Primary Plasma Cell Leukemia: Recent Advances in Molecular Understanding and Treatment Approaches

Abstract

Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell dyscrasia. According to revised diagnostic criteria, pPCL is defined by the presence of ≥5% circulating plasma cells (CPCs) in the peripheral blood of patients with newly diagnosed multiple myeloma (NDMM). pPCL is characterized by a distinct cytogenetic profile, including frequent t(11;14), MAF/MAB translocations, 1q gain, and del(17p). While t(11;14) is generally associated with a favorable prognosis, the coexistence of multiple high-risk cytogenetic abnormalities is linked to poorer outcomes. Tandem autologous hematopoietic stem cell transplantation and novel anti-myeloma agents have improved survival in some patients; however, overall prognosis remains poor, particularly in those ineligible for transplantation. Venetoclax and emerging immunotherapies, such as CAR-T cells and bispecific antibodies, show promise and merit clinical trials focused on pPCL-enriched cohorts. Additionally, recent findings associating even minimal CPCs with adverse outcomes in NDMM support broader inclusion criteria in future trials. A deeper understanding of pPCL's molecular pathology is critical for the development of effective targeted therapies. This article reviews recent advances in the molecular understanding of and treatment strategies for pPCL.

Keywords: 14); CAR-T; bispecific antibodies; circulating plasma cells; plasma cell leukemia; t(11; venetoclax.

Figure 1

A schematic diagram showing the relationship between CPC levels and overall survival in NDMM. In NDMM, even low CPC levels are a poor prognostic factor. CPC is a continuous variable, and survival rates decrease as the proportion of CPCs increases. Currently, patients with CPCs of 5% or more are defined as pPCL. CPC, circulating plasma cell; NDMM, newly diagnosed multiple myeloma; pPCL, primary plasma cell leukemia.

Figure 2

A schematic diagram of the proposed molecular pathology of pPCL based on chromosomal abnormalities. pPCL is classified into two types: one type that develops based on t(11;14) and another type that develops based on other factors. pPCL: primary plasma cell leukemia; PAX5: paired box protein 5; APOBEC: apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like.

Figure 3

Treatment approach for patients with newly diagnosed pPCL. CAR-T, chimeric antigen receptor T cell; BsAb, bispecific antibody; PI, proteasome inhibitor; IMiD, immunomodulatory drug; DEX, dexamethasone; ASCT, autologous hematopoietic stem cell transplantation; PD, progressive disease.