Bortezomib Active in Relapsed/Refractory Myeloma

PHILADELPHIA—Two 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 multiple myeloma.

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 related.

SUMMIT Results

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 apart.

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.

Dexamethasone was added in 78 nonresponders to bortezomib, usually relatively late in the treatment course. Of these patients, 17% had an improved response to combination therapy.

Median survival of the entire cohort was 16 months, median time to progression was 7 months, and in patients with a major response, the median response duration was 12 months.

"These outcomes indicate an important potential advance in the treatment of multiple myeloma and may offer new hope for increased survival in this patient population," Dr. Richardson said.

CREST Results

Sundar Jagganath, MD, of Saint Vincent’s Comprehensive Cancer Center, New York, presented results of the CREST study at an ASH poster session.

Two bortezomib doses were evaluated: 1.0 and 1.3 mg/m2, on the same schedule as the SUMMIT study and also with optional addition of dexamethasone. The 54 participants were a median of 2 years postdiagnosis and had relapsed disease after a median of three prior therapies, representing a less heavily pretreated cohort than the SUMMIT participants.

Overall response rates (complete, partial, and minor responses) to bortezomib alone were 33% for the lower dose and 50% for the higher dose. One patient in each dosage group had a complete remission with bortezomib alone. The addition of dexamethasone improved the overall response rate to 44% for the 1.0-mg dose and 62% for the 1.3-mg dose. Patients had a median time to progression of 11 months, and median survival of the cohort has not been reached after nearly 9 months of follow-up.

Toxicity

Similar toxicity was reported in the two trials. Gastrointestinal side effects and fatigue, usually of mild to moderate severity, affected half to three fourths of patients. Treatment-emergent peripheral neuropathy was seen in 34% of patients in the SUMMIT study. However, 80% of patients entered the trial with peripheral neuropathy at baseline, Dr. Richardson said. No patient had grade 4 peripheral neuropathy, but 12% of patients required a dose reduction and 4% withdrew from treatment because of this complication. In the CREST study, peripheral neuropathy developed in about 20% of patients receiving the lower dose and 60% on the higher dose.

High-grade neutropenia or throm-bocytopenia occurred in less than 5% of patients in the SUMMIT study but in a somewhat larger proportion in the CREST trial. "In such a sick, heavily pretreated population, side effects are an important consideration," Dr. Richard-son said. "However, we found that the toxicities were generally manageable."

Quality of Life

Quality of life was assessed in the SUMMIT study using the EORTC Quality of Life questionnaire. Patients with a response to treatment demonstrated significant improvement from baseline in global and physical quality of life, as well as improvement in myeloma symptoms, myeloma-related pain, and fatigue.

Responders to bortezomib also had increased hemoglobin levels, reduced transfusion requirements, and improvements in performance status and renal function, Dr. Richardson said. The study also identified candidate pharmacogeno-mic markers associated with response and nonresponse, which will be further evaluated in future phase II-III clinical trials.

Future directions include the multinational APEX trial, which is now accruing patients and will evaluate bortezomib vs high-dose dexamethasone, and preliminary studies of bortezomib combined with other agents.