Consultant, Division of Hematology, Department of Internal Medicine Mayo Clinic, Rochester Rochester, Minnesota
Introduction: Circulating plasma cells (cPCs) are emerging as powerful biomarkers in multiple myeloma (MM), offering prognostic insight beyond traditional staging systems. Prior studies have proposed thresholds such as ≥0.01%, ≥0.02%, ≥0.07%, and ≥0.105% but a consensus cutoff remains elusive.
Methods: We retrospectively analyzed 829 NDMM patients diagnosed between 2011–2023 at Mayo Clinic who underwent peripheral blood flow cytometry prior to therapy. Patients with cPC ≥1.2% were excluded to eliminate plasma cell leukemia, based on prior studies. Six-color flow cytometry was used to detect CD45, CD19, CD38, CD138, and cytoplasmic κ/λ expression across 150,000 events. cPC% was computed relative to circulating mononuclear fractions.
Results: The cohort had a median age of 66.4 years and median follow-up of 3.4 years. Median cPC% was 0.0113% (IQR: 0.072%). We tested 505 unique cPC cutoffs for OS and 501 for PFS using maximally selected log-rank statistics. The optimal OS threshold was 0.302% (~12 cPC/μL), and for PFS, 0.025% (~1 cPC/μL), both yielding C-statistics around 0.58. Five percentage-based thresholds (≥0.01%, ≥0.02%, ≥0.07%, ≥0.1%, ≥0.3%,), two absolute cutoffs (≥1 cPC/μL, ≥12 cPC/μL), and cPC presence were compared with bootstrapping. Among evaluated thresholds, cPC ≥0.02% demonstrated the strongest prognostic performance (C-statistic for OS: 0.567, PFS: 0.565). Addition of a three-tier cPC based staging system ( < 0.02%, ≥0.02- < 0.3%, ≥0.3%) yielded the highest overall performance (C-statistic for OS: 0.576, PFS: 0.577). 0.02% cPC is established independently by 3 studies including this study as a prognostic marker. 0.3% has previously been found to correspond with 2% cPC on blood smear and is studied as a lower threshold for plasma cell leukemia.
Adding the three-tier cPC based staging improved the prognostic accuracy of multiple staging systems including ISS, RISS, R2ISS and IMWG high risk criteria (2024). ISS with cPC staging (C-statistic for OS:0.625, PFS:0.66) was comparable to R2ISS alone (OS:0.62 PFS:0.65). R2ISS with three tier staging system yielded overall best performance (OS: 0.655, PFS: 0.687). A composite R2ISS-cPC score was constructed by assigning 0.5 for cPCs ≥0.02- < 0.3% and 1 for ≥0.3%. Stages I, II, III, IV were decided as per original R2ISS staging. Incorporating the CPC levels into R2ISS increases classification into both High (from 63 to 105) and Intermediate-High (from 253 to 259) risk categories, indicating risk upstaging in a subset of patients. R2ISS-cPC IV (3.8 years) and III (7.7 years) had inferior median overall survival. (p < 0.001). This was comparable to R2ISS IV (3.4 years) and III (6.4 years) median survival. Median survival wasn’t reached in remaining two groups in both staging systems.
Conclusions: This study provides a unifying approach for cPC incorporation into current myeloma staging systems by adding new and previously established thresholds.
