Progression-Free Survival Improved With All-Oral Ixazomib Triplet in Newly-Diagnosed Transplant-Ineligible Myeloma


Ixazomib in combination with lenalidomide plus dexamethasone achieved a clinically meaningful improvement of 13.5 months in the median progression-free survival as treatment of elderly patients with transplant-ineligible newly diagnosed multiple myeloma.

Thierry Facon, MD

Thierry Facon, MD

Ixazomib (Ninlaro) in combination with lenalidomide (Revlimid) plus dexamethasone (Rd) achieved a clinically meaningful improvement of 13.5 months in the median progression-free survival (PFS) as treatment of elderly patients with transplant-ineligible newly diagnosed multiple myeloma, although statistical significance was not reached in the phase 3 TOURMALINE-MM2 trial (NCT01850524), according to findings presented during the 2020 ASH Annual Meeting.1

Results showed that at a median follow-up of 53.3 months for ixazomib plus Rd and a median of 55.8 months for placebo plus Rd, the median PFS was 35.3 months vs 21.8 months, respectively (HR, 0.830; 95% CI, 0.676-1.018; log-rank test P = .073).

A PFS benefit was observed across most patient subgroups analyzed, particularly in those under the age of 75 years, those with International Staging System (ISS) stage III disease, and those with a creatinine clearance of 60 mL/min or lower. A clinically meaningful, obvious positive trend was also observed for patients with expanded high-risk cytogenetic abnormalities who received the triplet vs the doublet (P = .019).

“As a whole, these data demonstrate that ixazomib, plus lenalidomide and dexamethasone is a feasible treatment option for certain transplant-ineligible patients with newly diagnosed myeloma who could benefit from an all-oral triplet combination,” Thierry Facon, MD, professor of hematology in the Department of Hematology at Lille University Hospital in Lille, France, said in a virtual presentation during the meeting.

The population of patients with newly diagnosed multiple myeloma who are not eligible for transplant is diverse; this subset can comprise patients who are fit and 70 years of age to those who are elderly and frail with a poor performance status. Thus, the need to personalize treatment to individual patient settings is important, according to Facon.

Although more favorable long-term outcomes can be achieved when proteasome inhibitors (PIs) are given in either a continuous fashion or at higher cumulative doses, the long-term administration of these drugs can be challenging in terms of tolerability and treatment burden. “In this setting, an all-oral PI/lenalidomide/dexamethasone triplet may be useful for patients who do not want to, or are unable to, travel to the clinic frequently,” said Facon.

In the international, randomized, double-blind, multicenter, phase 3 trial, investigators examined the combination of ixazomib and Rd versus placebo plus Rd in patients with newly diagnosed multiple myeloma.

To be eligible for enrollment, patients had to be eligible for Rd treatment and were not candidates for autologous stem cell transplant. Patients had to have an ECOG performance status of 0 to 2, acceptable hematologic and hepatic function, and a calculated creatinine clearance level of 30 mL/min or higher. Patients who received previous treatment for their disease, have uncontrolled cardiovascular conditions, are unable to unwilling to receive thromboembolism prophylaxis, or they have grade 2 or higher peripheral neuropathy or grade 1 with pain, were not permitted.

A total of 705 patients were enrolled to the trial and underwent screening. Participants were randomized 1:1 to either ixazomib/Rd (n = 351) or placebo/Rd (n = 354) and were stratified based on age (less than 75 years vs over 75 years), ISS disease stage at screening (I or II vs III) and Brief Pain Inventory-Short Form (less than 4 vs 4 or greater).

“Following 18 cycles of treatment, dexamethasone was discontinued and lower doses of ixazomib and lenalidomide were administered until progression or unacceptable toxicity,” noted Facon.

The primary end point of the trial was PFS in the intent-to-treat population (α =.04). The trial was also powered to evaluate PFS in 3 subgroups: those with expanded high-risk cytogenetics, those aged younger than 75 years, and those with a creatinine clearance of greater than 60 mL/min (total α =.01). Key secondary objectives comprised overall survival (OS), complete response (CR) rate, and pain response rate.

Patient demographics and disease characteristics were well balanced between the 2 treatment arms. The median age in the experimental arm was 73 years versus 74 years in the control arm with 43% vs 44%, respectively, of patients aged 75 years or older. Sixteen percent of those in the ixazomib/Rd arm had ISS stage III disease versus 17% of those in the placebo/Rd arm; 38% versus 41%, respectively, had expanded high-risk cytogenetic abnormalities, which included t(4;14), t(14;16), del(17)p, and amp(1q21).

Participants were administered a median of 20 cycles of treatment. Fifty-four percent of patients in each arm entered cycle 19, at which point lower doses of ixazomib and lenalidomide were administered and dexamethasone was discontinued.

“The use of attenuated treatment after cycle 18 limits interpretation of TOURMALINE-MM2 findings in the context of other studies and may broadly explain the shorter median PFS in the placebo/Rd arm versus that in the continuous Rd arm in the phase 3 FIRST study in which patients could continue Rd at the starting doses until disease progression,” noted Facon. “Median PFS in TOURMALINE-MM2 might have been prolonged by continuing the full-dose ixazomib and lenalidomide and/or dexamethasone for longer. However, at the time the study was designed, the tolerability of prolonged PI-based triplet therapy was unclear.”

Additional results showed that the addition of ixazomib to Rd elicited an overall response rate (ORR) of 82.1% vs 79.7% with placebo/Rd (odds ratio [OR], 1.16; 95% CI, 0.79-1.70; P = .436). The CR rates, including stringent CR, were 25.6% in the ixazomib/Rd arm vs 14.1% in the placebo/Rd arm (OR, 2.10; 95% CI, 1.43-3.09; P < .001). Moreover, the rates of very good partial response (VGPR) or better in the ixazomib/Rd and placebo/Rd arms were 63.0% vs 47.7%, respectively (OR, 1.87; 95% CI, 1.38-2.53; P < .001).

Moreover, the median time to response was 1.0 month in the investigational arm (range, 0.99-1.08) vs 1.9 months in the control arm (range, 1.15-1.87). The median duration of response with the triplet was 50.6 months (95% CI, 39.98–not estimable) vs 37.5 (95% CI, 25.69-50.27) with the doublet.

Patients who received the ixazomib regimen also experienced a longer median time to progression than those given placebo/Rd, at 45.8 months vs 26.8 months, respectively (HR, 0.738; 95% CI, 0.589-0.925; log-rank test P = .008).

At a median follow-up of approximately 58 months, the median OS had not yet been reached in either arm (HR, 0.998; 95% CI, 0.790-1.261; log-rank test P = .988).

With regard to safety, the majority of treatment-emergent adverse effects (TEAEs) reported were mostly grade 1/2 in severity. The rates of TEAEs proved to be comparable between the arms, with 88.1% vs 81.4% of patients reporting a grade 3 or higher toxicity in the ixazomib/Rd arm vs the placebo/Rd arm, respectively. Thirty-five percent vs 26.9% of patients in the investigational and control arms, respectively, experienced adverse effects that led to treatment discontinuation; 7.6% vs 6.3%, respectively, died on study.

The most common adverse effects (AEs) of any grade in the ixazomib/Rd arm included diarrhea, rash, peripheral edema, constipation, and nausea. Moreover, grade 3 or higher treatment-emergent AEs with at least a 5% rate difference between the triplet and doublet arms included neutropenia, rash, thrombocytopenia, and diarrhea, noted Facon.

“The safety data show that ixazomib plus Rd was tolerable, manageable, and that the toxicity profile was generally consistent with the well-characterized profile of ixazomib and ixazomib/Rd,” concluded Facon.


Facon T, Venner CP, Bahils N, et al. The phase 3 TOURMALINE-MM2 trial: oral ixazomib, lenalidomide, and dexamethasone (IRd) vs placebo-Rd for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Abstract 551.

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