Maintenance Ixazomib Extends PFS in Newly Diagnosed Multiple Myeloma

Meletios A. Dimopoulos, MD

Two-year maintenance therapy with ixazomib (Ninlaro) led to a 39% improvement in progression-free survival (PFS) compared with placebo in patients with newly diagnosed multiple myeloma who achieved a partial response (PR) to induction treatment with a proteasome inhibitor and/or an immunomodulatory (IMiD) agent following autologous stem cell transplant (ASCT), according to results of the phase III TOURMALINE-MM3 trial presented at the 2018 American Society of Hematology Annual Meeting.

“This is the first randomized, double-blind, placebo-controlled trial of a proteasome inhibitor for maintenance treatment after transplant,” said lead study author Meletios A. Dimopoulos, MD, professor and chairman, Department of Clinical Therapeutics at the University of Athens School of Medicine in Athens, Greece, in a presentation during the conference. “Ixazomib represents a new treatment option for maintenance after transplantation.”

Relapse following ASCT is nearly unavoidable in multiple myeloma, Dimopoulos said, and explained that maintenance therapy after ASCT may delay disease progression and prolong survival. Although lenalidomide (Revlimid) is approved by the FDA in the maintenance setting, he noted that 29% of patients discontinue its use due to treatment-emergent adverse events. The justification for ixazomib, therefore, is that it is given as a once-weekly oral dose and has a manageable safety profile.

Ixazomib was approved by the FDA in November 2015 for use in combination with lenalidomide and dexamethasone as a treatment for patients with multiple myeloma who have received at least 1 prior therapy.

TOURMALINE-MM3 evaluated weekly treatment with ixazomib versus placebo in newly diagnosed patients who experienced a PR to a proteasome inhibitor or IMiD as induction therapy followed by single ASCT and 200 mg/m² of melphalan. A total 656 patients were randomized 3:2 to receive either ixazomib (n = 395) or placebo (n = 261) on days 1, 8, and 15 of 28-day cycles, for up to 26 cycles. After the first 4 cycles of treatment, patients increased their dose of ixazomib or placebo increased from 3 mg to 4 mg (n = 317 on ixazomib, n = 222 on placebo).

Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) as assessed by an independent review committee (IRC), and the key secondary endpoint was overall survival (OS).

To be eligible for enrollment, patients older than 18 years of age had a confirmed diagnosis of multiple myeloma with documented local cytogenetics/fluorescence in situ hybridization before ASCT, International Staging System (ISS) disease stage at the time of diagnosis, had a documented response to ASCT, and an ECOG performance status of 0 or 2. Patients were excluded if they relapsed following or were unresponsive to frontline therapy, underwent tandem ASCT, had comorbidities or other severe conditions, or received post-ASCT consolidation therapy.

Baseline patient and disease characteristics were similar between both arms. The median age was 59. There was an equal percentage of minimal residual disease (MRD)—negative patients in both arms (33%), and the percentage of MRD–positive patients was comparable (63% vs 61%). Fifteen patients in the ixazomib arm and 14 in the placebo arm were not evaluable.

In the ixazomib group, 15% of patients had high-risk cytogenetic features, 64% had standard risk, and 21% were unclassifiable compared with 21%, 58%, and 21% in the placebo group, respectively. Fifty-nine percent of patients in each arm had induction therapy comprising a proteasome inhibitor without an IMiD agent, 11% in each received an IMiD without a proteasome inhibitor, and 30% in each group received both agents. The most common induction regimens were bortezomib (Velcade), cyclophosphamide, and dexamethasone (46%); bortezomib, thalidomide (Thalomid), and dexamethasone (19%); and cyclophosphamide, thalidomide, and dexamethasone (5%). Thalidomide was used in 87% of patients who received an IMiD.

Patients were stratified by induction regimen, ISS disease stage, and response after transplantation. The median duration of treatment at 4 mg was 15.2 months on the ixazomib arm and 16.2 months in the placebo group.

Results showed the median PFS was 26.5 months with ixazomib compared with 21.3 months with placebo (HR, 0.72; 95% CI, 0.582-0.890; P = .002), meeting the study’s primary endpoint.

The PFS benefit was observed across patient subgroups, including those between 60 and 75 years of age, those with high- and standard-risk cytogenetics, and patients with ISS stage III disease. In patients with MRD—negative disease, the median PFS was 38.6 months and 32.5 months with ixazomib and placebo, respectively. The median PFS was 23.1 months with ixazomib and 18.5 months with placebo in patients with MRD–positive disease. Among those who had MRD–positive disease, 12% and 7% converted to MRD–negative disease in the ixazomib and placebo arms, respectively.

At a median follow-up of 31 months, 14% of deaths had been reported and OS data are not mature; however, Dimopoulos noted that the median OS has not been reached in either arm and investigators are continuing follow-up.

Additionally, 46% of patients on the ixazomib arm had improved IRC-assessed responses compared with 32% of those on the placebo arm. Patients on ixazomib who had a very good partial response (VGPR) at time of study entry had an improved response to a complete response (CR) after treatment at 43% versus 32% with placebo, respectively. Patients in PR at time of study entry also improved to a CR or VGPR with ixazomib (53%) versus placebo (34%).

Regarding safety, all-grade treatment-related adverse events (TRAEs) occurred in 78% of ixazomib-treated patients versus 58% of those in the placebo arm. Grade ≥3 adverse events (AEs) were more common with ixazomib (19%) versus placebo (5%). Overall, 7% of patients on ixazomib discontinued treatment compared with 5% of patients administered placebo, while 19% and 5% of patients on ixazomib and placebo had dose reductions, respectively. A total of 79% of patients on ixazomib versus 86% of those on placebo, who did not discontinue therapy due to disease progression, completed the full 24 months of treatment.

Dimopoulos noted that maintenance ixazomib was not associated with an increase in hepatic, cardiac, or renal AEs. Moreover, there was no difference in the rate of new primary malignancies (3% each). However, AEs of any cause were more present in the ixazomib arm versus placebo: nausea (39% vs 15%), diarrhea (35% vs 24%), vomiting (27% vs 11%), and arthralgia (22% vs 12%). There was 1 study death in the ixazomib arm and 0 in the placebo arm.

Quality of life (QoL) was also preserved with ixazomib treatment. EORTC QLQ-C30 and EORTC QLQ-MY-20 scores indicated similar patient-reported QoL in both arms over time.

Additional studies of ixazomib combinations and treatment to progression are ongoing to further improve patient outcomes, Dimopoulos concluded.

Dimopoulos MA, Gay F, Schjesvold 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. In: Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1 to 4, 2018; San Diego, California. Abstract 301.

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