Carfilzomib and Lenalidomide for the Treatment of Primary Plasma Cell Leukemia: Final Results of the Prospective Phase 2 EMN12/HOVON-129 Study for Patients Aged ≥66 Years

Abstract

Introduction. Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with a very poor prognosis, requiring urgent action to prevent early mortality and to control the disease and complications. The EMN12/HOVON-129 study assessed the efficacy of carfilzomib and lenalidomide as part of first-line therapy in pPCL. The trial enrolled patients (pts) aged 18 years and older, with different treatment for those 18-65 and ≥66 years. Here we report the results for pts in the age-group ≥66 years. Methods. The EMN12/HOVON-129 study is a prospective, non-randomized, phase 2, multicenter study for previously untreated pPCL pts. Inclusion criteria were newly diagnosed pPCL (in this study defined as >2x109/L circulating monoclonal plasma cells and/or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Main exclusion criteria were severe cardiac or pulmonary dysfunction and creatinine clearance <15 ml/min. There were no restrictions based on blood counts. Pts ≥66 years received induction therapy with eight 28-day cycles of carfilzomib-lenalidomide-dexamethasone (KRd; carfilzomib 20/36 mg/m2 on days 1,2,8,9,15,16; lenalidomide 25 mg on days 1-21; dexamethasone 20 mg on days 1,2,8,9,15,16,22,23), followed by maintenance with carfilzomib (27 mg/m2 on days 1,2,15,16 for the first twelve cycles; then 56 mg/m2 on days 1,15) and lenalidomide (10 mg on days 1-21/28 days) until progression. The primary endpoint was progression-free survival (PFS); secondary endpoints were response rate, overall survival (OS), and toxicity. Results. From October 2015 to August 2021, we enrolled 61 pts with pPCL: 36 aged ≤65 years and 25 aged ≥66 years. Among the 25 pts aged ≥66 years, median age was 71 years (range 66-84); 68% had bone disease; and WHO performance status was 2 in 24% and 3 in 16% of pts. Median plasma cell percentage in bone marrow biopsy was 80% (10-100). Median peripheral blood plasma cell count was 3.8x109/L (range 2.0-52); median platelet count was 142x109/L (range 13-384); and median GFR was 56 ml/min (range 24-95). Most of pts had high-risk disease features, as proved by elevated LDH in 52% and high frequency of poor-risk genetic lesions (del(17p) in 20%, t(4;14) in 4%, t(14;16) in 4%, and gain/amp(1q) in 48%). In addition, 12% of pts had extramedullary plasmacytomas. ISS stage III was present in 68% and Revised ISS stage III in 40%. At the data cut-off (July 1, 2022), among the 25 pts, 17 (68%) received the planned 8 cycles of induction treatment, achieving ≥partial response (PR) in 80%, ≥very good (VG)PR in 68%, and ≥complete response (CR) in 32% of pts. Sixteen pts (64%) received maintenance treatment. Best response on protocol was ≥PR in 80%, ≥VGPR in 68% and ≥CR in 36%; 3 out of 4 pts in CR who could be evaluated for minimal residual disease (MRD) achieved MRD negativity (10-5) by flow cytometry. With a median follow-up of 24.6 months (range 7.9-59.6), the median PFS was 13.8 months (95% CI 9.2-35.5), which was sufficient to reject our null hypothesis (median PFS=6.5 months). With 16 pts having died (8 due to disease progression, 2 unknown, 1 pneumonia, 1 sepsis, 1 systemic aspergillus infection, 1 small intestinal SPM, 1 disseminated intravascular coagulation, 1 respiratory failure due to COPD exacerbation), median OS was 24.8 months (95% CI 14-not reached [NR]; Figure). Adverse events mainly occurred during the first two cycles of KRd and decreased thereafter. Overall, 36% of pts had grade (G)3 and another 36% G4 adverse events. G3 and G4 hematologic toxicity rates were 8% and 12%, respectively. Infections (20% and 16%) and respiratory events (16% and 4%) were the most common G3 and G4 non-hematologic toxicities. Twenty-two pts (88%) discontinued protocol treatment, mainly because of progression (13 pts, 59%). Conclusions. KRd is a potent treatment strategy to control disease in pPCL pts over 65 years of age, with not negligible, but generally manageable, treatment-related toxicities. Of note, along with a significant improvement of PFS, median OS substantially doubled compared to what has been reported in recent retrospective studies and, particularly, in the only other prospective trial (with the doublet lenalidomide-dexamethasone) so far conducted in transplant ineligible, elderly pts with pPCL (Musto P et al. Leukemia. 2014;28:222-5). This trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR5350. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal