The purpose of this study was to assess the safety and identify the recommended doses of
enzastaurin and
bortezomib in combination for future Phase II studies in patients with relapsed or refractory
multiple myeloma. Three dose levels (DLs) of oral
enzastaurin and intravenous
bortezomib were used according to a conventional "3 + 3" design. A loading dose of
enzastaurin (250 mg twice/day [BID]) on Day 1 was followed by
enzastaurin 125 mg BID for 1 week, after which
bortezomib was added (Cycle 1, 28 days, 1.0 mg/m(2) : Days 8, 11, 15, and 18; seven subsequent 21-day cycles, 1.3 mg/m(2) : Days 1, 4, 8, and 11). Twenty-three patients received treatment; all patients received prior systemic
therapy. Most patients received ≥3 regimens; 17 patients were
bortezomib-refractory. A median of four treatment cycles (range 1-24) was completed. No dose-limiting toxicities were observed; thus, DL 3 was the recommended Phase II dose. The most common drug-related Grade 3/4 toxicities were
thrombocytopenia (n = 6) and
anemia (n = 2). No patients died on
therapy. One patient (DL 1) achieved a very good partial response; three patients (DLs 2 and 3), a partial response; nine patients, stable disease; and four patients, progressive disease. The recommended Phase II doses in patients with relapsed or refractory
multiple myeloma are as follows:
enzastaurin loading dose of 375 mg three times/day on Day 1 followed by 250 mg BID, with
bortezomib 1.3 mg/m(2) on Days 1, 4, 8, and 11 of a 21-day cycle. The combination was well-tolerated and demonstrated some antimyeloma activity.