Study Identifies Ideal Ixazomib Triplet Regimen for Newly Diagnosed Multiple Myeloma

The triplet regimen of of ixazomib (Ninlaro), cyclophosphamide, and dexamethasone (ICd) elicited higher rates of efficacy compared with ixazomib/dexamethasone, followed by single-agent ixazomib maintenance, in patients with transplant-ineligible newly diagnosed multiple myeloma, according to updated results of the phase 2 EMN10-UNITO trial (NCT02586038). Findings were presented during the 2nd European Myeloma Network Meeting.¹

“Based on safety and efficacy data, ixazomib, cyclophosphamide, and dexamethasone [were] the most promising triplet. Ixazomib maintenance confirmed the promising data reported in the previous TOURMALINE-MM4 study,” said lead study author Roberto Mina, MD, of the myeloma unit in the Division of Hematology at the University of Torino in Italy, in a virtual presentation of the data during the meeting.

Findings showed that the median progression-free survival (PFS) was 17.9 months with the combination of ixazomib, cyclophosphamide, and dexamethasone and 12.3 months with the regimen of ixazomib, thalidomide, and dexamethasone (ITd). For patients who received ixazomib, bendamustine, and dexamethasone (IBd), the median PFS was 13.9 months; with ixazomib/dexamethasone (Id) alone, the median PFS was 10.3 months.

The 2-year PFS rates were 39%, 27%, 40%, and 31%, respectively. The 2-year overall survival rates were 75%, 78%, 89%, and 85%, respectively.

From the start of ixazomib maintenance, the overall median PFS was 15.1 months; the differences in median PFS were not significant in the intermediate-fit (HR, 0.92) and frail patients (HR, 1.14) versus fit patients. The 2-year PFS rate was 34%, which did not meet the study’s primary end point (≥ 65%).

Ixazomib is currently approved by the FDA for use in combination with lenalidomide (Revlimid) and dexamethasone as a treatment for patients with multiple myeloma who have received at least 1 prior therapy.

In the EMN10-UNITO study (n = 171), investigators evaluated ixazomib in various combinations: Id (n = 41), ICd (n = 59), ITd (n = 60), and IBd (n = 11) in transplant-ineligible newly diagnosed myeloma. All combinations were given as induction therapy followed by single-agent ixazomib maintenance therapy.

Patients enrolled on the study were at least aged 65 years and ineligible for transplant. Additional criteria for eligibility included an ECOG performance status of 0 to 2, creatinine clearance of at least 30 ml/min, and adequate bone marrow and hepatic function.

The median age was 74 years. Using the International Staging System (ISS), 24.75% of patients were stage 1, 50% stage II, and 25.5% stage III. Using the revised ISS, 31.5% of patients were stage I, 72% stage II, and 12% stage III. Chromosomal abnormalities were found in 24.25% of patients overall. More patients were fit (51.75%) compared with intermediate fit (26%), and frail (21.75%).

Ixazomib was administered at 4 mg on days 1, 8, and 15; dexamethasone at 40 mg on days 1, 8, 15, and 22; cyclophosphamide at 300 mg/m2 orally on days 1, 8, 15; thalidomide at 100 mg daily; and bendamustine at 75 mg/m2 intravenously on days 1 and 8. All induction therapies were given in 9 cycles. Ixazomib was then given as maintenance at a 4-mg dose on days 1, 8, and 15 for up to 2 years.

The primary end point was 2-year PFS rate; secondary end points were second progression–free survival, overall survival, and safety. The trial had dual stopping rules with an efficacy end point of below a very good partial response (VGPR) and a predefined toxicity related to ixazomibin 5-patient cohorts in each arm during the first 4 cycles.

The IBd and Id arms were prematurely closed due to low enrollment and high risk of inefficacy, respectively.

At a median follow-up of 27 months, results showed that a partial response or better was achieved in 57%, 75%, 84% and 64% in the Id, ICd, ITd, and IBd arms, respectively. A VGPR or better was achieved in 24% of the Id arm, 46% of the ICd arm, 48% with ITd, and 27% with IBd. Complete responses or better were achieved in 10%, 10%, 5%, and 9% with Id, ICd, ITd, and IBd, respectively (TABLE).

Minimal residual disease negativity was achieved in 10% or better, 4% or better, 10% or better, 9% or better of the Id, ICd, ITd, and IBd, respectively.

Additional data showed that after induction, the response rates were similar in fit, intermediate-fit, and frail patients at 71%, 74%, and 76%, respectively. No significant differences were noted in these groups regarding median PFS, at 14.1 months, 14.8 months and 12.2 months, respectively. Sixty percent (n = 102) of patients completed the induction phase of treatment and then proceeded to maintenance therapy with ixazomib; 18% of patients upgraded their response during maintenance. Grade 3/4 nonhematological adverse events (AEs) were highest in the ITd arm (45%) compared with the ICd (17%), IBd (36%), and Id (17%) arms. Nonhematological AEs in the induction phase occurred more often in frail patients (37%) compared with the intermediate-fit (26%) and fit (24%) patients. Frail patients also had a higher risk of treatment discontinuation (21%) vs intermediate-fit (9%) and fit patients (11%).

_Reference:

_{Mina R, Larocca A, Corradini P, et al. Ixazomib-based induction followed by single-agent ixazomib maintenance in transplant ineligible, newly diagnosed multiple myeloma patients: updated results of the EMN10-UNITO trial. Presented at: 2nd European Myeloma Network Meeting; March 3-6, 2021; virtual. Abstract P28.}