Perifosine Plus Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients Previously Treated with Bortezomib: Final Results of a Phase I/II Trial

Perifosine, an orally-bioavailable, novel signal transduction modulator has multiple pathway effects including inhibition of Akt, NFkB and activation of JNK. We conducted a phase I/II study of perifosine + bortezomib (Vel) +/− dexamethasone (Dex) which demonstrated encouraging safety and preliminary clinical activity in relapsed and refractory multiple myeloma (MM) patients (pts) (ASH 2009 # 1869). We report final results, including overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) for the treatment of MM pts previously relapsed from and/or refractory to Vel.

The phase I stage of the study enrolled a total of 18 pts with a selected phase II dose of perifosine 50 mg qd + Vel 1.3 mg/m² (d 1, 4, 8, 11) in 21-d cycles, which enrolled 66 pts. Dex 20mg (on day of and after each Vel dose) could be added in pts with progressive disease (PD). NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by modified EBMT and Uniform Criteria.

A total of 84 pts were enrolled comprised of 51 men and 33 women, median age 63 y (range 35–89): 88% of pts had relapsed and refractory MM (73% Vel refractory), with a median of 5 lines of prior treatment (range 1–13). Prior therapy included Vel (100%), dex (98%), lenalidomide (76%), thalidomide (75%) and SCT (58%), with pts receiving a median of 2 prior Vel-based treatments. Median interval between diagnosis and inclusion was 4.5 years. Seventy three pts were evaluable for response (having completed at least two or more cycles of therapy), and all 84 were assessed for safety. Most common grade 1/2 events included nausea, diarrhea, fatigue and musculoskeletal pain, which were manageable with supportive care and dose reductions. Grade 3/4 adverse events included thrombocytopenia, neutropenia, anemia, pneumonia and musculoskeletal pain. Two pts had grade 3 peripheral neuropathy (PN), which was reversible with Vel dose reduction and/or treatment discontinuation. No grade 4 PN was observed. Overall 26 (31%) pts had treatment-related PN of any grade. Two pts had perifosine reduced to 50 mg (for GI related toxicity) in the phase 1 portion of the study, and 8 pts reduced to qod dosing in the phase II: 23 pts had Vel dose reductions primarily due to hematologic toxicity. No treatment-related mortality was seen. Eleven pts were inevaluable for response due to unrelated toxicity (n=5), rapid disease progression (< 1 cycle received; n=3), or withdrawal of consent (n=3). For 73 response-evaluable pts, the ORR was 41%, including 4% CR, 18% PR and 19% MR. Prior best response (≥ PR) to last Vel-based regimen was 43% (36/84 pts), of which most were triple drug combinations (eg RVD). Of 53 pts who were refractory to prior Vel, ORR to perifosine, Vel +/− Dex was 32%, including 2% CR, 11% PR and 19% MR. ORR for 20 Vel-relapsed pts was 65%; 10% achieved a CR and 35% a PR. Median PFS was 6.4 mos with a range of 5 wks to over 3 yrs (95% CI: 5.3, 7.1), and 8.0 mos (95% CI: 6.4, 9.8) for the 30 evaluable pts who achieved ≥ MR. Median PFS for the 53 Vel-refractory pts was 5.7 mos (95% CI: 4.3, 6.4), with 40% of pts achieving PFS of > 6 mos. For the 20 Vel-relapsed pts, median PFS was 8.8 mos (95% CI: 6.3, 11.2), with 70% of pts achieving PFS of > 6 mos. Importantly, median PFS for all pts receiving prior Vel-based regimens prior to study entry was 5.3 mos.

As of August 2011, median OS for all evaluable study pts was 25 mos (95% CI: 16.3, 31.1), 22.5 mos (95% CI: 14.2, 31.1) for the Vel-refractory pts and 30.4 mos (95% CI: 17.8, NR) for Vel-relapsed pts. Median OS for those pts who achieved PR + CR was 37 mos (95% CI: 13.8, NR) and for those pts who achieved SD + MR was 29 months (95% CI: 18, 32.4).

Perifosine in combination with Vel (+/− dex) demonstrated impressive and durable activity in both heavily pre-treated, Vel-refractory pts (with an ORR of 32% and median OS of 22.5 mos), and in Vel-relapsed pts (with an ORR of 65%, median PFS of 8.8 mos and OS of 30.4 mos), with manageable toxicity. Survival data were encouraging, even in pts exposed to and refractory to Vel, as well as prior IMiDs, so providing another example of a rational combination strategy integrating novel therapies to further improve patient outcome. An international phase III randomized trial evaluating perifosine vs. placebo when combined with Vel and Dex in Vel-exposed pts with relapsed and refractory MM has been granted special protocol assessment (SPA) status and is currently underway to confirm the efficacy of this approach.

Richardson:Celgene: 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; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Keryx Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Wolf:Millennium: Honoraria, Speakers Bureau. Jakubowiak:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria; Exelixis: Consultancy, Honoraria. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Medtronic: Consultancy; Celgene: Speakers Bureau. Lonial:Millennium: Consultancy; Novartis: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Krishnan:Millennium: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Raje:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Acetylon: Research Funding. Ghobrial:Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. 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. Allerton:Keryx Biopharmaceuticals: Consultancy. Hideshima:Acetylon: Consultancy. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees.