MM remains incurable and patients will ultimately acquire resistance to novel agents. Kumar et al. (Leukemia
. 2012;26:149-157) have shown that patients with MM who relapsed following or were refractory to bortezomib and the immunomodulatory drugs had a median overall survival (OS) of 9 months, which represents a historical control standard for this patient population. The IFM2009-02 phase 2 randomized study ought to determine the impact of the combination of pomalidomide; given orally either 4 mg daily on days 1–21 of a 28-day cycle (arm 21/28) or continuously on days 1–28 of a 28-day cycle (arm 28/28); in combination with dexamethasone (oral 40 mg weekly) in patients with resistant and refractory MM to lenalidomide and bortezomib (Leleu et al, ASH 2011). We have reported an overall response rate [ORR, ≥PR] of 34.5% with 48% stable disease [SD]. In this final analysis, we aimed to further demonstrate that treatment with pomalidomide and dexamethasone translated into prolonged survival.
Method. This study included MM patients who did not achieve a response (≤ SD) as per IMWG criteria with the last course of bortezomib and the last course of lenalidomide, or who were refractory tobortezomib and lenalidomide. The primary objective was ORR, assessed centrally and reviewed by an independent committee. The analysis is performed on ITT population and combines data from the 2 arms.
Results. As of February 1, 2012, 84 patients (57 male and 27 female) were enrolled; 43 in arm 21/28 and 41 in arm 28/28. The median age was 60 years (range 42-83). The median time from diagnosis to enrolment in IFM 2009-02 was 70.5 months (range 9-277). The median number of prior lines of therapy was 5 (range 1-13), and 100% of the patients had received bortezomib and lenalidomide as per protocol. Additionally, 70% had received alkylating agents, 81% were previously exposed to autologous stem cell transplantation, 76% had received anthracylines and 71% had received thalidomide. Most importantly, 84.5% were refractory to their last prior line of therapy and 77% were refractory to their last prior lines of both lenalidomide and bortezomib. With a median follow up of 22.8 months, 74 patients have discontinued treatment and 53 patients (63%) have died: 25 (58%) in arm 21/28 and 28 (68%) in arm 28/28. The most common reason for treatment discontinuation was disease progression(84%), and death was considered to be related to myeloma in 95% of patients (similar in the 2 arms). Importantly, 10 patients (12%) remain on treatment after 30 months. In the ITT population, the median (95%CI) PFS and TTP was 4.6 months (4-7) and 5.4 months (CI 4-8), with a median duration of response of 7.3 months (5-15). 28% of patients were free of progression and 44% responded, at 1 year respectively. The median OS was 14.9 months (11-20), similar in the 2 arms, with 57% and 44% of patients that survived at 12 and 18 months respectively.
We also compared for each patient the TTP on protocol and the TTP on the last prior line before entering in the study. The median TTP was 5 (4;8) months on study and 4 (3;5.5) months on the last prior line,with 28% and 15% of patients free of progression at 1 year; this difference in TTP dramatically increased when focusing on responders: the TTP on study has not been reached (43;-) and was 26 (20;39)months on the last prior line. 49% and 24% of patients were responders at 1year in the 2 groups, respectively. We found that TTP was greater on pomalidomide than on any other line of therapy that patientscould have access to in France at the time of the study.
Interestingly, we noticed that all survival end points were significantly more prolonged in responders when compared to patients with SD. Median OS that has not been reached in responders, (18.4;-); and was 13 (8;20) months in patients with SD, (HR [95% CI) 0.45 [0.2,0.9], p=0.018). Noteworthy, 83% of responders and 50% of patients with SD were still alive after 12 months of treatment, and 69% and 36% were still alive at 18 months, respectively.
Conclusion. Pomalidomide and dexamethasone is active and well tolerated in heavily pre-treated MM patients. The combination of pomalidomide and dexamethasone compared very favourably to the expected median OS reported in the historical control study in end stage MM. This study provides further evidence that pomalidomide can provide benefit for patients who have relapsed after other novel therapies.