Fernández de Larrea C, Kyle R, Rosiñol L, et al. Primary plasma cell leukemia: consensus definition by the International Myeloma Working Group according to peripheral blood plasma cell percentage. Blood Cancer J. 2021;11(12):192.

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.

The new definition of pPCL will aide in increasing awareness for the diagnosis of PCL and subsequent treatment adaptation. Conventional cytology used for the new definition of pPCL is a simple and inexpensive technique that is available worldwide without significant economic or technological constraints. However, additional methods to detect early pPCL warrant further investigation. Moreover, there remains an urgent need to prospectively investigate molecular characteristics of PCL to better understand the genomic mechanisms, as a basis to develop optimal, enrichment design trials for this area of unmet clinical need.

Dr. Tan and Dr. Usmani indicated no relevant conflicts of interest.

1.
Kyle
RA
,
Maldonado
JE
,
Bayrd
ED
.
Plasma cell leukemia. Report on 17 cases
.
Arch Intern Med
.
1974
;
133
(
5
):
813
818
.
2.
Noel
P
,
Kyle
RA
.
Plasma cell leukemia: an evaluation of response to therapy
.
Am J Med
.
1987
;
83
(
6
):
1062
1068
.
3.
International Myeloma Working Group
.
Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group
.
Br J Haematol
.
2003
;
121
(
5
):
749
757
.
4.
Dimopoulos
MA
,
Palumbo
A
,
Delassalle
KB
, et al
.
Primary plasma cell leukaemia
.
Br J Haematol
.
1994
;
88
(
4
):
754
759
.
5.
Usmani
SZ
,
Nair
B
,
Qu
P
, et al
.
Primary plasma cell leukemia: clinical and laboratory presentation, gene-expression profiling and clinical outcome with Total Therapy protocols
.
Leukemia
.
2012
;
26
(
11
):
2398
2405
.
6.
Katodritou
E
,
Terpos
E
,
Delimpasi
S
, et al
.
Real-world data on prognosis and outcome of primary plasma cell leukemia in the era of novel agents: a multicenter national study by the Greek Myeloma Study Group
.
Blood Cancer J
.
2018
;
8
(
3
):
31
.
7.
Mina
R
,
Joseph
NS
,
Kaufman
JL
, et al
.
Survival outcomes of patients with primary plasma cell leukemia (pPCL) treated with novel agents
.
Cancer
.
2019
;
125
(
3
):
416
423
.
8.
Granell
M
,
Calvo
X
,
Garcia-Guiñón
A
, et al
.
Prognostic impact of circulating plasma cell sin patients with multiple myeloma: implications for plasma cell leukemia definition
.
Haematologica
.
2017
;
102
(
6
):
1099
1104
.
9.
Ravi
P
,
Kumar
SK
,
Roeker
L
, et al
.
Revised diagnostic criteria for plasma cell leukemia: results of a Mayo Clinic study with comparison of outcomes to multiple myeloma
.
Blood Cancer J
.
2018
;
8
(
12
):
116
.
10.
Nandakumar
B
,
Kumar
SK
,
Dispenzieri
A
, et al
.
Clinical characteristics and outcomes of patients with primary plasma cell leukemia in the era of novel agent therapy
.
Mayo Clin Proc
.
2021
;
96
(
3
):
677
687
.