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Ixazomib emerges as potential maintenance therapy for MM

Roshini Claire Anthony
08 Jan 2019
Professor Meletios Dimopoulos

Patients with symptomatic multiple myeloma (MM) following induction and conditioning therapy and autologous stem cell transplant (ASCT) may derive survival benefit from maintenance therapy with ixazomib, according to the phase III TOURMALINE-MM3* trial.

“Ixazomib represents a new treatment option for maintenance after transplantation,” said study author Professor Meletios Dimopoulos from the National and Kapodistrian University of Athens, Athens, Greece, who presented the findings at ASH 2018.

“This … is a very important study because it is the first placebo-controlled trial that evaluated an oral proteasome inhibitor as maintenance showing that this can improve progression-free survival [PFS] with a good safety profile … [increasing] the options of maintenance therapy for newly diagnosed patients,” said study co-author Dr Francesca Gay from the Azienda Ospedaliero-Universitaria City of Health and Science of Turin, Turin, Italy.

Participants in this multinational (167 sites in 30 countries), double-blind trial were 656 adults (median age, 57 years) with MM with a partial response following standard-of-care induction therapy plus high-dose melphalan conditioning therapy (200 mg/m2) and single ASCT within 12 months of diagnosis. They were randomized to receive oral ixazomib (3 mg for cycles 1–4, increased to 4 mg from cycle 5 if tolerated; n=395) or placebo (n=261) on days 1, 8, and 15 in 28-day cycles for 26 cycles. 

At a median 31-month follow up, ixazomib recipients had a 39 percent improvement in PFS compared with placebo recipients (median, 26.5 vs 21.3 months, hazard ratio, 0.72, 95 percent confidence interval, 0.58–0.89; p=0.0023). [ASH 2018, abstract 301; Lancet 2018;doi:10.1016/S0140-6736(18)33003-4]

“The treatment advantage of ixazomib over placebo was noticed in most of the subgroups analysed and in particular … in patients with high-risk disease that currently represent an unmet medical need,” said Gay.

Ixazomib recipients also demonstrated greater depth of response compared with placebo recipients with 43 percent of ixazomib recipients demonstrating improvement from very good partial response (VGPR) at study entry to complete response (CR) compared with 32 percent of placebo recipients, and 53 percent vs 34 percent demonstrating improvement from partial response to CR or VGPR.

The PFS benefit was observed regardless of minimal residual disease (MRD) status at study entry with a median 38.6 vs 32.5 months among ixazomib vs placebo recipients who were MRD negative at study entry and a median 23.1 vs 18.5 months among those who were MRD positive at study entry. A greater proportion of ixazomib than placebo recipients who were MRD positive at study entry converted to MRD negativity (12 percent vs 7 percent).

Median overall survival has not been reached in either arm.

Incidence of new primary malignancy was comparable between ixazomib and placebo recipients (3 percent in each group). Serious adverse events (AEs) occurred in 27 and 20 percent of ixazomib and placebo recipients, respectively, with a 7 percent vs 5 percent rate of AE-related discontinuations. There was one on-study death among ixazomib recipients and none among placebo recipients.

Common grade ≥3 AEs in the ixazomib and placebo groups were infections (15 percent vs 8 percent), gastrointestinal disorders (6 percent vs 1 percent), neutropenia (5 percent vs 3 percent), and thrombocytopenia (5 percent vs <1 percent).

“Patients tolerated therapy extremely well with very few increases in serious side effects in the ixazomib arm compared with placebo,” said study co-author Professor Vincent Rajkumar from the Mayo Clinic, Rochester, Minnesota, US.

Relapse following ASCT is almost inevitable in MM, with maintenance therapy following ASCT potentially delaying disease progression and prolonging survival, said Dimopoulos.

Although lenalidomide is approved as maintenance therapy, treatment discontinuation occurs due to treatment-emergent AEs, he said. [N Engl J Med 2012;366:1782-1791; N Engl J Med 2012;366:1770-1781] Furthermore, the heterogeneity of MM calls for more maintenance treatment options.

“Lenalidomide gives a longer PFS so it’s probably the more preferred agent,” said Rajkumar.

“Ixazomib can be considered for patients who are not able to tolerate lenalidomide or who have no access to lenalidomide or maybe some patients who have high-risk myeloma for whom lenalidomide does not work that well,” he added.

 

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Most Read Articles
Dr Margaret Shi, 13 Jul 2020

An MRI-first diagnostic pathway, combined with risk-tailored screening, is shown to improve the benefit-to-harm profile and cost-effectiveness of screening for prostate cancer (PCa), according to results of a recent lifetable modelling study presented at AACR 2020 Virtual Meeting II.

Christina Lau, 14 Jul 2020

Flat-dose nivolumab, administered as a 30-minute infusion, is well tolerated and active in Asian patients with previously treated advanced non-small-cell lung cancer (NSCLC), according to results of the phase IIIb CheckMate 870 study.

Natalia Reoutova, 17 Jul 2020

At a median follow-up of 22.9 months, atezolizumab plus carboplatin and etoposide (CP/ET), given as a first-line treatment, continued to demonstrate an improvement in overall survival (OS) vs placebo plus CP/ET in patients with extensive-stage small-cell lung cancer (ES-SCLC), according to updated results of the IMpower133 trial presented at the American Association for cancer Research (AACR) 2020 Virtual Annual Meeting II.

13 Feb 2020
At the recent National Haematology Expert Meeting 2019, a panel of experts was convened to discuss the role of targeted therapy in the management of haematological malignancies. Highlights of their lectures are summarised below.