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Oral Triplet Regimen Including Ixazomib Inferior to Other Treatments for PFS in Newly Diagnosed MM

May 31, 2022

June 2022

Ixazomib, the first-in-class oral proteasome inhibitor, is approved for the treatment of relapsed or refractory multiple myeloma (MM) in combination with lenalidomide and dexamethasone. Researchers led by Cyrille Touzeau, MD, PhD, of Centre Hospitalier Universitaire de Nantes in France, aimed to examine an all-oral combination therapy comprising ixazomib, lenalidomide, and dexamethasone (IRD) as induction and consolidation therapy in untreated, symptomatic patients with newly diagnosed MM. Results of the phase II IFM (Intergroupe Francophone du Myelome) study were published in Haematologica.

A total of 42 transplant-eligible patients with previously untreated, symptomatic, newly diagnosed MM were enrolled in the study. Overall, the median age of the cohort was 60. Approximately 19% of patients had a high-risk cytogenetic profile.

Patients received an induction therapy, which consisted of three 28-day, oral treatment cycles of IRD. Most patients (95%) completed induction.

All patients underwent planned hematopoietic cell harvest following high-dose cyclophosphamide plus granulocyte-colony stimulating factor (G-CSF). Around 88% of patients underwent autologous hematopoietic cell transplantation (AHCT), with melphalan 200 mg/m2 used as the conditioning regimen.

Patients who didn’t progress proceeded to early consolidation therapy comprising two 28-day cycles of IRD followed by late consolidation therapy that consisted of six cycles of ixazomib and lenalidomide. Maintenance therapy with ixazomib was subsequently administered for one year.

The stringent complete response (sCR) rate at completion of extended consolidation therapy was the primary endpoint. Additional secondary endpoints were response at each step of the program, time to response, progression-free survival (PFS), overall survival (OS), and safety.

The overall response rate by the end of induction was 80%, which included 30% very good partial response and 12% complete response (CR)/sCR. In 37 patients, the sCR rate at the end of the consolidation period was 41%.

The median follow-up from the start of treatment was 62.6 months. The median time to partial response was one month, while the median time to CR was eight months.

A total of 29 patients progressed, and seven patients died due to disease progression. The median PFS was 41.8 months, and the three-year OS was 92.8%.

According to researchers, the findings related to PFS were inferior to those reported with bortezomib, lenalidomide, and dexamethasone (VRD), AHCT, and lenalidomide maintenance.

“This suboptimal efficacy can be partially explained by inferior in vitro proteasome inhibition with ixazomib in comparison with other [proteasome inhibitors],” the researchers wrote. They added that in newly diagnosed patients, ixazomib may be suitable for frail, comorbid patients who cannot tolerate bortezomib or carfilzomib-based combination regimens.

The researchers suggested that the efficacy of IRD could be improved with the addition of an anti-CD38 antibody and explained that further research is seeking to determine the safety and efficacy of IRD with anti-CD38 monoclonal antibody daratumumab in transplant-eligible patients with newly diagnosed MM.

No treatment-related deaths occurred. Nearly 17% of patients discontinued the oral triplet regimen permanently as a result of treatment-related toxicities, including one patient during the induction phase (skin rash), three during the consolidation phase (skin rash and thrombocytopenia), and three during the maintenance phase (colon cancer, thrombocytopenia, and pneumonia).

Grade 3-4 neutropenia was the most frequently reported treatment-related adverse event (AE) that occurred during induction (19%). Approximately 29% of patients reported skin rash. Neutropenia and thrombocytopenia represented the most frequent AEs during consolidation. Lung infection and thrombocytopenia were the most common AEs that occurred during maintenance.

Limitations of the study included the small sample size, as well as the inclusion of patients with a mostly standard cytogenetic risk profile, which may reduce the generalizability of the findings

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Touzeau C, Perrot A, Roussel M, et al. All-oral triplet combination with ixazomib, lenalidomide, and dexamethasone in newly diagnosed transplant-eligible myeloma patients: final results of the phase 2 IFM study 2013-06 [published online ahead of print, 2022 Feb 17]. Haematologica. doi: 10.3324/haematol.2021.280394.

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