Primary Plasma Cell Leukemia Re(de)fined

Primary plasma cell leukemia (pPCL) is an aggressive form of multiple myeloma (MM) that arises de novo in patients without a history of MM. The original diagnostic criteria of pPCL established by Dr. Robert A. Kyle and colleagues in 1974 required more than 20 percent circulating plasma cells (CPCs) and an absolute count of 2 × 10⁹/L or more plasma cells in the peripheral blood.^1-3  These criteria have provided a framework to define this disease entity and describe the poor clinical outcomes associated with it. Using the original diagnostic criteria, pPCL appears in about 1 to 4 percent of patients with newly diagnosed MM (NDMM).^4,5  pPCL has an aggressive clinical course with a high tumor burden and remains associated with a poor prognosis despite therapeutic advances gained in MM management in recent decades. Median overall survival (OS) in several studies, using the diagnostic criteria of more than 20 percent CPCs and/or more than 2 × 10⁹/L absolute plasma cells, ranged from 12 to 36 months with use of immunomodulatory agents, proteasome inhibitors, and hematopoietic cell transplantation (HCT).^5-7 

In the 2013 PCL consensus statement, the International Myeloma Working Group (IMWG) advised that the original criteria by Dr. Kyle may be too restrictive and had not been evaluated prospectively to determine the need for modifications. In many PCL series, the presence of one of the two criteria was sufficient for establishing the diagnosis.^6,7  Patients with poor bone marrow reserve and baseline leukopenia may not meet absolute count criteria but may fulfill the percentage criteria. Moreover, a low proportion of plasma cells can be detected in the peripheral blood of patients within the entire spectrum of plasma cell disorders, including NDMM, smoldering MM, and monoclonal gammopathy of undetermined significance (MGUS). The consensus statement proposed that prospective studies investigate if lower values have the same prognostic impact as the original criteria.

In this 2021 position paper, the IMWG aimed to re-evaluate the diagnostic criteria of pPCL according to the presence of CPCs in patients otherwise meeting diagnostic criteria of MM. The consensus recommendation was to define pPCL by the presence of 5 percent or greater CPCs in peripheral blood smears in patients with symptomatic MM. An experienced pathologist/hematologist should systemically analyze the peripheral blood of patients with MM by conventional microscopy with a minimum of 100 to 200 cells per smear. Moreover, patients meeting this new definition should not be routinely excluded from clinical trials; instead, 5 percent or more CPCs should be reported as a high-risk feature.

The new definition is based on findings from two large retrospective studies investigating whether lower thresholds of CPCs have the same prognostic impact as the original criteria.^8,9  Dr. Miquel Granell and colleagues presented results from patients in Catalonia, Spain between 2008 to 2013, who were classified into four categories according to the percentage of CPCs: 0 percent (382 patients; 79.2%), 1 to 4 percent (83 patients; 17.2%), 5 to 20 percent (12 patients; 2.5%), and greater than 20 percent (5 patients; 1%); there were 100 patients with 1 percent or greater CPCs.⁸  Dr. Praful Ravi and colleagues presented the Mayo Clinic's experience between 1971 to 2006, with 176 patients classified according to three categories: 1 to 4 percent (54 patients; 31%), 5 to 19 percent (63 patients; 36%), 20 percent or higher (59 patients; 34%).⁹  These cases were compared with consecutive controls during the same period in the Catalonian series (382 patients) and historical controls in the Mayo series (9,724 patients).

Morphologic examination was essential to identifying and calculating CPC percentage on peripheral blood smears. The primary outcome was OS in both studies. The more frequently used regimen in the Mayo study was cytotoxic chemotherapy without new agents (58%), while bortezomib-based regimens were used more frequently in the Catalonian series (47.7%). HCT was more frequently reported in the Catalonian series (32% vs. 20%). Median OS based on CPC categories (0%, 1-4%, 5-20%, and >20%) in the Catalonian study was 47, 50, six, and 14 months, respectively.⁸  In the Mayo series, median OS for the four groups (0%, 1-4%, 5-19%, and ³ 20%) was 53, 17, 13, and 13 months, respectively.⁹  In both series, shorter survival was observed in the groups of patients with 5 percent or more CPCs compared to less than 5 percent (1.1 vs. 4.4 years; RR, 4; 95% CI, 2.1-7.3; p<0.001 in the Catalonian series; 1.17 vs. 4.8 years; p<0.001 in Mayo series).^8,9  Prognosis in both studies was similar to outcomes reported for patients with pPCL diagnosed using the original criteria. In a separate Mayo Clinic series, time to next treatment (TTNT) and OS were similar in patients with pPCL with 5 to 19 percent CPCs, compared with 20 percent or higher (TTNT, 16 vs. 12 months; p=0.93; OS, 25 vs. 21 months; p=0.72).¹⁰ 

The IMWG panel acknowledged several limitations to this new consensus definition, including the retrospective nature of the two studies, which were not entirely comparable, as well as the scarcity of data in the literature about CPCs by morphology. There is also a lack of information in this regard on secondary PCL; the change in criteria of pPCL, in principle, is not applicable to secondary PCL, which requires further investigation.