Maintenance Therapy with Ixazomib Significantly Prolongs Progression-Free Survival Following Autologous Stem-Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma: Results from the TOURMALINE-MM3 Trial

Web Exclusives — February 1, 2019

San Diego, CA—In patients with multiple myeloma (MM), the use of drug therapy as maintenance has been shown to prolong the length of time the disease is controlled. Specifically, use of maintenance therapy may affect overall survival, particularly when it is used after an autologous stem-cell transplant (ASCT).

For several years, lenalidomide (Revlimid)—an immunomodulating drug (IMiD) that is taken orally—has been the only medication approved by the US Food and Drug Administration (FDA) specifically for use as maintenance therapy in MM. Although lenalidomide is clearly effective as a maintenance therapy, its use can increase the chance of side effects as well as the risk for developing a second cancer.

Proteasome inhibitors (PIs) are another class of drugs used as a backbone of MM treatment. As of December 2018, 3 PIs have been approved for use in MM in the United States: bortezomib (Velcade), which is given by subcutaneous injection or intravenous infusion; carfilzomib (Kyprolis), which is given by intravenous infusion; and ixazomib (Ninlaro), which is given orally.

Bortezomib-based maintenance therapy has shown some evidence of activity in patients who have undergone ASCT, but this benefit was not demonstrated when the treatment was compared with placebo in a phase 3 trial. Bortezomib maintenance is also limited by concerns regarding side effects and the need for regular injections or infusions.

Ixazomib is an orally administered PI that is currently approved by the FDA in combination with lenalidomide and dexamethasone for patients with MM who have received at least 1 prior therapy. Because its oral administration is potentially more convenient for patients, investigators were interested in learning whether ixazomib can be used as maintenance therapy.

To assess the value of ixazomib maintenance therapy in patients with MM, Meletios A. Dimopoulos, MD, Professor and Chairman, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Greece, and colleagues initiated a phase 3, double-blind, placebo-controlled, multicenter clinical trial called TOURMALINE-MM3. This trial compared weekly ixazomib maintenance with placebo in patients with newly diagnosed MM or IMiD (lenalidomide) followed by single ASCT. The investigators presented their results at the 2018 American Society of Hematology (ASH) annual meeting.

Patients received ixazomib or placebo on days 1, 8, and 15 of 28-day cycles for up to 2 years or until progressive disease or unacceptable toxicity. The ixazomib dose was 3 mg during the first 4 cycles, and then was increased to 4 mg from cycle 5 onward if it was tolerated well during cycles 1 to 4.

The primary measure of the efficacy of ixazomib maintenance was progression-free survival (PFS), which was assessed by an independent review committee of physicians who were blinded to treatment assignment. A key secondary measure of the efficacy of ixazomib maintenance was overall survival. At ASH 2018, researchers reported data from the final assessment of PFS.

A total of 656 patients enrolled in the TOURMALINE-MM3 trial; 395 received ixazomib maintenance and 261 received placebo. Median age in both groups was 57 years (range, 24-73 years), and more than half (59%) had received a PI without an IMiD during their induction therapy. Most (79%) of these patients had achieved a complete response or very good partial response following induction along with ASCT. A minority of patients in this trial (18%) had high-risk cytogenetics (del[17p], t[4;14], or t[14;16]).

After following these patients for an average of 31 months, researchers in this trial observed a 28% reduction in the risk for progression or death for those who received ixazomib compared with those who received placebo. Stated differently, there was a 39% improvement in PFS with ixazomib compared with placebo. The median time over which patients were free from progressive disease improved by approximately 6 months for those receiving ixazomib (27 months) compared with those receiving placebo (21 months). This difference in median PFS was statistically significant.

Patients who underwent ASCT after their induction regimen and who received ixazomib had longer PFS compared with those who received placebo maintenance. The median PFS for patients who underwent ASCT and then received ixazomib maintenance was 31 months compared with 25 months for placebo. Ixazomib maintenance also led to a higher percentage of patients with no evidence of minimal residual disease compared with placebo (12% vs 7%).

The benefit in PFS was seen across all subtypes of MM, including patients with high-risk disease, those who received a PI as a part of induction, and those who did not receive a PI as a part of induction.

In the TOURMALINE-MM3 trial, 7% of patients in the ixazomib group and 5% of patients in the placebo group discontinued maintenance therapy because of adverse events. Approximately one-quarter (27%) of patients receiving ixazomib experienced 1 or more severe adverse events compared with 20% of patients receiving placebo. Frequently observed severe adverse events associated with ixazomib versus placebo were infections (15% vs 8%), such as pneumonia (6% vs 4%), gastrointestinal disorders (6% vs 1%), low white blood cell count (5% vs 3%), and low platelet count (5% vs <1%). Peripheral neuropathy (any severity level) was reported by 19% of patients in the ixazomib group and 15% of those in the placebo group. The rate of second primary cancers was low (3%) in both study groups. Quality-of-life (QoL) survey scores were similar between patients receiving ixazomib and those receiving placebo, suggesting that maintenance therapy with ixazomib did not negatively affect QoL.

In summary, the TOURMALINE-MM3 trial demonstrated a 28% reduction in risk for progression or death, corresponding to a 39% improvement in PFS for maintenance therapy with ixazomib. Over time, researchers noted deepening of responses and more conversions to minimal residual disease negativity, as well as a good safety profile, including low rates of peripheral neuropathy. They concluded that ixazomib is valuable as a future option for maintenance therapy in patients with MM, particularly those who have undergone ASCT.


Dimopoulos MA, Gay F, Schjesvold FH, 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. Presented at the 2018 ASH Annual Meeting, December 2, 2018; San Diego, CA. Abstract 301.

Related Articles

Subscribe Today!

To sign up for our newsletter or print publications, please enter your contact information below.

I'd like to receive: