MM-004: A Phase 1, Dose-Escalation Study to Determine the Maximum Tolerated Dose, Safety, Efficacy, and Pharmacokinetics of Pomalidomide Alone or in Combination with Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma in Japan

Background: Patients (pts) with refractory or relapsed and refractory multiple myeloma (RRMM) who have exhausted treatment (Tx) with lenalidomide (LEN) or thalidomide (THAL) and bortezomib (BORT) have shortened overall survival (OS; Kumar, Leukemia, 2012). Pomalidomide (POM) is a novel oral IMiDs^® immunomodulatory agent with direct antimyeloma and stromal cell inhibitory effects (Quach, Leukemia, 2010; Mark, Leuk Res, 2014). POM 4 mg (± dexamethasone) is approved in some countries for Tx of pts with RRMM based on phase 3 results showing significant improvement vs high-dose dexamethasone in response, progression-free survival (PFS), and OS and phase 1/2 results showing high and durable overall response rates (ORRs; Richardson, Blood, 2013; Richardson, Blood, 2014; San Miguel, Lancet Oncol, 2013). MM-004 is a phase 1, open-label, dose-escalation study designed to assess the tolerated dose (TD), safety, efficacy, and pharmacokinetics (PK) of POM alone or POM + low-dose dexamethasone (LoDEX) in Japanese pts with RRMM.

Methods: Pts must have been ≥ 20 yrs old with a documented diagnosis of MM, have had ≥ 2 prior lines of anti-MM Tx including ≥ 2 cycles of LEN and BORT (alone or in combination), and have RRMM defined as progressive disease (PD) during or within 60 days of completing their last anti-MM Tx. Tx consisted of POM 2 mg (Cohort 1) or 4 mg (Cohort 2) day (D) 1-21 of a 28-D cycle and DEX 40 mg (20 mg for pts > 75 yrs) D1, 8, 15, and 22 (starting on cycle 2). Tx was continued until PD, unacceptable adverse event (AE), or voluntary withdrawal. Pts enrolled in Cohort 1 received a single dose of POM 0.5 mg at D7 for PK evaluation. The primary endpoint was TD; secondary endpoints included ORR based on International Myeloma Working Group criteria, objective response, duration of response (DOR), PFS, PK, and safety.

Results: Twelve pts were enrolled (6 in each cohort); 2 pts remain on Tx as of June 27, 2014 (Cohort 2, n= 2). Median age was 68 yrs (range, 52-76 yrs); 75% of pts were aged > 65 yrs. Median number of prior anti-MM Tx was 6 (range, 4-10) and baseline creatinine clearance (CrCl) was ≥ 60 mL/min for all pts except one. Six pts received prior THAL-based Tx (Cohort 1, n= 3; Cohort 2, n= 3). TD was determined to be POM 4 mg D1-21 of a 28-D cycle (a dose-limiting toxicity of grade 4 neutropenia for ≥ 7 days was observed in 1 pt in cohort 1). This result showed that the TD of POM in Japanese pts with MM was the same as that in Caucasian pts with MM. Median duration of treatment was 6.5 cycles in all pts. The best ORR (≥ partial response [PR]) was 25% (3/12 pts) across both cohorts; ORR was 17% (1/6) in Cohort 1 and 33% (2/6) in Cohort 2. Overall median PFS was 5.5 months (5.1 months in Cohort 1; not reached in Cohort 2). Maximum POM plasma concentration (C_max) was 9.1, 35.6, and 70.2 ng/mL after single dose of POM 0.5, 2, and 4 mg, respectively, and was reached at times ranging from 0.9 to 6 h. C_max was 37.6 and 71.2 ng/mL after multiple doses of POM 2 and 4 mg. Systemic POM exposure as measured by geometric means of area under the plasma concentration time curve (AUC) was 84.9, 364.4, and 685.7 ng•h /mL after a single doses of POM 0.5, 2, and 4 mg, respectively. AUC was 411.5 and 713.8 ng•h /mL after multiple doses of POM 2 mg and 4 mg. Both C_max and AUC exposures increased in a dose-proportional manner from 0.5 to 4 mg, as assessed by both visual inspection and statistical analysis. Clearance and volume of distribution were similar across dose levels. The mean half-life (t_1/2) of POM was comparable across dose levels, with t_1/2 of approximately 6.4, 6.9, and 6 h after single doses of POM 0.5, 2, and 4 mg, respectively. After multiple doses of POM 2 mg and 4 mg, t_1/2was approximately 7.3 and 5.5 h. Grade ≥ 3 AEs occurred in 11 pts (92%), and the most frequently reported AE was neutropenia (8 pts, 67%). Other frequently reported AEs (all grades) were thrombocytopenia, anemia, leukopenia, and peripheral edema.

Conclusions: POM 4 mg was identified as the TD in Japanese pts with RRMM, which is consistent with previous findings in Caucasian pts with MM. However, pts should be monitored for the known AE profile of POM and managed appropriately. The combination of POM with LoDEX was also found to be tolerable in Japanese pts with RRMM. Systemic exposure to POM increased dose proportionally, and limited drug accumulation was observed following multiple doses. Responses (≥ PR) were observed in 25% of pts. Further investigation of the efficacy and safety of POM + LoDEX in Japanese pts with RRMM in a phase 2 trial is warranted.