A Phase I/II Trial Of Pomalidomide, Bortezomib and Dexamethasone In Patients With Relpased Or Refractory Multiple Myeloma

Pomalidomide is a recently approved IMiD® immunomodulatory agent that has been validated and approved in relapsed and refractory multiple myeloma. The combination of IMiDs and proteasome inhibitors together offers the potential for deeper and more durable responses due to enhanced efficacy through biological synergy and reduced overlapping toxicities. The combination of pomalidomide and bortezomib has not been investigated extensively; preliminary results of a phase 1 study of twice weekly bortezomib with pomalidomide have been reported with promising results (Richardson, ASH 2012). This trial was designed to evaluate the safety and efficacy of the combination of pomalidomide, weekly bortezomib and dexamethasone - Pom-Bor-Dex or “PVD”.

We designed a phase I/II trial of pomalidomide, bortezomib and dexamethasone in patients with relapsed myeloma who had 1-4 prior lines of therapy, including being resistant or refractory to lenalidomide. In the phase I portion of the trial, dose level 1 consisted of pomalidomide 4 mg days 1-21 PO, bortezomib 1.0mg/m² days 1,8,15,22 IV and dexamethasone 40 mg days 1,8,15,22 PO every 28 days. Dose level 2 increased the bortezomib to 1.3mg/m². The primary endpoint was to determine the maximum tolerated dose of the combination. The 6 phase I patients treated at dose level 2 will also be included in the phase II portion of the trial. The phase II portion of trial expanded dose level 2 to assess for efficacy. Response was assessed by the IMWG criteria and toxicity was graded using the CTCAE v4.0. As determined a priori, if at least 9 of the first 16 patients responded to therapy, preliminary reporting of efficacy and toxicity would be permitted.

A total of 19 patients have been accrued to the trial: 9 in phase I (3 at dose level 1 and 6 at dose level 2) and 10 additional at dose level 2 for 16 total in phase II. At dose level 1, no DLTs were observed. Two of three patients responded (both CR) and one patient had SD for two cycles then progressed.

At dose level 2 (n=16) median age was 66, 50% were female and median time from diagnosis to study was 45 months (15-121). Twenty five percent had mSMART defined high risk status. Median prior lines of therapy was 3 (1-6), with all patients treated with lenalidomide, 75% had stem cell transplant, 31% received thalidomide, and 50% had bortezomib. The most common AEs at least possibly attributable to the combination were anemia, fatigue, leukopenia and thrombocytopenia; however, the majority of these were grade 1-2. In 14 evaluable patients Grade ≥3 AEs included neutropenia (5), leukopenia (3), lung infection (1), lymphopenia (1) and atrial flutter (1). One DLT has occurred (hospitalization for infection). All patients are alive and remain on therapy (none have progressed). Of 12 patients evaluable for response, 10 (83%) have responded: 1sCR, 3 CR, 3 VGPR and 3 PR.

The MTD of this combination was determined to be pomalidomide 4 mg (day 1-21), IV bortezomib 1.3mg/m² (days 1,8,15,22) and dexamethasone 40 mg (days 1,8,15,22) every 28 days. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy or DVT. Pom-Bor-Dex (PVD) is a highly effective combination in patients refractory to lenalidomide with confirmed responses in over 80% with the enhanced tolerability and convenience of weekly administration of bortezomib. Furthermore, no patients treated at the MTD have progressed thus far. Pom-Bor-Dex (PVD) is a highly attractive option in patients with relapsed and refractory myeloma.

Mikhael:Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Richardson:Millennium: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Jakubowiak:BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy, Research Funding; Binding Site: Consultancy; Millennium: Consultancy; AMGEN: Consultancy; Cylene: Research Funding; Prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease, Prognostication of MM based on genetic categorization of the disease Patents & Royalties. Bergsagel:Onyx: Consultancy. Witzig:Celgene: Research Funding. Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Stewart:Onyx: Research Funding; Millenium: Honoraria, Research Funding; Celgene: Honoraria.