Ixazomib in Combination with Thalidomide and Dexamethasone for Induction and Ixazomib Maintenance Therapy Overcomes High-Risk Cytogenetics (but not of 1q21 Gain) in Relapsed/Refractory Multiple Myeloma — AGMT_MM1

Introduction Ixazomib is an effective PI that combines the advantage of oral administration with a favorable toxicity profile. Recent results showed significant activity, both in newly diagnosed, and in pretreated patients (pts). Ixazomib in combination with lenalidomide-dexamethasone (IRd) was significantly superior over Rd in pts with relapsed/refractory multiple myeloma (RRMM), and was able to overcome the negative impact of poor risk cytogenetics. Ixazomib-thalidomide-dexamethasone (IxaThalDex) has been shown to be effective in pts with newly diagnosed MM and is used in this trial in pts with RRMM. Here, we evaluate the impact of cytogenetic risk factors on outcome in pts with RRMM treated with IxaThalDex. Patients and Methods Ninety pts with RRMM and one or more prior lines of therapy (TX) were enrolled. Treatment regimen: Ixazomib (4mg, d 1, 8 and 15), thalidomide (100mg/d), and dexamethasone (40mg once/week). Pts aged ≥75 years received lower doses of thalidomide (50mg/d) and of dexamethasone (20mg). Pts were scheduled for 8 cycles followed by ixazomib maintenance therapy (4mg, days 1, 8, 15 of a 28 cycle and 3mg in pts aged ≥75 years) for one year. Preplanned FISH analysis was performed on CD138 selected bone marrow plasma cells. The cut-off level for positivity was 10% for t(4;14), and 20% for del(17p) and 1q21 gain, respectively. The previously defined primary endpoint was progression-free survival (PFS), and secondary objectives were overall response rate, overall survival (OS), and impact of cytogenetic risk and of renal impairment, safety and myeloma frailty status. PFS and OS was estimated according to Kaplan-Meier and differences evaluated by log-rank test. Response rates were compared using Fisher's Exact Test. Findings Seventy-six of the 90 pts of the intent to treat group (ITT) received at least two cycles and comprise the per protocol population (PP). Complete FISH data are available in 61 pts. Pt characteristics of the ITT group: Age, median 67 (44 -84) years, ISS stage I: 37, II 30, III: 22, not known: 1, median number of prior TX lines: 1 (range: 1-8). Forty-three pts have completed all 8 cycles of induction therapy (median number of cycles: 6). Forty-one pts started Ixazomib maintenance therapy and 6 completed the planned 12 cycles as yet. Median follow-up is 15.3 months. PR or better was achieved in 46 pts (60.5%), CR in 8 (10.5%), VGPR in 13 (17.1%), PR in 25 (32.9%), and MR in 6 (7.9%) pts, yielding a clinical benefit rate of 68.4