A Phase 1/2 Multi-Center, Randomized, Open Label Dose Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Efficacy of Pomalidomide Alone or In Combination with Low-Dose Dexamethasone In Patients with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide and Bortezomib

Pomalidomide (POM) is a distinct immunomodulatory drug (IMiD^®) with potent antiproliferative activities in vitro. It has demonstrated clinically significant responses in heavily-pretreated patients (pts) with relapsed and refractory (R/R) multiple myeloma (MM). Phase (Ph) 1b data on POM alone from a single-center, ascending dose, open-label study in heavily pretreated pts with R/R MM (Schey 2004) identified a maximum tolerated dose (MTD) of 2mg orally once daily (QD), and encouraging response rates were observed. Based on these data, a Ph 1/2, multicenter, randomized, open-label, 3×3 dose-escalation study evaluating MTD, safety and efficacy of POM alone and POM plus 40mg dexamethasone weekly (POM+dex) in pts with R/R MM after at least 2 prior regimens including bortezomib and lenalidomide (Len) was performed. Results from Ph 1 of this study are reported with enrolment to the Ph 2 ongoing.

The Ph 1 portion of the study to determine MTD (n=38) was followed by a Ph 2 open-label segment that randomized pts to receive POM+dex vs POM alone (192 planned). Eligible pts had documented R/R MM. All pts received low-dose prophylactic aspirin QD and were monitored for venous thromboembolic events (VTE). In Ph 1, POM was given QD on Days 1–21 of each 28-day cycle. Four dose levels of POM (2, 3, 4, 5mg) were studied with option to add dex 40mg/wk after 4 cycles for lack of response or disease progression (PD). Pts previously enrolled in Ph 1 and discontinued either for intolerance or PD could not be enrolled in Ph 2. Toxicities and responses were assessed using CTCAE v3 and modified EBMT criteria, respectively.

As of May 31, 2010, 38 pts have been enrolled in Ph 1. Thirty-two pts have discontinued therapy and 6 pts are ongoing for both safety and efficacy analyses. Median age is 67 yrs with a median number of prior MM regimens of 6 (range 2–17). MTD has been determined to be 4mg/day and validated by Data Monitoring Committee. Neutropenia and anemia were the most common grade 3/4 toxicities. Eighteen (47%) pts had at least one serious adverse event (SAE); POM-related SAEs included infection, retropharyngeal abscess, neutropenia, thrombocytopenia, diarrhea, musculoskeletal chest pain, brain edema, deep vein thrombosis. Dex-related SAEs included infectious arthritis, infection, retropharyngeal abscess, sepsis, lung infection, and musculoskeletal chest pain. During the study, there were 3 deaths all considered related to MM complications (1 due to rapid PD, 1 to pneumonia and 1 GI perforation due to amyloidosis). Thirty-two pts treated with single-agent POM were evaluable for response. Confirmed response (≥PR) was seen in 22% of evaluable pts (1 CR, 6 PR) with an additional 5 pts achieving MR. In addition, 14 (44%) pts had stable disease (SD). Estimated median duration of response was 28.1 wks, and estimated median progression-free survival was 16.1 wks. Of 24 evaluable pts who were refractory to both Len and bortezomib, a response was seen in 25% (1 CR, 5 PR). Importantly, 28% (9/32) of pts were also refractory to carfilzomib. Dex was added to the regimens of 20 pts due to PD or lack of response with POM alone (median POM treatment duration before dex: 11.8 wks); 19/20 pts (15 after progression, 4 after lack of response) were evaluable for response. During treatment with POM+dex, confirmed response (2 PR) was observed in 11% with an additional 7 pts achieving MR. In addition, 37% (7/19) pts achieved SD. Of the 38 pts who received any POM dose during the Ph 1 of the study, 26 (68%) were still alive as of July 27, 2010. Kaplan-Meier estimate of median overall survival for the 38 pts in Ph 1 was 17 months. Enrollment to the Ph 2 portion of the study has since followed and is now fully accrued (n=215).

Preliminary results indicate that single-agent POM achieves clinically significant durable responses with a manageable safety profile in heavily pretreated pts with R/R MM. The addition of dex to POM can re-induce response in selected patients. The MTD in this study was 4mg/day. Overall, these data suggest that POM could provide a clinically active therapeutic option, and warrants further investigation in this pt population. Response and safety data from the Ph 2 study will be presented at the meeting.

Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide and Bortezomib for treatment of Multiple Myeloma. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board. Baz:Celgene: Consultancy, Research Funding; Millennium: Research Funding. Kelley:MMRF/MMRC: Employment. Munshi:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees. Sullivan:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Alsina:Celgene: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy; Ortho Biotech: Research Funding. Doss:Celgene: Speakers Bureau. Larkins:Celgene: Employment, Equity Ownership. Lizza:Celgene: Employment. Yu:Celgene: Employment. Zaki:Celgene: Employment. Jacques:Celgene: Employment. Anderson:Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.