Genetic Alterations in Primary and Secondary Plasma Cell Leukemia: A Comparative Study Involving Patients with Non-PCL Myeloma
Authors: Nakanishi Yoko , Suzuki Tomotaka , Kanamori Takashi , Sasaki Hirokazu , Asano Arisa , Kinoshita Shiori , Narita Tomoko , Sanda Takaomi , Ri Masaki , Komatsu Hirokazu , Iida Shinsuke 
Published: December 2024

Background: Plasma cell leukemia (PCL) occurs rarely, and its prognosis is poor. PCL comprises primary PCL (pPCL) and secondary PCL (sPCL), the latter of which arises from multiple myeloma (MM). Information on the genetic characteristics of PCLs is limited. Further research is crucial to learn more about its pathogenesis and develop effective therapies. In this study, we aimed to characterize the genetic abnormalities at the time of pPCL diagnosis and assess the genetic abnormalities associated with sPCL development at the time of MM diagnosis.
Methods: We previously conducted targeted sequencing using genomic DNA extracted from the bone marrow plasma cells of 112 patients with newly diagnosed MM between 2009 and 2018 at Nagoya City University (NCU) and NCU West Medical Center (Kanamori et al., Br J Haematol 2020). We designed a sequencing panel to detect genetic alterations in 340 genes as well as several structural variants that have been reported in MM.
Genetic evaluation of PCLs: Within Kanamori's cohort, ten patients who were originally diagnosed with MM but had peripheral blood plasma cell fractions of ≥5% were re-classified as pPCL, while the remaining 102 were classified as non-pPCL. Additionally, five patients with pPCL diagnosed at the NCU and analyzed by whole exome sequencing of initial tumor samples were also included, for a total of 15 patients with pPCL. The frequencies of genetic alterations were compared between pPCL and non-pPCL groups. Nine patients within the non-pPCL group progressed to sPCL by May 2024, defined in this study as peripheral blood with plasma cell-like lymphocytes ≥5% in two or more assessments. After excluding 28 patients who were lost to follow-up or died before confirmation of the first progressive disease, the genetic alteration patterns of 65 patients who did not develop sPCL during follow-up (defined as non-sPCL) were compared with those of patients with sPCL.
Ultra-high-risk cytogenetic abnormalities (CAs) were defined as the presence of two or more of the following: t(4;14), t(14;16), del(17p), and 1q21 gain. Fisher's exact test was used to compare the groups. Overall survival (OS) after sPCL development was assessed using the Kaplan-Meier method.
Results: In patients with pPCL (n=15), the top four frequently mutated genes were KRAS (n=7, 47%), IRF4 (n=4, 27%), NRAS (n=3, 20%), and ATM (n=3, 20%). IRF4 mutations were significantly more frequent in pPCL patients than in non-pPCL patients. In addition, t(11;14) was significantly more frequent in patients with pPCL (n=8, 53%) than in those without non-pPCL patients (n=23, 23%; P =0.024). Notably, in patients with pPCL, the IRF4 mutation was found only in patients with t(11;14).
Among the 102 non-pPCL patients, nine developed sPCL at a median of 12 months (IQR, 2-20) after MM diagnosis. The median OS after the development of sPCL was 4.5 months. The baseline genetic alterations of 9 sPCL patients were compared with those of 65 non-sPCL patients. Notably, ATM (n=3, 33% vs. n=1, 1.5%) and CYLD (n=2, 22% vs. n=0, 0%) mutations were significantly more frequent in patients with sPCL. Additionally, the frequencies of t(14;16) (n=5, 56%) and del(17p) (n=4, 44%) were significantly higher in sPCL patients. Furthermore, six of the nine patients with sPCL had ultra-high-risk CAs, which were already present at the time of MM diagnosis. Interestingly, in our overall analysis (n=117), all four patients who harbored CYLD mutations developed PCLs; two of them were diagnosed with pPCL and the other two developed sPCL.
Conclusion: This study highlights the genetic characteristics of pPCL and sPCL by comparing them with those of a non-PCL population. pPCL is enriched in patients with t(11;14) and IRF4 mutations. Although half of the pPCL patients did not harbor either of these abnormalities, indicating the heterogeneity of pPCL, our results suggest that the co-occurrence of t(11;14) and IRF4 mutations may be associated with the development of pPCL.
The majority of patients with sPCL already had ultra-high-risk CAs, most frequently t(14;16) translocations, at the time of MM diagnosis. This suggests that CAs form the basis for sPCL development. Additionally, our study indicates that ATM and CYLD mutations may play a role in the pathogenesis of both pPCL and sPCL.