Post-Transplant Ixazomib Maintenance Prolongs Survival in Newly Diagnosed Myeloma

For patients with newly diagnosed multiple myeloma (MM) who relapse following autologous hematopoietic cell transplantation (AHCT), maintenance therapy with the oral proteasome inhibitor (PI) ixazomib extended survival, compared with placebo, according to results from the TOURMALINE-MM3 trial that were presented at the 2019 Transplantation & Cellular Therapy Meetings of the American Society for Blood and Marrow Transplantation and the Center for International Blood & Marrow Transplant Research.

Gareth Morgan, MD, from the Myeloma Center at the University of Arkansas for Medical Sciences, shared the results.

TOURMALINE-MM3 is a double-blind, placebo-controlled, phase III study that enrolled 656 adult patients with newly diagnosed MM who had received standard of care with a PI or immunomodulatory drug prior to undergoing a single AHCT with high-dose melphalan. Eligible patients had experienced at least a partial response to AHCT; those whose disease relapsed, were unresponsive to frontline therapy, or underwent a tandem AHCT or received post-AHCT consolidation therapy were excluded from the analysis.

Patients were stratified based on induction protocol, pre-induction International Staging System (ISS) stage disease, and response following AHCT, then randomized 3:2 to receive either weekly ixazomib (n=395) or matched placebo (n=261). Ixazomib 3 mg was administered on days 1, 8, and 15 of 28-day cycles for two years or until disease progression or unacceptable toxicity, up to 26 cycles. If patients tolerated ixazomib 3 mg during the first four cycles, the dose was increased to 4 mg (n=317 in the ixazomib group and n=222 in the placebo group).

Baseline characteristics were “standard and consistent between placebo and treatment groups,” Dr. Morgan said. The median age in the ixazomib and placebo groups were 58 years (range = 24-73 years) and 60 years (range = 37-73 years), respectfully.

Approximately one-third of patients were minimal residual disease (MRD)–negative at the time of randomization, and nearly one-fifth of patients in each group had high-risk cytogenetics. Patients began maintenance therapy at a median of 3.4 months after transplant (range = 2.8-5.8 months).

As of April 16, 2018 (data cutoff), with a median follow up of 31 months (interquartile range [IQR] = 27.3-35.7 months), the researchers observed a median progression-free survival of 26.5 months in the ixazomib group (range = 23.7-33.8 months) and 21.3 months (range = 18.0-24.7 months) in the placebo group. This translated to a 28-percent reduction in the risk of disease progression or death for patients who received ixazomib (hazard ratio = 0.72; 95% CI 0.58-0.89; p=0.002).

Ixazomib maintenance also was associated with a deepening of responses over time, the authors reported. Among participants who had a very good partial response at study entry, for example, 43 percent of ixazomib-treated patients improved to a complete response (n=92/213), compared with 32 percent in the placebo arm (n=48/152; p=0.004).

Ixazomib treatment also was associated with a higher rate of conversion from MRD-positive to MRD-negative status (12% vs. 7%; p value not provided). “Outcomes for MRD-negative patients were better if they received maintenance with ixazomib,” Dr. Morgan added, “which suggests that merely achieving MRD-negativity is not an endpoint in itself, and you can improve the outcome of these patients with prolonged therapy.”

In subgroup analyses, ixazomib was “active across the board,” Dr. Morgan reported, and the progression-free survival benefit was evident across age groups, ISS stage, cytogenetics, and renal function.

Discontinuation due to adverse events (AEs) was low and similar across both groups (7% for ixazomib and 5% for placebo). However, the incidence of grade ≥3 AEs appeared to be higher in the ixazomib group (42% and 26%, respectively), the most common of which were infections (15% and 8%), gastrointestinal disorders (6% and 1%), neutropenia (5% and 3%), and thrombocytopenia (5% and <1%; [p values for comparisons were not reported]). Rates of secondary primary malignancies were low, at 3 percent in both arms.

“AEs could be managed easily in the clinic or with simple remedies and small doses of steroids,” Dr. Morgan said.

He also noted that it is “too soon to comment on the impact of ixazomib on overall survival because there are not enough follow-up data.”

In response to audience questions following the presentation about where ixazomib fits into the landscape of available maintenance therapy options, including lenalidomide, Dr. Morgan cautioned against a head-to-head comparison of the agents. The choice between ixazomib or lenalidomide depends on a patient’s underlying disease characteristics, he added. With this information, “we can target [disease factors] to select the group that would benefit most [from either treatment].”

The authors report relationships with Takeda and Millennium Pharmaceuticals, which provided funding for the study.

Reference

Morgan G, Dimopoulos M, Gay F, et al. Maintenance therapy with the oral proteasome inhibitor (PI) ixazomib significantly prolongs progression-free survival (PFS) following autologous stem cell Transplantation (ASCT) in patients with newly diagnosed multiple myeloma (NDMM): phase 3 Tourmaline-MM3 trial. Abstract #23. Presented at the Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR, February 20, 2019; Houston, TX.

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