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Dr. Richardson - Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) as Front-Line Therapy for Patients with Multiple Myeloma (MM): Preliminary Resultsof a Phase 1/2 Study.
Paul Richardson, MD
Jerome Lipper Myeloma Center
Dana Farber Cancer Institute
Boston, MA
Member, IMF Board of Scientific Advisors

"Of 42 patients that are currently evaluable for response, we are very pleased to report that PR or better has been seen in 98% of the patients. That is probably one of the highest response rates we have seen in the upfront setting to date."
Dr. Paul Richardson

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Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) as Front-Line Therapy for Patients with Multiple Myeloma (MM): Preliminary Results of a Phase 1/2 Study. Session Type: Oral Session
Paul Richardson, Sundar Jagannath, Noopur Raje, Andrzej Jakubowiak, Sagar Lonial, David Avigan, Irene Ghobrial, Robert Schlossman, Amitabha Mazumder, Nikhil Munshi, Robin Joyce, Deborah Doss, Diane Warren, Stephen Hayes, Lawrence Giove, S. Kaster, Carol Delaney, Marisa Lauria, Constantine Mitsiades, Teru Hideshima, Robert Knight, Dixie-Lee Esseltine, Kenneth Anderson Dana-Farber Cancer Institute, Boston, MA, USA; St. Vincents Comprehensive Cancer Center, New York, NY, USA; Massachusetts General Hospital, Boston, MA, USA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA; Winship Cancer Institute, Atlanta, GA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; Celgene, Inc., Summit, NJ, USA; Millennium Pharmaceuticals, Inc., Boston, MA, USA

Background: Bortezomib (VELCADE, Vel) as a single agent and lenalidomide (Revlimid, Rev) plus dexamethasone (Dex) are approved for the treatment of relapsed MM patients (pts) following 1 prior therapy. Rev/VelDex is active and well tolerated in relapsed/refractory MM, and Rev/Dex and Vel/Dex have substantial activity in front-line MM. The aims of this phase 1/2 study were to determine the MTD of Rev/Vel/Dex in newly diagnosed MM pts, and to assess safety and efficacy. Methods: Pts received Rev 1525 mg on d 114, Vel 1.01.3 mg/m2 on d 1, 4, 8, 11, and Dex 40/20 mg (cycles 14/58) on d 1, 2, 4, 5, 8, 9, 11, 12, for up to 8 21-d cycles, initially at 4 planned dose levels (Rev/Vel: 15/1.0, 15/1.3, 20/1.3, 25/1.3). Dose escalation proceeded (3-pt cohorts) depending on DLTs (G3 non-hematologic toxicity; G4 thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; G4 neutropenia for >5 d and/or resulting in neutropenic fever; inability to receive cycle 2/d 1 dose due to drug-related toxicity). Based on safety data, dose level 4M was added with a reduced Dex starting dose (Rev/Vel 25/1.3, Dex 20 mg in all cycles). Toxicities were graded by NCI CTCAE v3.0. Pts with G>2 peripheral neuropathy (PNY) were excluded. Responses were assessed by modified EBMT and Uniform criteria. Pts with CR/nCR/VGPR/PR could proceed to ASCT after 4 cycles. Results: 33 pts (median age 56 yrs, 55% men, 84% IgG MM, 47% with ISS Stage II/III) have been enrolled to date in dose levels 14 and 4M, respectively, including 10 pts enrolled at the maximum planned dose (Dose Level 4M). Pts have received a median of 5 cycles; 9 pts have completed all 8 cycles. Two DLTs of G3 hyperglycemia due to high dose Dex were seen in dose level 4. Dose reductions in cycle 2 and beyond have occurred in dose levels 14 for Rev in 9 pts, Vel in 7 pts, and Dex in 17 pts, with 3 dose reductions having occurred in dose level 4M. Toxicities to date have been manageable. Only 1 G4 toxicity (thrombocytopenia) has been reported, plus 1 G3 DVT (reversed with LMWH), and no G3 PNY has been seen. The response rate across all dose cohorts (CR/nCR+VGPR+PR: subject to confirmation) is currently 89% in 25/28 evaluable pts, including 35% CR/nCR/VGPR. After median follow-up of 3 mos, median DOR, TTP, PFS, and OS have not been reached; all responders except 1 remain in remission, with 2 pts proceeding to ASCT. Conclusions: Rev/Vel/Dex is very active and well tolerated in newly diagnosed MM pts. The maximum planned dose has been reached at Rev 25 mg, Vel 1.3 mg/m2, and Dex 20 mg, with Phase 1 enrollment now complete using the lower dose of Dex. Enrollment to the Phase 2 component is ongoing.
Abstract #187 appears in Blood, Volume 110, issue 11, November 16, 2007

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