Blood cancers

Ixazomib a valuable maintenance option in newly-diagnosed MM


Dr Hang Quach

Ixazomib is a novel induction-agnostic maintenance option for transplantation-ineligible patients with newly diagnosed multiple myeloma, a study suggests.

The drug is a second generation proteasome inhibitor (PI) and the only one that can be taken orally. And according to results from the phase III TOURMALINE-MM4 trial, it significantly lowered the risk of disease progression compared to placebo when used as single-agent maintenance therapy for patients with newly diagnosed multiple myeloma ineligible for stem cell transplantation.

The study of 706 participants is the first to investigate ixazomib –  as maintenance therapy after best response to any standard-of-care induction.

Results published in the Journal of Clinical Oncology showed that patients taking the weekly tablet had a 34% relative risk reduction in progression or death compared to placebo. Progression free survival (PFS), the primary endpoint, was significantly longer in the ixazomib arm, with a median of 17.4 months compared with 9.4 months with placebo (hazard ratio [HR], 0.66; 95% CI, 0.54-0.80; P <.001) over a median follow-up of 21.1 months.

The PFS benefit was seen across all subgroups, including preinduction ISS stage, age, prior PI exposure, prior immunomodulator drug (IMiD) exposure, and frailty.

“To our knowledge, ixazomib is the first induction-agnostic maintenance option investigated for transplantation-ineligible patients with NDMM and represents a valuable treatment option in this setting,” the study authors concluded.

Associate Professor Hang Quach, Director of Haematology Clinical Trials at St Vincent’s Hospital, Melbourne, and a lead investigator on the trial told the limbic the ‘induction agnostic’ maintenance regimen was both convenient and well-tolerated among the mostly elderly cohort, which had a median age of 73. Meanwhile ISS stage III disease was present in 35% of patients, and 17% had high risk cytogenetics.

“It’s one tablet per week taken for 28-day cycles as maintenance for 24 months, so it’s incredibly convenient and very suitable for maintenance therapy because it doesn’t interfere with your quality of life – patients don’t have to go into hospital,” says Professor Quach adding that, unlike other PIs, there are no notable cumulative side effects associated with ixazomib taken long-term.

“Unlike the first generation PI bortezomib there is less associated peripheral neuropathy and unlike the second-generation PI carfilzomib, which is given intravenously, it doesn’t have any cardiac issues.”

A majority of patients experienced grade 1 to grade 2 treatment-emergent adverse events (TEAEs). Discontinuation due to TEAEs occurred in 13% of patients in the ixazomib arm and 8% of patients in the placebo arm. Common TEAEs that occurred more frequently with ixazomib compared with placebo included nausea, vomiting, and diarrhoea.

Agreeing that most TEAEs were ‘very mild’, Professor Quach also pointed out that patient reported quality of life scores remained stable over the duration of the trial.

“The patient’s quality of life did not decline with ongoing treatment indicating no cumulative side-effects or no cumulative adverse effects to quality of life.”

Ixazomib is currently approved for use in combination with lenalidomide and dexamethasone in previously treated multiple myeloma patients. Meanwhile maintenance therapy is currently limited to lenalidomide – but use of the IMiD in this setting is only approved following lenalidomide-based induction therapy.

Professor Quach says the current trial should pave the way for an alternative option – which is important because not all patients will tolerate the IMiD.

“Lenalidomide maintenance is generally well tolerated but there are cumulative intolerances – up to 20-30% of patients actually stop treatment with it because of side-effects like progressive cytopenia, marrow hypoplasia, rash and renal impairment. That’s a limiting factor long-term and in those situations ixazomib offers a very viable alternative choice.”

She adds: “The most important treatment is first-line followed by second and third line  because not many people live long enough to reach fourth line treatment. So every effort has to be made to give the best treatment options upfront – you get your best shot first go and that’s why maintenance therapy is so important.”

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