Phase II Trial of Weekly Bortezomib in Combination with CCI-779 (temsirolimus) in Relapsed or Relapsed/Refractory Multiple Myeloma.

This study aimed to determine activity and safety of weekly bortezomib (Millennium Pharmaceuticals, Inc, MA) and CCI-779 (temsirolimus, Wyeth Pharmaceutical, PA) in patients with relapsed/refractory Multiple Myeloma (MM). Our prior phase I study determined the MTD at 1.6 mg/m2 bortezomib Days 1, 8, 15, and 22 every 35 days in combination with 25 mg IV CCI-779 Days 1, 8, 15, 22, and 29 every 35 days.

Eligibility criteria include: 1) patients with relapsed or relapsed/refractory MM with any prior lines of therapy including bortezomib, 2) measurable disease, 3) no chemotherapy within 3 weeks, or biological/novel therapy for MM within 2 weeks of study start. Primary endpoint was the percent of patients with at least a minor response (MR) with secondary endpoints including toxicity, OS and PFS.

Twenty-seven patients have been treated to date, with 19 being evaluable for response. At least minor response (MR) was observed in 15/19 (79%) patients, including 1 (5%) complete remission (CR), 3 (16%) very good partial remission (VGPR), 5 (26%) partial remission (PR), and 5 (26%) MR. Two patients (10%) had stable disease, and 2 (10%) showed progressive disease. Dose reductions occurred in 7 patients due to diarrhea, neutropenia, and pulmonary toxicity. Death (Grade 5) occurred in one patient due to ventricular fibrillation that was considered unrelated to therapy. Grade 4 toxicities occurred in 4/27 (15%) patients and included thrombocytopenia, lymphopenia, anemia and neutropenia. The most common grade 3 related adverse events among the 27 patients included thrombocytopenia in 12 (44%), neutropenia in 7 (26%), lymphopenia in 8 (30%), anemia in 5 (18%), GI toxicity including diarrhea and nausea and anorexia in 3 (11%), sepsis in 2 (7%), pneumonia and other infections in 2 (7%), hyperglycemia in 2 (7%), pulmonary hemorrhage and GI bleed in 1 each (3%).

The combination of weekly bortezomib and CCI-779 showed an exciting response rate in patients with relapsed or refractory multiple myeloma, with at least MR or better seen in 79% of patients to date. Cytopenias were the most common toxicities, specifically thrombocytopenia, as well as GI toxicity, but overall side effects proved manageable.

Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Laubach:Novartis:. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson:Keryx Biopharmaceuticals: Honoraria.