Ixazomib, Pomalidomide and Dexamethasone (IxPd) in Relapsed or Refractory Multiple Myeloma (RRMM) Characterized with High-Risk Cytogenetics. IFM 2014-01

Background: High risk (HR) cytogenetics remains of poor prognosis, particularly in the RRMM setting. IFM 2010-02, Pd in advanced HR RRMM, had demonstrated limited activity with no addition of a proteasome inhibitor (PI), and a good safety profile. We hypothesized that addition of Ixazomib (oral PI at increased dose density) to Pd (IxPd) in HR RRMM would improve convenience, thus adherence to treatment, and in parallel improve efficacy with no increased toxicity. Aims: We aimed to determine the efficacy and safety profile of the association ixazomib, pomalidomide and dexamethasone HR RRMM. Methods: Eligible patients had a RRMM in L2 refractory to lenalidomide but not to pomalidomide and ixazomib. HR was defined by presence of either del(17p) and/or t(4;14) at diagnosis or study entry. Patients received 17 induction cycles, 21-days long, consisting of ixazomib 3mg/day (d 1, 4, 8 and 11), pomalidomide 4mg/day (d1 to 14) and weekly dexamethasone, followed by a maintenance phase of 28-day cycles with ixazomib 4mg/day (d 1, 8 and 15) and pomalidomide 4mg/day (d 1 to 21), until progression. The primary endpoint was time to progression (TTP). The number of patients to be recruited was initially calculated based on an expected doubling of the median TTP obtained in IFM 2010-02 with Pd in either 2 HR RRMM population, but the number was recalculated due to difficulties in recruitment to demonstrate an expected doubling of the median TTP from 3 months, as a whole. No statistical comparison can be done across HR groups given that the study was powered to analyze the 2 groups as a whole and not separately with 26 patients. Results: Twenty-six patients were enrolled in the study. Median age was 72 years (Interquartile range: 67-78). Ten patients presented with del(17p) and twelve patients with t(4;14). All patients were refractory to lenalidomide. With a median follow-up time of 9.8 months, the median TTP was 9.7 months (95% confidence interval (CI) 4.4;-). The median OS was 12.2 months (CI95% 11.1;-). The ORR and ≥VGPR rate was 15 (58%) pts and 7 pts (27%) in the study as a whole. The ≥VGPR rate was 30% and 33% in del(17p) and t(4;14), respectively. No CR was observed with IxPd in our series. The most common adverse events (≥10% occurrence) were neutropenia (n=13), thrombocytopenia (n=12), asthenia (n=9), anemia (n=7), rash (n=4), diarrhea (n=3), dizziness (n=3), general physical health deterioration (n=3), muscle spasms (n=3), peripheral oedema (n=3), pyrexia (n=3). Ten SUSARs were declared with no modification to the safety profile of ixazomib and pomalidomide according to the independent data monitoring committee. Summary/Conclusion: The study IFM 2014-01/IxPd in HR L2 RRMM met its primary end point objective since the median TTP was superior to 3 months, the median TTP reported in IFM2010-02 as a whole, with the addition of Ixazomib to Pomalidomide and dexamethasone in this population characterized with a very poor outcome. This data confirms the importance of proteasome inhibitors in HR RRMM. This phase 2 study needs confirmation in a larger cohort.