Treatment of Primary Plasma Cell Leukemia with Carfilzomib and Lenalidomide-Based Therapy: Results of the Final Analysis of the Prospective Phase 2 EMN12/HOVON-129 Study for Patients Aged 18-65 Years (2022)

Introduction. Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with a very poor prognosis. The median PFS for transplant-eligible patients (pts) is approximately 9 months. The aim of the EMN12/ HOVON-129 study was to improve the outcome of pPCL by incorporating carfilzomib and lenalidomide in induction, consolidation, and maintenance. The trial enrolled 61 pts aged 18 years and older, with different treatment for those aged 18-65 (n=36) and ≥66 years (n=25). Here we report the results of the final analysis for pts aged 18-65 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 (defined as >2x109/L circulating monoclonal plasma cells 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 of <15 ml/min. There were no restrictions based on blood counts. Pts aged 18-65 years were treated with induction therapy with four 28-day cycles of carfilzomib-lenalidomide-dexamethasone (KRd; carfilzomib 20/36 mg/m2 on days 1,2,8,9,15,16; lenalidomide 25 mg days 1-21; dexamethasone 20 mg on days 1,2,8,9,15,16,22,23). KRd induction was followed by tandem autologous stem cell transplantation (ASCT), 4 cycles of KRd consolidation, and then maintenance with carfilzomib (27 mg/m2 on days 1,2,15,16) and lenalidomide (10 mg on days 1-21/28 days) until progression. Pts who were eligible for allo-SCT, could also receive one ASCT, followed by 2 KRd consolidation cycles, reduced-intensity conditioning allo-SCT, and carfilzomib/lenalidomide maintenance. The primary endpoint was PFS, and secondary endpoints were response rate, OS, and toxicity. Results. From October 2015 till August 2021, we enrolled 36 pts with pPCL aged ≤65 years. Median age was 60 years; 67% had bone disease; and WHO performance status was ≥2 in 33% of pts. Pts had a high tumor burden with a median plasma cell percentage in BM of 80%. The median peripheral blood plasma cell count was 4.1x109/L (range 1.6-60.0); median platelet count was 111x109/L (range 20-517); and median eGFR was 54.0 ml/min (range 15.0-123). Pts had high-risk disease as evidenced by elevated LDH in 58%; and high frequency of high-risk genetic lesions (del(17p) in 47%, t(4;14) in 9%, t(14;16) in 19%, gain/ampl(1q) in 61%). Two or more high-risk cytogenetic abnormalities were present in 38%. The frequency of t(11;14) was 26%. In addition, 17% of pts had extramedullary plasmacytomas. ISS stage 3 was present in 64%, and revised ISS stage 3 in 50%. Response to induction was ≥PR in 72%, ≥VGPR in 64%, and ≥CR in 14%. Twenty-four pts (67%) received high-dose melphalan (HDM)/ASCT; 12 pts (33%) underwent a second course of HDM/ASCT; and 5 (14%) received allo-SCT after first HDM/ASCT. Eighteen pts (50%) received maintenance treatment. Best response on protocol was ≥PR in 83%, ≥VGPR in 81% and ≥CR in 50%; 10 (28%) pts achieved MRD-negative (10-5) CR. With a median follow-up of 40.8 months (range 8-2-74.5), the median PFS was 15.5 months (95% CI 9.4-38.4), which was sufficient to reject our null hypothesis (median PFS=9 months). With 19 pts having died (14 due to disease progression, 4 due to infections, and 1 due to cardiac disorder), median OS was 28.4 months (95% CI 15.1-not reached). In exploratory analyses, the presence of elevated LDH, t(14;16), and del(17p) were associated with both inferior PFS and OS. For patients who underwent first HDM/ASCT, median PFS and OS were 32.9 and 34.1 months from date of ASCT, resp. Adverse events mainly occurred during the first cycle of KRd, and decreased thereafter. Overall, grade ≥3 adverse events were observed in 67% of pts, including infections (25%) and cardiovascular disorders (14%). One patient developed a second primary malignancy (MDS). As of July 24 2022, 25 pts (69%) pts discontinued protocol treatment, mainly because of progression, but none because of treatment-related toxicity. Conclusions. KRd induction provides efficient and rapid disease control, which allows two-thirds of pts to undergo a first course of HDM/ASCT. Toxicity occurred mainly during the first cycle of induction, and was manageable with appropriate interventions. However, median PFS and OS remain low in pPCL, compared to MM. This trial was registered at https://trialsearch.who.int as NTR5350 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal