Real-World Confirmatory Analysis of the Current IMWG Diagnostic Criteria Identifies Early Transformation As Major Risk Factor in Plasma Cell Leukemia
Authors: Peter Jessica , Danhof Sophia , Zhou Xiang , Steinhardt Maximilian J. , Krippner Sven , Gebauer Anna , Reinhard Franz , Fette Georg , Ertl Maximilian , Einsele Hermann , Mersi Julia , Kortüm Martin K. , Rasche Leo , Waldschmidt Johannes 
Published: December 2024

Introduction
Plasma cell leukemia (PCL) is a genetically distinct and difficult-to-treat plasma cell disorder, which often remains underrepresented in clinical trials. To allow for timely detection and optimized treatment of PCL, the International Myeloma Working Group (IMWG) has recently adjusted the diagnostic criteria for PCL by lowering the threshold of circulating plasma cells in the peripheral blood from ≥20% to ≥5%. The goal of this study was to validate these criteria in a clinical real-world scenario and to screen for additional risk factors associated with poor prognosis.
Methods
We collected data from PCL patients at a single academic center via retrospective chart review. Survival analyses were conducted using the Kaplan-Meier method and risk parameters were identified using multivariable Cox proportional hazard modelling.
Results
A total of n=67 PCL cases were diagnosed between January 2005 and September 2023, including n=24 (36%) cases of primary and n=43 (64%) cases of secondary PCL. Median age at PCL diagnosis was 64 (range 34-82) years. PCL diagnosis was based on the ≥5% vs. ≥20% threshold in n=26 vs. n=35 patients (n=6 not reported). At time of diagnosis, 57% of the patients were ISS stage III and 21% had extramedullary disease (EMD). Patients were enriched for high-risk cytogenetics (del17p, t(4;14), t(14;16), ampl1q) and translocation t(11;14) was found in 65% of those patients tested. In first-line, 22% of patients were transplant-eligible and treated with triplet/quadruplet induction therapy followed by ASCT (19% ASCT/tandem-ASCT, 3% allo-SCT). Over the course of their disease, patients received a median of 2 lines of therapy (range 0-12) and median OS was 12.7 months (range 0.1-NR). At a median follow-up of 4.0 months after PCL diagnosis (mean 11.6 months), n=33 patients were deceased, most commonly due to PCL progression (42%) or infectious complications (40%).The OS for the ≥5-19% (8.2 months) and ≥20% (8.4 months) thresholds showed no significant difference (HR 0.9, 95% CI 0.4-1.9, P=0.81).
As expected, patients with primary PCL showed superior outcome (OS 42.8 months) when compared to those cases with secondary PCL occurring after previously treated multiple myeloma (MM, OS 3.4 months, HR 0.3, 95% CI 0.1-0.6, P=0.0002).
Shortest OS (2.6 months, n=21) was noted in those patients who developed secondary PCL within the first 36 months after MM diagnosis (defined as “early-onset” PCL), followed by “late-onset” secondary PCL (5.7 months, n=22) and primary PCL (42.8 months, n=24, P=0.0002).
In addition, we observed a trend for high-risk cytogenetics conferring shorter OS in patients aged ≥65 years at time of diagnosis (OS 5.7 vs. 55.2 months, HR 2.1, 95% CI 0.6-6.9, P=0.20), whereas high-risk cytogenetics did not negatively affect OS in younger patients (OS 16.4 months vs. NR, HR 1.6, 95% CI 0.4-5.5, P=0.52). In line with this finding, patients treated with stem cell transplant (ASCT and/or allo-SCT) had a favorable outcome (OS 22.1 months) as compared to their transplant-ineligible controls (OS 8.4 months, HR 0.6, 95% CI 0.3-1.2, P=0.14). To note, neither a high extent of bone marrow infiltration (P=0.68) nor presence of EMD (P=0.31) were associated with a statistically significant inferior OS in our univariate analysis.
Multivariate risk modelling using a Cox proportional hazard model for age ≥65 years, high-risk cytogenetics, sex and “early-onset” PCL was subsequently added and confirmed “early-onset” PCL as an independent risk factor (P=0.008) for poor OS. In contrast, multivariate hazard modelling did neither confirm high-risk cytogenetics (P=0.33) nor age (P=0.18) as independent risk factors, most likely since high-risk cytogenetics could be overcome by more intense treatment approaches in younger, transplant-eligible patients.
Conclusions
In summary, we describe here a multivariate analysis to stratify the prognostic risk of PCL patients. Our observations align with the recently revised IMWG diagnostic criteria for PCL and indicate that early transformation of MM into secondary PCL within the first 3 years of diagnosis represents an independent risk factor for short OS. Molecular analyses are ongoing to characterize the mutational landscape of these functional high-risk patients.