Overall Survival (OS) Benefit of Oral Ixazomib in Combination with Lenalidomide and Dexamethasone (IRd) Vs Lenalidomide and Dexamethasone (Rd) in Asian Patients (pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): Pooled-Analysis from the Tourmaline-MM1 and the China Continuation Studies

Introduction: Ixazomib (Ninlaro) is the first orally administered proteasome inhibitor (PI) approved in more than 50 countries worldwide, including China. The TOURMALINE-MM1 study was a large randomized, double-blind, global registration study assessing treatment with either ixazomib or placebo added to lenalidomide and dexamethasone. The China Continuation Study (CCS) was a separate regional expansion of the global study that used the same study design. (Panel A) In the global study, IRd treatment extended progression-free survival (PFS), the primary endpoint, by 35% (HR=0.74) vs Rd.

Here we report results of a pooled analysis of data from a subgroup of Asian patients enrolled in these two studies.

Demographics and Methods: Asian patients from China (n=6 from the global study; n=115 from the CCS), Singapore (n=6), South Korea (n=6), and 3 non-Asian countries (n=5) were included in this pooled analysis.

Overall response rate (ORR) was based on the International Myeloma Working Group criteria. The median OS and PFS were calculated using the Kaplan-Meier method. Comparative analysis of treatment groups used stratified log rank tests and the Cox proportional hazard regression model. Safety assessments were based on treatment-emergent adverse events (TEAEs), changes in laboratory parameters, and 12-lead electrocardiogram results.

Results: Data from 138 pts were analyzed (67 IRd; 71 Rd). Baseline characteristics were balanced between the treatment groups; overall median age was 61 (range, 30-80) years, 67% of pts were < 65 years; 97% of pts had Eastern Cooperative Oncology Group Performance Scores 0-1; 37% had International Staging System (ISS) stages II/III; and 72% had lytic bone disease. The median number of prior treatments was 2, with 82% exposed to thalidomide of which 61% were thalidomide refractory, 61% were exposed to bortezomib, and 48% exposed to both drugs.

The ORR was 57% in the IRd group vs 37% in the Rd group. Median OS was 25.8 mos and 15.8 mos in the IRd and Rd treatment groups, respectively (HR=0.346). (Panel B). OS also was longer with IRd therapy regardless of prior exposure to bortezomib (HR=0.322) or thalidomide (HR=0.317) as well as in pts with thalidomide refractory tumors (HR=0.273). (Panel C). The median PFS was 7.3 mos and 4.6 mos in the IRd and Rd treatment groups, respectively (HR=0.559). Longer PFS was also observed with IRd treatment in pts with prior exposure to bortezomib (HR=0.467) or thalidomide (HR= 0.580) as well as pts with thalidomide refractory tumors (HR= 0.631).

The rates of drug-related TEAEs (IRd, 96%; Rd, 97%), serious TEAEs (IRd, 37%; Rd, 34%), Grade 3/4 TEAEs (IRd, 74%; Rd, 73%) and discontinuations due to AEs (IRd, 12%; Rd, 13%) were similar in both treatment groups. Grade 3/4 TEAEs reported in ≥10% of either treatment group were anemia (IRd, 14%; Rd, 31%), lower respiratory infection (IRd, 23%; Rd, 21%), neutrophil count decrease (IRd, 13%; Rd, 16%), platelet count decrease (IRd, 15%; Rd, 13%), neutropenia (IRd, 17%; Rd, 9%), thrombocytopenia (IRd 11%; Rd 6%). There was no increased cardiotoxicity, renal toxicity, hepatoxicity or secondary primary malignancy in the IRd group.

Conclusions: Asian pts with RRMM treated with oral IRd showed superior OS and PFS vs those treated with Rd. The benefit was consistent regardless of prior exposure to thalidomide and bortezomib. The addition of ixazomib to Rd was well-tolerated, and no new safety signals were identified. The safety profile of IRd was consistent with the safety findings of the large global study (Moreau P, Masszi T, Grzasko N, et al. for the TOURMALINE-MM1 Study group. N Engl J Med. 2016;374:1621-1634.)

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