A PHASE 1 STUDY OF BORTEZOMIB (VELCADE) IN COMBINATION WITH LENALIDOMIDE (REVLIMID) IN RELAPSED AN

abstract nr.: 0245

A PHASE 1 STUDY OF BORTEZOMIB (VELCADE) IN COMBINATION WITH LENALIDOMIDE (REVLIMID) IN RELAPSED AND REFRACTORY MULTIPLE MYELOMA

Author:

P.G. Richardson, Dana-Farber Cancer Institute, Boston, United States of America

Co-author(s):

R. Schlossman, Dana-Farber Cancer Institute, Boston, United States of America

N. Munshi, Dana-Farber Cancer Institute, Boston, United States of America

D. Avigan, Dana-Farber Cancer Institute, Boston, United States of America

S. Jagannath, St. VincentÕs Cancer Center, New York, United States of America

M. Alsina, Moffitt Cancer Center, Tampa, United States of America

D. Doss, Dana-Farber Cancer Institute, Boston, United States of America

M. McKenney, Dana-Farber Cancer Institute, Boston, United States of America

K. Hande, Dana-Farber Cancer Institute, Boston, United States of America

D. Warren, Dana-Farber Cancer Institute, Boston, United States of America

C. Mitsiades, Dana-Farber Cancer Institute, Boston, United States of America

T. Hideshima, Dana-Farber Cancer Institute, Boston, United States of America

T. Myers, Millennium Pharmaceuticals, Cambridge, United States of America

R. Knight, Celgene Inc., Warren, United States of America

K.C. Anderson, Dana-Farber Cancer Institute, Boston, United States of America

Topic:

19A. Myeloma and other monoclonal gammopathies

Keywords Only one keyword per text field only:

Bortezomib, Lenalidomide, Multiple Myeloma

Background: Bortezomib and lenalidomide have demonstrated activity in relapsed and refractory multiple myeloma (MM). Both agents inhibit proliferation and angiogenesis and promote apoptosis of MM cells (Anderson. Cancer. 2003;97:796). These agents exhibit immunomodulatory effects and prevent secretion of cytokines by reducing interactions of MM cells with the bone marrow microenvironment. In phase 2 trials, bortezomib has induced durable responses with manageable toxicity in heavily pretreated patients with MM. Lenalidomide has also produced durable responses in relapsed and refractory patients with MM, including those who received prior bortezomib. Lenalidomide and bortezomib do not appear to have overlapping toxicities and appear to have synergistic apoptotic effects in vitro. These findings suggest that this regimen may result in improved activity in MM. In phase 1 trials, the maximum tolerated doses (MTD) of bortezomib and lenalidomide were 1.3 mg/m2 (twice weekly) and 25 mg/day, respectively.

Aim: A phase 1 dose-escalation trial was initiated to determine the MTD and activity of bortezomib with lenalidomide in patients with relapsed and/or refractory MM.

Methods: Eligible patients were enrolled in 3-patient cohorts to receive bortezomib 1.0 or 1.3 mg/m2 in combination with lenalidomide 5, 10, 15, or 20 mg/day, for a total of 8 cohorts. Bortezomib was administered on days 1, 4, 8, and 11, and lenalidomide on days 1Ð14 of a 21-day cycle. Toxicity was assessed using NCI CTC criteria version 3.0. Dose-limiting toxicities (DLT) included grade ³ 3 nonhematologic toxicity, grade 4 hematologic toxicity (grade 4 neutropenia lasting ³ 5 days and/or neutropenic fever were DLT) other than thrombocytopenia, and platelet count ² 10,000 on > 1 occasion despite transfusion. Evaluation of response was assessed using BladŽ criteria at the end of cycle 2 and subsequent cycles.

Results: Twelve patients with MM have been enrolled into cohorts 1Ð4. MTD was not reached in the first 3 cohorts. Nine have been treated, including 3 with relapsed and 6 with relapsed and refractory disease. The median number of prior therapies was 3 (range, 1Ð9). Five patients had undergone prior SCT; 7 had received thalidomide; 4 had received bortezomib. With a median of 6 cycles completed, patients have tolerated bortezomib 1.0Ð1.3 mg/m2 and lenalidomide 5Ð10 mg/day without DLT. Grade 4 neutropenia occurred in 2 patients for < 5 days, and grade 3 thrombocytopenia was observed in 4 patients. No other significant toxicities have been reported. Nine patients are evaluable for response. In cohort 1 (bortezomib 1.0 mg/m2, lenalidomide 5 mg/d), 3 of 3 patients achieved MR. In cohort 2 (bortezomib 1.3 mg/m2, lenalidomide 5 mg/d), 2 of 3 achieved PR, and one had MR. In cohort 3 (bortezomib 1.0 mg/m2, lenalidomide 10 mg/d), 2 of 3 had MR, and one had SD.

Conclusions: Bortezomib and lenalidomide can be combined at active doses, and promising activity has been seen. Further investigation is ongoing to determine the MTD. Enrollment of an additional cohort of 10 patients at the MTD is planned for further evaluation of this regimen in relapsed and/or refractory MM.

revimid