Triplet May Improve PFS in Patients with Newly Diagnosed Multiple Myeloma

The triplet therapy of carfilzomib, lenalidomide, and dexamethasone may improve progression-free survival (PFS) when compared with lenalidomide alone in patients with newly diagnosed multiple myeloma who have undergone initial induction treatment followed by autologous hematopoietic stem cell transplantation, according to interim results from the ATLAS phase III study.

The investigator-initiated, open-label, randomized clinical study, led by Dominik Dytfeld, MD, PhD, of Poznan University of Medical Sciences in Poland, was conducted at 12 academic and clinical centers in the US and in Poland.

Between June 10, 2016 and October 21, 2020, the study’s investigators enrolled 180 patients who were randomly assigned to receive either the triplet of carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone. Patients needed to have completed transplantation after any initial pre-transplantation therapy with no progression within twelve months from the initiation of therapy.

Patients in the carfilzomib, lenalidomide, and dexamethasone arm received either eight or 36 cycles of the treatment based on the risk of disease progression and minimal residual disease (MRD) status. Patients who had standard-risk disease and achieved MRD negativity at the end of six cycles of carfilzomib, lenalidomide, and dexamethasone maintenance received a total eight cycles of the triplet followed by lenalidomide maintenance. The remaining patients continued the triplet therapy for 36 cycles followed by lenalidomide maintenance.

The primary endpoint of the study was PFS, and the secondary endpoints included MRD-negativity rates, safety, and tolerability.

The median follow-up was 33.8 months. The median PFS for the carfilzomib, lenalidomide, and dexamethasone arm was 59.1 months compared with 41.6 months for the lenalidomide arm—a 49% reduction in the risk of progression or death.

This risk reduction occurred despite a shorter duration (eight cycles) of treatment with carfilzomib, lenalidomide, and dexamethasone in 44% of patients in the triplet arm with standard risk and MRD-negativity after cycle six. The improvement of PFS was associated with a higher rate of MRD negativity in the triplet arm compared with the lenalidomide arm at the completion of six cycles (53% vs 31%).

As expected, patients treated with the triplet experienced higher rates of toxicity, but the differences did not translate into higher rates of treatment discontinuation or dose reductions, the authors noted. Based on these results, investigators concluded that MRD- and risk-adapted carfilzomib, lenalidomide, and dexamethasone can be considered as a new option for post-transplant maintenance in newly diagnosed myeloma.

“Overall, the efficacy and toxicity results of this study indicate a favorable therapeutic index, making [carfilzomib, lenalidomide, and dexamethasone] a compelling consideration for post-transplant treatment after autologous [hematopoietic] stem cell transplantation, said Andrzej Jakubowiak, MD, PhD, the Director of the Myeloma Program at the University of Chicago and the lead Principal Investigator of the ATLAS study.

According to the investigators, one limitation of the study was the low number of patients in both arms, which was sufficient to evaluate PFS, the primary endpoint of the study, but not the secondary endpoints of MRD-negativity rates, safety, and tolerability.

“This interim analysis provides support for considering carfilzomib, lenalidomide, and dexamethasone therapy in patients with newly diagnosed multiple myeloma who completed any induction regimen followed by autologous [hematopoietic] stem cell transplantation, which requires confirmation after longer follow-up of this ongoing phase [III] trial,” the investigators concluded.

Funding provided by Amgen and Celgene (Bristol Myers Squibb).

Reference

Dytfeld D, Wróbel T, Jamroziak K, et al. Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023. doi:10.1016/S1470-2045(22)00738-0