In the Italian phase II FORTE trial reported in The Lancet Oncology, Francesca Gay, PhD, and colleagues found that induction therapy with carfilzomib, lenalidomide, and dexamethasone (KRd) produced a higher response rate vs carfilzomib, cyclophosphamide, and dexamethasone (KCd) among patients aged ≤ 65 years with newly diagnosed multiple myeloma. Additionally, the combination of carfilzomib and lenalidomide as maintenance improved progression-free survival compared to lenalidomide alone.
Francesca Gay, PhD
Study Details
In the multicenter open-label trial, 474 transplant-eligible patients were randomly assigned 1:1:1 between February 2015 and April 2017 to:
- Four 28-day induction cycles of KRd plus ASCT followed by four 28-day KRd cycles (KRd-plus-ASCT group, n = 158)
- Twelve 28-day KRd cycles (KRd12 group, n = 157)
- Four 28-day induction cycles with KCd plus ASCT followed by four 28-day KCd cycles (KCd-plus-ASCT group, n = 159).
Subsequently, 356 eligible patients stratified by treatment group were randomly assigned to maintenance with carfilzomib/lenalidomide (n = 178) or lenalidomide alone (n = 178); carfilzomib was given in 28-day cycles (for up to 2 years) and lenalidomide was given on days 1 to 21 every 28 days until disease progression or intolerance. The primary outcome measures were the proportion of patients with very good partial response or better after induction with KRd vs KCd and progression-free survival with carfilzomib/lenalidomide vs lenalidomide maintenance.
Efficacy Outcomes
Median duration of follow-up was 50.9 months (interquartile range [IQR] = 45.7–55.3 months) from the first random assignment. Very good partial response or better after induction was observed in 222 (70%) of 315 patients receiving KRd induction vs 84 (53%) of 159 patients receiving KCd induction (odds ratio [OR] = 2.14, 95% confidence interval [CI] = 1.44–3.19, P = .0002). The rate of 1-year sustained measurable residual disease negativity (10-⁵ cutoff) was higher with KRd plus ASCT (47%) vs KRd12 (35%; OR = 1.69, P = .024) and KCd plus ASCT (25%; OR = 2.72, P < .0001). Progression-free survival at 4 years from first random assignment in the intention-to-treat population was 69% with KRd plus ASCT, 56% with KRd12, and 51% with KCd plus ASCT.
Median duration of follow-up from second random assignment was 37.3 months (IQR = 32.9–41.9 months). Progression-free survival at 3 years was 75% (95% CI = 68%–82%) with carfilzomib/lenalidomide vs 65% (95% CI = 58%–72%) with lenalidomide alone (hazard ratio [HR] = 0.64, 95% CI = 0.44–0.94, P = .023).
KEY POINTS
- KRd induction significantly improved response rate vs KCd induction.
- The addition of carfilzomib to lenalidomide maintenance improved progression-free survival.
Adverse Events
During induction and consolidation, the most common grade 3 or 4 adverse events were neutropenia (13% in the KRd-plus-ASCT group, 10% in the KRd12 group, 11% in the KCd-plus-ASCT group), dermatologic toxicity (6%, 8%, 1%), and hepatic toxicity (8%, 8%, 0%). Treatment-related serious adverse events were reported in 11%, 19%, and 11% of patients, respectively, the most common being pneumonia (4%, 3%, and 3%). Adverse events led to death in 1%, 1%, and 2% of patients, respectively.
During maintenance, the most common grade 3 or 4 adverse events were neutropenia (20% in the carfilzomib/lenalidomide group vs 23% in the lenalidomide group), infections (5% vs 7%), and vascular events (7% vs 1%). Treatment-related serious adverse events occurred in 14% vs 8% of patients, most commonly pneumonia (3% vs 3%). Adverse events led to death in one patient in the carfilzomib/lenalidomide group.
The investigators concluded, “Our data show that KRd plus ASCT showed superiority in terms of improved responses compared with the other two treatment approaches and support the prospective randomized evaluation of KRd plus ASCT vs standards of care (eg, daratumumab plus bortezomib plus thalidomide plus dexamethasone plus ASCT) in transplant-eligible patients with multiple myeloma. Carfilzomib plus lenalidomide as maintenance therapy also improved progression-free survival compared with standard-of-care lenalidomide alone.”
Dr. Gay, of the Division of Haematology, University of Torino, Azienda Ospedaliero-Universitaria Citta della Salute e della Scienza di Torino, Turin, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Amgen and Celgene/Bristol Myers Squibb. For full disclosures of the study authors, visit thelancet.com.
