Long-term follow-up of the transplant-eligible cohort of the EMN12/HOVON-129 study for primary plasma cell leukemia patients

Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder 1 , 2 . Compared to multiple myeloma (MM), pPCL is characterized by a higher frequency of poor-risk features, such as high-risk cytogenetic abnormalities (HRCAs) and elevated LDH 1 , 2 . Although MM treatment has improved, the survival of pPCL patients remains poor 1 , 2 . We therefore initiated the phase 2 EMN12/HOVON-129 study for patients with newly diagnosed pPCL, which showed that carfilzomib and lenalidomide-based therapy in conjunction with autologous stem-cell-transplantation (ASCT) provides efficient disease control 3 . Here, we present the long-term follow-up of patients aged 18–65 years included in the EMN12/HOVON-129 study. We also aimed to evaluate if patients with HRCAs, elevated LDH, or other high-risk features have a worse clinical outcome. Inclusion criteria were newly diagnosed pPCL (defined as >2 × 10 9 /L circulating plasma cells or >20% plasma cells in peripheral blood) 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. All patients gave written informed consent before inclusion. The protocol and consent documents were approved by the Research Ethics Committee of Amsterdam University Medical Center (2014.456) and the study was undertaken according to the principles of the Declaration of Helsinki and the International Conference on Harmonization Guidelines on Good Clinical Practice. All methods were performed in accordance with the relevant guidelines and regulations. Patients aged 18–65 years were treated with induction therapy with four 28-day cycles of carfilzomib-lenalidomide-dexamethasone (KRd; carfilzomib 20/36 mg/m 2 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). KRd induction was followed by tandem high-dose melphalan (HDM) and ASCT, four cycles of KRd consolidation, and then carfilzomib-lenalidomide maintenance (carfilzomib 27 mg/m 2 on days 1,2,15,16 and lenalidomide 10 mg on days 1–21) until progression or undue toxicity. Patients eligible for allogeneic-SCT could also receive 1 HDM/ASCT, followed by two KRd consolidation cycles, reduced-intensity conditioning allogeneic-SCT, and carfilzomib-lenalidomide maintenance. The primary endpoint was PFS. As exploratory analyses, we evaluated PFS and OS in subgroups based on ISS disease stage, LDH, true extramedullary disease, cytogenetic risk per original definition (del(17p), t(4;14), and/or t(14;16)), and risk per modified Consensus Genomic Staging (CGS) criteria 4 , 5 . The CGS criteria were developed to more accurately capture prognosis in the context of contemporary MM therapies 4 . In EMN12/HOVON-129, data were not collected on TP53 mutation or differentiation between monoallelic versus biallelic del(1p32), at the time of pPCL diagnosis; hence, the CGS high-risk definition was modified to the following, as previously described 5 : ≥20% del(17p); del(1p32) co-occurring with gain/amp(1q21); and t(4;14), t(14;16), and/or t(14;20) co-occurring with gain/amp(1q21) and/or del(1p32). Additional details can be found in the Supplemental Methods or were previously published 3 . A total of 36 transplant-eligible patients were included with a median age of 60 years (see Table S1 for patient and disease characteristics). Patients presented with a high tumor burden and high frequency of poor-risk features (e.g., ISS stage 3 64%, elevated LDH 58%, or presence of true extramedullary plasmacytomas 17%). In addition, 59% of evaluable patients were high-risk according to the original high-risk cytogenetic criteria and 65% were high-risk per modified CGS criteria. t(11;14) was present in 26% of evaluable patients. After KRd induction, 24 patients (67%) received HDM/ASCT, 12 (33%) underwent a second course of HDM/ASCT, and 5 (14%) received allogeneic-SCT after a first HDM/ASCT. 18 patients received maintenance with median duration of carfilzomib maintenance of 22.1 months (95% CI 12.6–34.7) and median duration of lenalidomide maintenance of 26.6 months (95% CI 17.0–52.0). At database-lock (January 29, 2025), 4 patients were still receiving maintenance treatment (Fig. 1 ). Across treatment phases, the most frequent cause of attrition was disease progression (Fig. 1 ). After a median follow-up of 73.6 months, 31 events of disease progression or death were reported. The median PFS was 15.4 months (95% CI 9.4–37.1). PFS at 5 years was 17% (95% CI, 7–30) (Fig. S1A ). Overall, 26 of 36 patients (72%) had died. Most of them (19, 73%) died from disease progression; non-relapse mortality occurred in 7 (27%) patients (none on protocol treatment, all 7 in follow-up during subsequent therapy). Reasons for non-relapse mortality after withdrawal from protocol treatment were infections ( n = 4), cardiac ( n = 1), and unknown cause of death ( n = 2). Non-relapse mortality did not occur in the allogeneic SCT cohort. Median OS was 24.7 months (95% CI 14.7–50.8). The 5-year OS rate was 28% (95% CI, 14–44) (Fig. S1B ). The best response achieved on the entire protocol was ≥PR in 86%, ≥VGPR in 83%, and ≥CR in 50%. Among the 20 patients evaluated for MRD, 16 (80%) achieved MRD negativity (10 − 5 ). For the 24 patients who underwent first HDM with ASCT, median PFS was 26.2 months (95% CI 9.4–39.1) and median OS was 34.1 months (95% CI 17.0–not reached) from the date of first ASCT, respectively. Fig. 1: Trial profile. Full size image Of the 36 patients who started induction treatment, 24 received HDM/ASCT and 12 patients did not receive HDM/ASCT (7 because of disease progression, 1 because of an adverse event, 2 patients withdrew from protocol treatment because of withdrawal of consent, and 2 patients were not fit enough for HDM/ASCT and continued with KRd treatment total of eight courses, followed by maintenance treatment). During the transplantation/consolidation stages, 8 patients went off protocol (5 because of disease progression, 1 because of an adverse event, 1 because of physician’s decision, and 1 patient was ineligible for allogeneic SCT after KRd consolidation). KRd indicates carfilzomib, lenalidomide, and dexamethasone, G-CSF granulocyte colony-stimulating factor, HDM high-dose melphalan, ASCT autologous stem cell transplantation, RIC reduced-intensity conditioning, ALLO-SCT allogeneic stem cell transplantation, and KR carfilzomib and lenalidomide. 23 of the 36 patients (64%) received second-line treatment, mostly with CD38-targeting antibody or pomalidomide-based regimens. Only 10 patients (28%) received third-line treatment (Fig. S2 ). Median PFS2 was 24.7 months (95% CI 14.7–41.3). Because outcomes were highly heterogeneous with a subset of patients surviving longer than 5 years, we analyzed whether baseline characteristics with prognostic impact in MM were of value in pPCL. Patients with HRCAs per the original definition or elevated LDH had significantly shorter PFS than those without HRCAs (HR, 3.15; 95% CI 1.35–7.37) or normal LDH (HR, 2.81; 95% CI, 1.32–6.00) (Fig. 2A, B ). Elevated LDH was also associated with shorter OS (HR, 2.66; 95% CI 1.15–6.14), while there was a trend towards decreased OS in patients with HRCAs per the original definition (HR, 2.20; 95% CI, 0.90–5.35) (Fig. 2C, D ). There was also an impaired PFS (HR, 2.99; 95% CI 1.19–7.56) and a trend for impaired OS (HR, 2.19; 95% CI 0.85–5.64) in patients with HRCAs per modified CGS criteria (Fig. S3A, C ). Of note, we observed a cumulative impact of multiple HRCAs with worst outcomes in patients with 2 or more poor-risk aberrations (Fig. S3B, D ). Presence of ISS stage 3, true extramedullary plasmacytomas, or t(11;14) was not significantly associated with PFS and OS. Baseline and treatment characteristics of patients alive and progression-free for ≥5 years are shown in Table S2 . Fig. 2: Survival outcomes according to LDH level or cytogenetic risk per original definition. Full size image A Progression-free survival (PFS) for patients with normal or elevated LDH (36 evaluable patients). B PFS for patients with high-risk disease or standard risk disease per original cytogenetic risk definition (high risk: presence of del(17p), t(4;14) and/or t(14;16); 32 evaluable patients). C Overall survival (OS) for patients with normal or elevated LDH. D OS for patients with high-risk disease or standard risk disease per original cytogenetic risk definition. N number of patients, p/d number of progression or death, and d number of death. Adverse events of grade 2 or worse that occurred during induction and consolidation were previously reported 3 . Table S3 presents an update of adverse events during maintenance. The rate of cumulative hematologic and non-hematologic toxicity grade 3 or greater during maintenance was 7/18 (39%) and 6/18 (33%), respectively. One patient developed a second primary malignancy (myelodysplastic syndrome) during subsequent pomalidomide-based therapy. Treatment discontinuation due to adverse events occurred in 3 patients (Fig. 1 ). Our long-term follow-up analysis of the EMN12/HOVON-129 study shows that continuous use of carfilzomib- and lenalidomide-based therapy was associated with improved PFS and OS, as compared with historical data 6 , 7 , 8 , 9 , 10 . Best clinical outcomes were observed in patients who received HDM/ASCT after responding to KRd induction therapy with superior PFS, compared to what has been reported in retrospective EBMT and CIBMTR studies with median PFS from ASCT of approximately 14 months 7 , 9 , 11 . This may be related to the effective carfilzomib and lenalidomide-based consolidation and maintenance to sustain remission. Despite this progress, the outcome of pPCL remains poor compared to MM, highlighting the need for new studies incorporating novel therapies, such as CD38-targeting antibodies. Of note, recent phase 2 studies (e.g., OPTIMUM and GMMG-CONCEPT) have shown that intensifying therapy before and after ASCT with CD38-targeting antibody-based combination therapy improves outcomes of patients with high-risk MM. Future pPCL studies should also evaluate the incorporation of T-cell immunotherapy into frontline treatment (e.g., CAR T-cell therapy replacing HDM/ASCT or use of T-cell-engaging bispecific antibodies in induction/maintenance). The strong association between t(11;14) translocation (common in pPCL) and response to the Bcl-2 inhibitor venetoclax supports further evaluation of venetoclax into the upfront treatment strategy in the t(11;14) subgroup. The high attrition rates across treatment lines, mainly due to death, underscore the need to use the best therapeutic option upfront. Of note, supportive care is essential to prevent treatment- and disease-related complications and mortality. In the present study, there was substantial heterogeneity in outcome. Our findings indicate that the presence of HRCAs contributes to more aggressive disease behavior in pPCL, similar to what is seen in MM. The median PFS for individuals without HRCAs was nearly 3 times longer than for patients with HRCAs (40 vs. 14 months). Similar poor outcomes were observed in high-risk subgroups per original and modified CGS criteria. Elevated LDH was also associated with markedly impaired PFS and OS. The adverse impact of HRCAs and LDH on clinical outcomes is consistent with what has been observed in retrospective studies, but interpretation of these studies is complicated by therapeutic variability and inclusion of both younger and elderly patients 12 , 13 , 14 . Improved risk stratification may contribute to the identification of subsets of patients who may particularly benefit from more intensive therapy. Patients with pPCL have a higher incidence of t(11;14) compared with MM. Data from several retrospective studies indicate that isolated t(11;14) is associated with prolonged survival, but patients with t(11;14) plus additional HRCAs have worse prognosis 12 , 13 . In our study, patients with t(11;14) had similar survival compared to patients without this abnormality, which may be explained by a relatively high frequency of concurrent HRCAs (75% per original criteria, and 88% per modified CGS criteria). The strength of our study includes the uniform treatment of young pPCL patients, use of liberal eligibility criteria, and the long follow-up duration. Although our study is among the largest prospective studies performed in pPCL, its relatively small sample size limits definite conclusions on prognostic factors in this disease. Furthermore, the sample size did not allow for multivariable modeling. Another limitation of our study, which enrolled patients between 2015 and 2021, is that pPCL was defined according to the previous IMWG criteria, while since 2021, a less restrictive definition for pPCL is used with a decrease in the cut-off for circulating tumor cells from 20 to 5% 1 . Finally, CD38-targeting antibodies were not incorporated in the treatment strategy, which is recommended in recent guidelines 15 . In conclusion, continuous carfilzomib and lenalidomide-based treatment in conjunction with ASCT improves survival in patients with newly diagnosed pPCL. However, despite this progress, the survival of patients with pPCL remains unsatisfactory, especially in patients with HRCAs or elevated LDH.