MM-005: A Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Determine the Maximum Tolerated Dose for the Combination of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone in Subjects with Relapsed or Refractory Multiple Myeloma

Pomalidomide (POM) is a distinct IMiD® immunomodulatory agent whose mechanism of action consists of 3 primary effects: potent direct anti-myeloma activity, inhibition of stromal cell-support, and immune modulation (Quach, Leukemia, 2010). Combining an immune modulator (lenalidomide), a proteasome inhibitor (bortezomib [BTZ]), and dexamethasone (DEX) has shown preclinical synergy as well as promising efficacy both as frontline and salvage treatment in myeloma patients (pts) (Mitsiades, Blood, 2002; Richardson, J Clin Oncol, 2009; Richardson, Blood, 2010). This phase 1 study was conducted in pts with relapsed or refractory multiple myeloma (RRMM) to identify the maximum tolerated dose (MTD) of POM in combination with BTZ and low dose DEX (LoDEX). Based on the MTD finding of this trial, POM + BTZ + LoDEX will be compared with BTZ + LoDEX in a large Phase III confirmatory trial with an estimated sample size of 782 RRMM pts.

Eligible pts had 1–4 prior lines of therapy, were refractory to LEN, and must have been exposed to a proteasome inhibitor (PI) (but could not be BTZ-refractory). Refractory disease was defined as documented progressive disease (PD) during treatment or within 60 days of last dose. MTD determination will follow a traditional 3 + 3 design. Pts were treated with escalating doses of oral POM (cohort [CHT] 1: 1 mg; CHT 2: 2 mg; CHT 3: 3 mg; CHT 4 and 5: 4 mg) on days 1–14 and intravenous BTZ (CHTs 1–4: 1 mg/m2; CHTs 5: 1.3 mg/m2) on days 1, 4, 8, and 11 for cycles 1–8 then on days 1 and 8 for C9 and onward. All CHTs received oral DEX (20 mg or 10 mg for patients ≤ 75 or > 75 years of age, respectively) on days 1, 2, 4, 5, 8, 9, 11, and 12 in 21-day cycles. All pts received thromboprophylaxis with low-dose aspirin, low molecular weight heparin, or an equivalent agent. Herpes zoster prophylaxis was with acyclovir or equivalent per institutional guidelines. Dose-limiting toxicities (DLTs) were assessed during C1. Treatment was continued until PD or unacceptable toxicity. The primary objective was MTD determination. Secondary objectives included safety, response, overall survival, time to response, and duration of response.

Based on data available as of 31Jul2012, a total of 9 pts (3 men and 6 women) were enrolled in the first 3 dose CHTs. The median age was 61 years old (range: 36–75) with a median time from diagnosis of 48.9 months (range: 30.1–146.3). The median number of prior anti-MM regimens was 3 (range: 2–4). All 9 pts were refractory to LEN at study entry and had prior exposure to a PI, but were not BTZ refractory.

As of 31Jul2012, 8 pts were on study treatment in the first 3 dose CHTs, with a median of 3 cycles (range 1 –6) of treatment. One pt (CHT 1) discontinued treatment at Cycle 5 (C5) due to PD.

All pts enrolled in the first 3 CHTs, CHT 1 (n=3), CHT 2 (n=3), CHT 3 (n=3) completed at least 1 treatment cycle. No DLTs were observed in any pts in the first 3 CHTs. Pts in CHT 1, CHT 2 and CHT 3 have been treated for 4 to 6 cycles, 2 to 3 cycles, and 1 cycle respectively.

Overall, 9 (100%) pts had at least 1 adverse event (AEs) of any grade reported, with Grade 3 or 4 AEs reported in 7 (78%) pts. No Grade 4 AEs were reported during C1. The following Grade 3 AEs were reported during C1: neutropenia (CHT 3), thrombocytopenia (CHT 3), and UTI (CHT 1). No ≥ Grade 3 peripheral neuropathy was reported. No thromboembolic AEs were reported. No pts required a reduction in POM dosing due to AE. Three pts required interruption of POM due to AE (after C1). Two pts required an interruption/reduction in BTZ dosing due to AEs (after C1).

Disease response was assessed using the IMWG criteria by the investigators. In CHT 1, one pt achieved stable disease (SD) prior to discontinuing due to PD at C5; 2 pts achieved confirmed response (1 PR, 1 VGPR) and continue on therapy. In CHT 2, two pts have achieved SD, and 1 pt has reached an unconfirmed PR (uPR) with treatment ongoing in all 3. In CHT 3, one pt achieved SD and 2 pts attained uPR. Enrollment into CHT 4 (POM = 4mg) is underway at this time.

POM in combination with 1mg/m2 of IV BTZ and oral LoDEX administered according to the classical schedule appears to be well tolerated from 1 mg up to 3 mg dose levels given daily for 14 days every 3 weeks. This combination shows rapid onset of response and promising clinical activity in LEN-refractory pts with prior exposure to PI therapy. The study is ongoing with rapid accrual; results for all dosing cohorts with longer follow-up will be presented at the meeting.

Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory board Other, Honoraria. Siegel:BMS: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Merck: Consultancy. Lonial:BMS: Consultancy; Onyx: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Merck: Consultancy; Celgene Corp: Consultancy. Zaki:Celgene Corp: Employment, Equity Ownership. Hua:Celgene Corp: Employment, Equity Ownership. Shah:Celgene Corp: Employment, Equity Ownership. Wang:Celgene Corp: Employment, Equity Ownership. Anderson:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.