Investigating Efficacy, Safety, and Biomarkers in a Phase 2 Trial of Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) Following Second-Line Lenalidomide-Based Therapy (Tx) in Relapsed or Refractory Multiple Myeloma (RRMM)

Background: Preclinical studies indicate that lenalidomide (LEN) and POM are not cross-resistant (Ocio et al Leukemia, 2015) and that POM remains active in LEN-resistant myeloma cells (Lopez-Girona et al Leukemia, 2012). Likewise, POM + LoDEX showed comparable efficacy in patients (pts) refractory to LEN administered as last prior Tx vs the full population in subanalyses of the clinical trials MM-002 and MM-003 (San Miguel et al Lancet Oncol, 2013; Richardson et al Blood, 2014). To confirm these observations, we initiated a single-arm, phase 2 trial evaluating POM + LoDEX immediately following second-line LEN-based Tx in advanced RRMM (MM-014; NCT01946477).

Methods: Eligible pts (aged ≥ 18 yrs) had received 2 prior lines of Tx, with ≥ 2 cycles of LEN-based Tx in the second line. Pts must have had documented progressive disease (PD) during or after their last antimyeloma Tx and Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. POM was administered 4 mg/day on days 1-21 of a 28-day cycle with LoDEX 40 mg/day (20 mg/day for pts aged > 75 yrs) on days 1, 8, 15, and 22 until PD or discontinuation for any reason. Pts received mandatory thromboprophylaxis. The primary end point was overall response rate by modified International Myeloma Working Group criteria (including minor response). Secondary end points included progression-free survival, overall survival, time to progression, safety, and duration of response. Exploratory end points were included to identify molecular, immune, and cellular biomarkers that might inform POM + LoDEX response, resistance, or mechanism of action.

Results: As of March 20, 2015, 27 of the 85 planned pts were enrolled and received POM + LoDEX. Twelve pts remain on Tx, whereas 15 have discontinued, due to PD (n = 7) and withdrawal (n = 5), but not adverse events (n = 0). Males comprised 59% of pts; 85% were white and the median age was 69 yrs (range, 44-85 yrs), with 67% of pts aged ≥ 65 yrs. The median time since diagnosis was 3.9 yrs (range, 1.3-13.3 yrs), and 59% of pts received prior stem cell transplant. Most pts (81%) were refractory to the most recent prior LEN-containing Tx, and the median duration of the most recent prior LEN Tx was 8.3 mos (range, 0.3-56.3 mos). The 19% of pts who were not refractory to the most recent prior LEN-containing Tx remain on Tx. Pts predominantly had ECOG performance status 0 or 1 (30% and 63%, respectively) vs 2 (7%). Of the 19 pts with International Staging System assessment reported, most were stage I (n = 7) or II (n = 11) vs III (n = 1). Efficacy and safety data will be presented.

Conclusions: The MM-014 study is assessing the efficacy and safety of POM + LoDEX in pts with RRMM who have received second-line LEN-based Tx.  MM-014 is designed to confirm and expand the results from MM-002 and MM-003 with translational data. Clonality and biomarkers, including Aiolos, Ikaros, IRF-4, and c-Myc, will be evaluated to determine association with POM + LoDEX synergy, high-risk MM-associated genetic aberrations, clonal evolution, and minimal residual disease.