Tourmaline-MM1 Study: Ixazomib Added to Standard Therapy Improved Survival in RRMM

di Mary Mosley

The first all-oral triplet regimen for patients with relapsed or refractory multiple myeloma (RRMM) significantly increased by 35% the primary endpoint of progression-free survival (PFS) in the phase 3 Tourmaline-MM1 study. A longer time to progression (TTP) and improved response rates were also achieved. Ixazomib, the first oral proteasome inhibitor, was added to lenalidomide and dexamethasone in the randomized, double-blind, placebo-controlled, international, multicenter study. The results were reported by Philippe Moreau, MD, University Hospital Hotel Dieu, Nantes, France.

Previously, the combination of ixazomib, lenalidomide, and dexamethasone (IRd) as induction therapy in patients with untreated multiple myeloma was associated with an overall response rate (ORR) of 92% [Kumar SK et al. Lancet Oncol 2014]. Importantly, this phase 1/2 trial also showed ixazomib was well tolerated and had a manageable safety profile, thus addressing a concern about toxicities limiting the use of proteasome inhibitors (PI).

In Tourmaline-MM1, 722 patients were randomized to ixazomib 4 mg (n = 360) or matching placebo (n = 362) weekly on days 1, 8, and 15, plus lenalidomide 25 mg on days 1 to 21 (dose adjusted for renal function) and dexamethasone 40 mg on days 1, 8, 15, and 22, in 28-day cycles, until disease progression or unacceptable toxicity. Patients were stratified by the number of previous therapies, exposure to a PI, and International Staging System (ISS) stage. Treatment response and disease progression were assessed by an independent review committee using the International Myeloma Working Group criteria. Notably, patients had to have a creatinine clearance ≥30 mL/min, representing the real-world patient population.

The median age of the study patients was 66 years, most were men (58%) and white (86%), and most (>90%) had an ECOG performance status of 0 or 1, and 87% had an ISS stage of I or II. Seven percent of the IRd and 6% of the placebo-Rd patients had primary refractory disease. Prior treatment included a PI in 70% of patients and stem cell transplantation in >50%.

Ixazomib extended PFS compared with placebo, with a median PFS of 20.6 months versus 14.7 months in the IRd and placebo-Rd groups, respectively (HR, 0.742; 95% CI, 0.587-0.939; p = 0.012). There were 129 deaths in the IRd group and 157 in the placebo-Rd group. All pre-specified subgroups had a greater benefit with the addition of ixazomib. The 15% of patients who were >75 years old also had a significant benefit with ixazomib (HR, 0.868). Patients with and without prior exposure to PI had a similar benefit with IRd versus placebo-Rd.

In the nearly 20% of patients who had high-risk cytogenetics at baseline, the median PFS with IRd (21.4 months) was similar to the overall group and to those with standard risk (20.6 months for both) and greater than in the placebo-Rd group (HR, 0.543). High risk was defined as a 17p deletion or translocation of 4;14 or 14;16. The improvement in response rates, durable responses, and TTP with IRd compared with placebo-Rd are detailed in Table 1. Notably, with ixazomib versus placebo, a response was seen in 1.1 months versus 1.9 months, and there was a significant increase in median TTP of 21.4 months versus 15.7 months.

A prespecified interim analysis of overall survival conducted at 23 months was not statistically robust because of an insufficient number of deaths in each group. However, this analysis showed that treatment-related adverse events and treatment discontinuation were similar in both groups, supporting the safety profile of the IRd regimen (Table 2). There was a median of 17 treatment cycles in the IRd group and 15 in the placebo-Rd group. The proportion of patients in the IRd and placebo-Rd groups who received ≥18 cycles was 48% and 43% and ≥25 cycles was 20% and 19%. The higher rate of thrombocytopenia with ixazomib (31%, vs. 16% with placebo) did not translate into a higher number of transfusions. The rate of peripheral neuropathy was similar at 27% and 22% in the IRd and placebo-Rd groups. Overall, no safety concerns were identified.

Quality of life was maintained with the addition of ixazomib, with a similar mean global health score at the end of the trial.

The results of the Tourmaline-MM1 trial suggest this all-oral regimen of IRd may become a new standard of care for RRMM, according to Prof. Moreau, who noted that ixazomib was approved by the US FDA in November 2015 for the treatment of multiple myeloma in patients with at least one unsuccessful prior treatment. Expanded access is expected worldwide in early 2016.

Source: ASH 2015,
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