China continuation study: a regional expansion of the TOURMALINE-MM1 clinical trial

The China continuation study was a regional expansion of the global TOURMALINE-MM1 study: a double-blind, placebo-controlled, randomized phase III study of ixazomib plus lenalidomide-dexamethasone (Rd) in patients with Relapsed and Refractory Multiple Myeloma (RRMM). Such an expansion into the Asian population is important in light of differences observed in both the clinical profile of MM and treatment responses in Asian patients, in comparison to patients of European and North American descent. The study was published in May 2017 in the Journal of Hematology and Oncology by Jian Hou from the Second Military Medical University in Chang Zheng, Shanghai, along with numerous collaborators from the original TOURMALINE study. The primary endpoint was progression free survival (PFS).

Key Findings:

• The regional expansion of the global TOURMALINE-MM1 study utilized identical eligibility criteria, treatment and assessment methodology and endpoints
• Chinese patients (n = 115) with RRMM (average of 1-3 prior lines of therapy) were randomized to receive either ixazomib-Rd (n=57) or placebo-Rd (n=58)

All data is given as: ixazomib-Rd vs. placebo-Rd:

• PFS (after median follow-up of 7.4 vs. 6.9 months) = 6.7 vs. 4.0 months; HR = 0.598 (p = 0.035)
• Overall survival (OS) ( after median follow-up of 20.2 vs. 19.1 months) = 25.8 vs. 15.8 months; HR = 0.419 (p = 0.001)
• Overall response rate (ORR): 56% vs. 31% (odds ratio (OR) = 2.84 (95% CI 1.33–6.10); p = 0.007
• Duration of response (DOR) = 7.4 vs. 5.6 months
• Median time to progression (TTP) = 7.3 months (95% CI 4.70–9.53) vs. 4.1 months (95% CI 2.99–5.52)
• Comparison of AEs:
  • AEs ≥grade 3; 67% vs. 74%
  • Thrombocytopenia grade 3 or 4: ixazomib-Rd = 18% and 7%; placebo-Rd = 14% and 5%
  • Neutropenia grade 3 or 4: ixazomib-Rd = 19% and 5%; placebo-Rd = 19% and 2%
  • Anaemia grade 3 or 4: ixazomib-Rd = 12% and 0%; placebo-Rd = 26% and 2%
  • Serious AEs: 33% vs. 31%
  • Patients with AEs leading to discontinuation of study drug, or the study regimen, was comparable for both groups
  • Events of death: 7% vs. 9%

In conclusion, treatment of Chinese patients with ixazomib, on a background of lenalidomide plus dexamethasone, significantly improved PFS and OS. Positive results were also demonstrated for secondary efficacy endpoints of ORR, DOR and TTP. The data is in line with that previously observed in the global study, but PFS, TTP and response rates were lower overall, possibly due to the fact that Chinese patients often present at a more advanced stage of the disease, which was noted in the recorded baseline characteristics. Interestingly, limited additional toxicity was observed, despite rapid absorption of ixazomib and markedly higher systemic exposures – 80% higher than in White patients. In conclusion, this study supports the use of a triplet regimen of ixazomib-Rd in Chinese patients with RRMM.

 Abstract

Background:

The China Continuation study was a separate regional expansion of the global, double-blind, placebo-controlled, randomized phase III TOURMALINE-MM1 study of ixazomib plus lenalidomide-dexamethasone (Rd) in patients with relapsed/refractory multiple myeloma (RRMM) following one to three prior therapies.

Methods:

Patients were randomized (1:1) to receive ixazomib 4.0 mg or placebo on days 1, 8, and 15, plus lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22, in 28-day cycles. Randomization was stratified according to number of prior therapies, disease stage, and prior proteasome inhibitor exposure. The primary endpoint was progression-free survival (PFS). In total, 115 Chinese patients were randomized (57 ixazomib-Rd, 58 placebo-Rd).

Results:

At the preplanned final analysis for PFS, after median PFS follow-up of 7.4 and 6.9 months, respectively, PFS was improved with ixazomib-Rd versus placebo-Rd (median 6.7 vs 4.0 months; HR 0.598; p = 0.035). At the preplanned final analysis of overall survival (OS), after median follow-up of 20.2 and 19.1 months, respectively, OS was improved with ixazomib-Rd versus placebo-Rd (median 25.8 vs 15.8 months; HR 0.419; p = 0.001). On the ixazomib-Rd and placebo-Rd arms, respectively, 38 (67%) and 43 (74%) patients reported grade ≥3 adverse events (AEs), 19 (33%) and 18 (31%) reported serious AEs, and 4 (7%) and 5 (9%) died on-study. The most frequent grade 3/4 AEs were thrombocytopenia (18%/7% vs 14%/5%), neutropenia (19%/5% vs 19%/2%), and anemia (12%/0 vs 26%/2%).

Conclusions:

This study demonstrated that PFS and OS were significantly improved with ixazomib-Rd versus placebo-Rd, with limited additional toxicity, in patients with RRMM. (ClinicalTrials.gov number, NCT01564537.)