Ixazomib Improves PFS as Frontline Maintenance in Multiple Myeloma

Ixazomib significantly improved progression-free survival as a first-line maintenance therapy compared with placebo in adult patients with multiple myeloma who have not undergone stem cell transplantation, meeting the primary endpoint of the phase III TOURMALINE-MM4 study.

Phil Rowlands, PhD

Phil Rowlands, PhD

Phil Rowlands, PhD

Ixazomib (Ninlaro) significantly improved progression-free survival (PFS) as a first-line maintenance therapy compared with placebo in adult patients with multiple myeloma who have not undergone stem cell transplantation, meeting the primary endpoint of the phase III TOURMALINE-MM4 study.1

TOURMALINE-MM4 comprised the concept of switch maintenance therapy and enrolled patients who had completed 6 to 12 months of initial therapy and achieved a partial response (PR) or better, according to Takeda Pharmaceutical Company Limited, the developer of the proteasome inhibitor.

Ixazomib’s safety profile in this setting was consistent with previously reported data of single-agent ixazomib, and no new safety signals were identified in the TOURMALINE-MM4 trial. Full findings will be submitted for presentation at an upcoming medical meeting, the company stated in a press release.

“We are very encouraged by the results of the TOURMALINE-MM4 trial and continue our forward momentum in developing maintenance options for multiple myeloma patients. Importantly, this is the third positive phase III readout from the TOURMALINE clinical trial program,” Phil Rowlands, PhD, head, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company Limited, stated in the press release. “We remain committed to bringing this convenient and well-tolerated treatment option to patients.”

In the international, multicenter, placebo-controlled, double-blind, phase III TOURMALINE-MM4 study, investigators randomized 706 adult patients with newly diagnosed multiple myeloma who had not received stem cell transplantation to receive ixazomib maintenance or placebo orally at 3 mg on days 1, 8, and 15 of each 28-day cycle for up to 26 cycles.

Patients make 28 visits to the clinic during the treatment period and have follow-up visits every 4 weeks until the next line of therapy begins. Patients are also be contacted by telephone every 12 weeks after their last treatment visit for a follow-up assessment.

To be eligible for enrollment, patients must have been ≥18 years old with confirmed newly diagnosed myeloma with a documented major response, according to International Myeloma Working Group criteria, after initial therapy of 6 to 12 months; had an ECOG performance status of 0 to 2; and have an absolute neutrophil count (ANC) ≥1000/mm3 without growth factor support and a platelet count ≥75,000/mm3. Additionally, platelet transfusions to assist in patients meeting eligibility criteria were not permitted within 3 days before randomization. Other levels in order to be eligible for enrollment included total bilirubin ≤1.5 times the upper limit of the normal (ULN), alanine aminotransferase and aspartate aminotransferase ≤3 times ULN, and calculated creatinine clearance ≥30 mL/min via Cockcroft-Gault equation.

Patients who relapsed on or did not have a response to initial therapy, received prior stem cell transplant, received radiation or major surgery within 14 days prior to randomization, were treated for another malignancy within 5 years, had central nervous system involvement, and had uncontrolled cardiovascular conditions were excluded from enrollment. Additionally those with Waldenström macroglobulinemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome also could not enroll on the trial.

The primary endpoint is PFS; secondary endpoints include overall survival (OS), best response, time to progression, PFS2, time to next line of therapy, time to end of next line of therapy after study treatment, duration of next line of therapy, new primary malignancies, minimal residual disease (MRD) negativity, PFS and OS in the high-risk population, ECOG performance status, adverse events (AEs), quality of life, correlation between frailty status and PFS and OS, laboratory abnormalities, pharmacokinetics, time to resolution and improvement of peripheral neuropathy events.

The FDA initially approved ixazomib in 2015 for use in combination with lenalidomide (Revlimid) and dexamethasone as a treatment for patients with multiple myeloma who have received ≥1 prior therapy.

In 2018, results of the phase III TOURMALINE-MM3 trial showed that 2-year maintenance therapy with ixazomib led to a 39% improvement in PFS compared with placebo in patients with newly diagnosed multiple myeloma who achieved a PR to induction treatment with a proteasome inhibitor and/or an immunomodulatory agent (IMiD) following autologous stem cell transplant (ASCT).2

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 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 PFS as assessed by an independent review committee (IRC), and the key secondary endpoint was OS.

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, 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, International Staging System (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).

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; but at the time, the median OS had not been reached in either arm and investigators were 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 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.

Moreover, 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.


  1. Phase 3 Trial of NINLAROTM (ixazomib) as First Line Maintenance Therapy Met Primary Endpoint in Multiple Myeloma Patients not treated with Stem Cell Transplantation. Takeda Pharmaceutical Company Limited. Published November 7, 2019. https://bwnews.pr/2JZRdMn. Accessed November 7, 2019.
  2. 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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