). Preclinical work suggests that bortezomib targets the myeloma
cell and its environment, making it a promising agent for clinical trials,
said Paul Richardson, MD, of the Dana-Farber Cancer Institute, who presented
the SUMMIT results.
In this study, treatment consisted of bortezomib 1.3 mg/m2 on
days 1, 4, 8, and 11 of a 21-day cycle for up to eight cycles, with optional
addition of dexa-methasone after the second cycle in the absence of benefit.
Patients were an average of 4½ years postdiagnosis and had received a
median of six prior lines of therapy. Response was classified using the
stringent Bladé criteria and required confirmation on two occasions 6 weeks
Of 193 evaluable patients, complete remission (CR) was observed in 7
patients (4%). A further 12 patients (6%) achieved "near-CR" by meeting all
Bladé criteria except absence of M protein on immunofixation, for an overall
CR or near-CR rate of 10%. The overall response rate (complete, partial, and
minor responses) was 35%, and 27% of patients had a major response,
consisting of complete or partial remission. "In terms of the activity of
bortezomib used alone, 70% of patients achieved stable disease or better,"
Dr. Richardson said.