Ixazomib Combination Improves PFS Versus Placebo in Patients With Transplant-Ineligible Myeloma

When researchers added ixazomib to continuous lenalidomide-dexamethasone (Rd) in patients with newly diagnosed, transplant-ineligible multiple myeloma (MM), they observed that the treatment regimen was safe and led to a nearly 14-month improvement in progression-free survival (PFS) – though this finding did not reach statistical significance.

Findings from the TOURMALINE-MM2 trial, published in Blood, suggest the all-oral triplet combination approach of ixazomib plus Rd represents a feasible option for select patients who may not be eligible for standard-of-care autologous hematopoietic cell transplantation (AHCT) due to age and/or comorbidity burden. Lead study author Thierry Facon, MD, of the University of Lille in France, told ASH Clinical News that the ideal patient for the ixazomib-Rd protocol “would be an elderly patient, somewhat frail, who is not able or does not want to travel to the hospital, and/or who does not want to receive intravenous or even subcutaneous drugs.”

In this study, Dr. Facon and colleagues enrolled 705 patients with confirmed symptomatic MM who were considered eligible for Rd but ineligible for AHCT because they were either 65 years or older or had comorbidities that made transplant challenging. Participants were randomly assigned to receive either oral ixazomib 4 mg (n=351) or matching placebo (n=354) to be taken on days one, eight, and 15.

Treatment assignment was combined with lenalidomide 25 mg on days one through 21 (10 mg for patients with creatinine clearance [CrCl] ≤60 or ≤50 mL/min, depending on local prescribing information) and dexamethasone 40 mg on days one, eight, 15, and 22 of each cycle in 28-day cycles.

Dexamethasone doses were reduced to 20 mg in patients over 75 years of age at time of randomization. Treatment was continued for either 18 cycles or until the occurrence of progressive disease or unacceptable toxicity. Response was assessed every cycle until disease progression, or every four weeks in patients who stopped treatment before progression occurred.

The median ages of patients in the ixazomib-Rd and placebo groups were 73 and 74 years, respectively, and 38.2% and 41.2% of patients in the triplet and placebo group had high-risk cytogenetic abnormalities. At time of data cutoff, a total of 54 patients in the ixazomib-Rd arm and 57 patients in the placebo arm were continuing to receive treatment.

After a median follow-up of 53.3 months in the ixazomib-Rd group and 55.8 months in the placebo group, the researchers observed a slightly longer median PFS in patients who received ixazomib: 35.3 vs. 21.8 months (hazard ratio [HR] = 0.830; p=0.073).

This PFS benefit with ixazomib was also observed in patients with high-risk cytogenetics (23.8 vs. 18.0 months; HR=0.690; p=0.019), but not in patients younger than 75 years (41.4 vs. 26.2 months; HR=0.799; p=0.106) or in patients with CrCl >60 mL/min (31.8 vs. 30.8 months; HR=0.992; p=0.955).

The ixazomib combination led to higher response rates, as well, including rates of complete response (25.6% vs. 14.1%; p<0.001) and very good partial response or better (63.0% vs. 47.7%; p<0.001). The median time to response was also lower in patients treated with the triplet combination (1.0 vs. 1.9 months; HR=1.402; p<0.001). The median duration of response was 50.6 months in the ixazomib-Rd arm, compared with 37.5 months in the placebo group.

A total of 112 patients in the ixazomib-Rd arm and 141 patients in the placebo arm had disease relapse or progression or had died by the time of data cutoff. Overall, 88.1% of patients in the ixazomib-Rd group and 81.4% of patients in the placebo arm experienced grade ≥3 or higher treatment-emergent adverse events (TEAEs), while 65.8% versus 62.5% experienced serious TEAEs. TEAEs led to treatment discontinuation in 35.0% of the ixazomib group and 26.9% of the placebo group.

The study investigators concluded that the all-oral ixazomib combination could provide an alternative regimen and lower the treatment burden for this patient population, which “is highly diverse, comprising patients of widely differing fitness and age who often have limited mobility and reduced ability to frequently attend clinic or hospital.”

According to the authors, a limitation of this study was the reliance on a stratified log-rank test for the primary PFS analysis.

Study authors report no relevant conflicts of interest.


Facon T, Venner C, Bahlis N, et al. Oral ixazomib, lenalidomide, and dexamethasone for newly diagnosed transplant- ineligible multiple myeloma patients. Blood. 2021 March 24. [Epub ahead of print]

“In the TOURMALINE-MM2 trial, it is notable that the PFS curves for the control arm did not start to split from the experimental arm until around 25% of patients had progressive disease. What that tells us is that somewhere around 25% to approximately 30% of patients who receive ixazomib derive no significant benefit from the therapy at all. I think it’s important to determine the patients who will benefit from the addition of ixazomib to Rd. We don’t yet have a biomarker that can truly tell us the difference between a patient best suited for ixazomib and a patient who isn’t.

At Emory, we are in the process of looking for clinical and biologic features that can serve as a biomarker for sensitivity to ixazomib prior to initiation of therapy in a phase II study (NCT02765854) of 90 patients with relapsed/refractory MM. The study will specifically examine how well ixazomib-Rd works based on the presence of the rearrangement of NFKB2.”

Jonathan Kaufman, MD
Emory University School of Medicine
Atlanta, Georgia