Carfilzomib-Based Regimens are ‘Effective Strategies’ in Standard, High-Risk Multiple Myeloma

Carfilzomib-based induction-intensification-consolidation regimens are “effective strategies” in patients with standard-risk or high-risk multiple myeloma, but patients with ultrahigh-risk multiple myeloma “still have an increased risk of progression or death,” according to a preplanned analysis of the FORTE trial.

Roberto Mina, MD, of the University of Torino and the Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino in Italy, and colleagues conducted the research to address the “unmet medical need” of patients with newly diagnosed multiple myeloma and high-risk cytogenetic abnormalities. The prespecified analysis describes the outcomes of patients according to their cytogenetic risk.

UNITO-MM-01/FORTE was a randomized, open-label, phase II trial done at 42 Italian academic and community practice centers. The study’s investigators 477 enrolled transplant-eligible patients aged 18 to 65 years who had newly diagnosed multiple myeloma, a Karnofsky performance status of at least 60%, and had not received any previous treatment for myeloma.

The researchers stratified patients at enrollment by age and International Staging System stage. They randomly assigned patients 1:1:1 to receive lenalidomide, dexamethasone, and carfilzomib induction and consolidation plus autologous hematopoietic stem cell transplantation (AHSCT); 12 cycles of lenalidomide and dexamethasone plus carfilzomib; or carfilzomib, cyclophosphamide, and dexamethasone induction and consolidation plus AHSCT.

After consolidation, the researchers stratified patients according to induction-consolidation treatment and randomly assigned patients 1:1 to receive maintenance treatment with carfilzomib plus lenalidomide or lenalidomide alone.

One of the study’s primary endpoints was the proportion of patients with at least a very good partial response after induction with lenalidomide, dexamethasone, and carfilzomib versus those who underwent induction with carfilzomib, cyclophosphamide, and dexamethasone. The study’s other primary endpoint was progression-free survival (PFS) with carfilzomib plus lenalidomide versus lenalidomide alone as maintenance treatment.

In the preplanned analysis, the investigators included data from patients who were enrolled in the trial and had complete cytogenetic data on del(17p), t(4;14), t(14;16), del(1p), gain(1q) (three copies), and amp(1q) (four or less copies) assessed by fluorescence in situ hybridization analysis on CD138-positive sorted cells. Of the 477 patients included in the study, 83% had complete cytogenetic data and were analyzed by researchers.

They assessed PFS, overall survival (OS), minimal residual disease (MRD) negativity, and one-year sustained MRD negativity, according to the presence of zero, one, and two or more high-risk cytogenetic abnormalities across treatment groups. The median follow-up from first randomization was 51 months.

The four-year PFS rate was 71% in patients who did not have any high-risk cytogenetic abnormalities, while it was 60% in those with one high-risk cytogenetic abnormality, and 39% in patients with two or more.

Across the induction-intensification-consolidation groups, patients with one high-risk cytogenetic abnormality had a “similar” risk of progression or death to those with no high-risk cytogenetic abnormalities, according to the researchers.

Patients with two or more high-risk cytogenetic abnormalities had a significantly higher risk of progression or death than those with no high-risk cytogenetic abnormalities (hazard ratio [HR], 2.56; 95% CI, 1.74 to 3.75; P<.0001) across the treatment groups.

The risk of progression or death was also higher in patients with two or more high-risk cytogenetic abnormalities than in those with one (HR, 1.92; 95% CI, 1.34 to 2.76; P=.0004).

The four-year OS rate from the first randomization was 94% in patients without high-risk cytogenetic abnormalities, 83% in those with one high-risk cytogenetic abnormality, and 63% in those with two or more.

The risk of death was significantly higher in patients with two or more high-risk cytogenetic abnormalities than in those with no high-risk cytogenetic abnormalities (HR, 6.53; 95% CI, 3.24-13.18; P<.0001). Patients with one high-risk cytogenetic abnormality also had a significantly higher risk of death than those with none (HR, 2.55; 95% CI, 1.22-5.36; P=.013).

Furthermore, those who had two or more high-risk cytogenetic abnormalities also had a significantly higher risk of death than those with one (HR, 2.56; 95% CI, 1.53-4.28; P=.0004).

The rate of one-year sustained MRD negativity was 35% in those with no high-risk cytogenetic abnormalities, while it 41% in those with one high-risk cytogenetic abnormality, and 24% in patients with two or more.

The median follow-up duration from the second randomization was 37 months. The three-year PFS from the second randomization was 80% in patients with no high-risk cytogenetic abnormalities, 68% in those with one, and 53% in those with two or more. The risk of progression or death was higher in patients with one high-risk cytogenetic abnormality (HR, 1.68; 95% CI, 1.01-2.80; P=.048) or two or more (HR, 2.74; 95% CI, 1.60-4.69; P=.0003), than in patients with none.

The preplanned analysis of the FORTE trial showed “carfilzomib-based induction-intensification-consolidation regimens are effective strategies” in patients with standard-risk and high-risk myeloma and resulted in “similar” rates of PFS and one-year sustained MRD negativity in both risk groups, Dr. Mina and colleagues wrote.

“Despite promising progression-free survival, patients with ultrahigh-risk disease (those with two or more [high-risk cytogenetic abnormalities]) still have an increased risk of progression and death and therefore represent an unmet medical need,” the study’s authors concluded.

Reference

Mina R, Musto P, Rota-Scalabrini D, et al. Carfilzomib induction, consolidation, and maintenance with or without autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: pre-planned cytogenetic subgroup analysis of the randomised, phase 2 FORTE trial. Lancet Oncol. 2023;24(1):64-76. doi:10.1016/S1470-2045(22)00693-3