Clinical, Biological and Prognostic Characterization of Multiple Myeloma According to the Presence of Circulating Plasma Cells

Introduction: According to the updated IMWG consensus definition patients with symptomatic multiple myeloma (MM) presenting with ≥5% circulating plasma cells (cPC) by cytomorphology should be considered as having plasma cell leukemia (PCL). It is a matter of debate whether patients with cPC <5% are associated with an adverse prognosis. The objective of this study is to characterize and evaluate the prognosis of MM according to the level of cPC.

Methods: Single-center retrospective study of patients diagnosed with symptomatic MM between 2019-2022 (N=77). A blinded review of blood smears at diagnosis was performed by two experienced cytomorphologists to determine the percentage of cPC by counting a minimum of 200 nucleated cells per smear. Considering cPC, patients were separated into 3 categories: 0-1%, 2-4% and ≥5%. Clinical and biological data were collected from medical records. Twenty-seven percent of the available FISH studies were performed on purified plasma cells. Between-group comparisons were performed using Chi2, Fisher's test, Student's t-test, and Mann-Whitney U statistics. Event-free survival (EFS) defined as time to first evidence of progression or death, and overall survival (OS) were analyzed by Kaplan-Meier curves (log-rank test), using Cox regression to calculate univariate (UV) and multivariate (MV) hazard ratios (HR).

Results: The distribution of subgroups according to cPC count was: 66/77 (85.7%) cPC 0-1%, 8/77 (10.4%) cPC 2-4% and 3/77 (3.9%) cPC ≥5%. The median age of the overall cohort was 71 years (range 36-88) with no differences between groups. Male/Female ratio was similar among the cPC 0-1% (40/26) and cPC 2-4% (5/3) groups, while all patients in the latter group were female. Schemes incorporating anti-CD38 monoclonal antibodies were the most frequent therapeutic option (45%) and 36% of patients received a stem cell transplant. There were no significant differences in myeloma isotype, creatinine, albumin, and beta 2-microglobulin between categories. Compared to patients with 0-1% cPC, patients with 2-4% cPC showed lower mean hemoglobin (g/dL) (9.4 vs 11.8; P=0.003) and mean platelet count (x10⁹/L) (167 vs 235; P=0.03), presenting values close to patients with cPC ≥5% (mean hemoglobin 8.8 g/dL, mean platelet count 141 x10⁹/L). Patients with cPC 2-4% showed higher percentage of marrow infiltration quantified by various techniques when compared to the first group (P<0.006). In addition, patients with 2-4% cPC showed a higher frequency of elevated LDH when compared to 0-1% cPC category (62.5% vs 16.6%; P=0.01) being analogous to that of the ≥5% cPC group (66%). A higher percentage of patients in the 2-4% cPC group were classified as International Staging System (ISS) stage III with respect to the cPC 0-1% group (50% vs 23%), with no patients in the cPC 2-4% group being categorized as ISS stage I. Cytogenetic data revealed a significant difference in the frequency of deletion 17p with this abnormality found in 2/62, 3/8 and 2/3 of patients with assessable cytogenetics in the 0-1%, 2-4% and ≥5% cPC groups, respectively. Incorporating available cytogenetic data for the stratification of patients according to the Second Revision of the ISS (R2-ISS), a higher percentage of patients in the 2-4% cPC group were also classified as ISS-R2 stage IV with respect to the 0-1% group (4/8 vs 1/55). The median follow-up of the cohort was 28.9 months (range 0.4-63.4). Median EFS for the 0-1%, 2-4% and ≥5% cPC groups was 44.7, 13.3 months and 2.9 months (P<0.001), with median OS not reached, 21.8 and 2.9 months, respectively (P=0.051). In the UV analysis the presence of 2-4% vs 0-1% cPC was associated with worse EFS (HR 3.3, 95% CI 1.4-7.9, P=0.006) along with age >65 years, ISS II-III, deletion 17p and high-risk cytogenetics (defined as either deletion 17p or 1q gain/amplification in association with t(4;14) or del(1p32)). The presence of 2-4% cPC retained significance in the MV analysis for EFS with a HR 2.8 (1.06-7.8, P=0.03), considering the preceding variables. The only factor associated with worse OS was age with a trend towards worse OS observed for the presence of ≥5% cPC, ISS-R2 III-IV and deletion 17p.

Conclusions: This study suggests that the presence of 2-4% cPC at MM debut is associated with a more aggressive clinical presentation, an unfavorable cytogenetic profile, and an adverse prognosis. We intend to expand this cohort and further study biological variables in this group of patients.