Multiple myeloma with ≥1% circulating plasma cells in peripheral blood has a poor prognosis

Abstract Introduction Plasma cell leukemia (PCL) is a rare and aggressive form of plasma cell dyscrasia, historically defined in 1974 as the presence of ≥20% circulating plasma cells (CPCs) and an absolute count of ≥2,000/μL in peripheral blood. The International Myeloma Working Group (IMWG) updated the diagnostic definition of primary PCL in 2021, reducing the CPC threshold to ≥5% based on equivalent survival outcomes compared to ≥20%. Recent studies suggest that even lower levels of CPCs (≥2%) may confer poor prognosis in newly diagnosed multiple myeloma (NDMM). To further clarify the prognostic implications of low-level CPCs, we investigated whether morphologically identified CPCs ≥1% are associated with inferior outcomes in NDMM, aiming to assess whether such cases might warrant consideration in future revisions of PCL diagnostic criteria. Methods We retrospectively analyzed 854 NDMM patients diagnosed between 2017 and 2023 and registered in the North Japan Hematology Study Group database. CPCs were morphologically assessed at diagnosis using peripheral blood smears. The study procedures were conducted in accordance with the Helsinki Declaration and institutional ethical guidelines and were approved by the institutional review boards. Results Among 854 patients from 15 facilities, peripheral blood smears were evaluable in 829. Patients with CPCs ≥1% and 1% were observed in 77 (9.3%) and 752 (90.7%), respectively. Median age was 72 years (range, 30–94), with no difference between groups (p=0.20). The ≥1% CPCs group exhibited significantly worse baseline characteristics compared to the 1% group: lower hemoglobin (8.15 vs 9.58 g/dL, p0.001), higher serum creatinine (1.89 vs 1.58 mg/dL, p0.001), more frequent elevated LDH (48.1% vs 22.6%, p0.001), higher β2-microglobulin levels (13.5 vs 7.5 mg/L, p0.001), more frequent high-risk cytogenetics t(4;14), t(14;16), or del(17p) (39.0% vs 23.8%, p=0.004), and R2-ISS distribution skewed toward higher stages (p=0.002). Both groups showed the highest proportion in stage III (37.7% and 38.7%, respectively). Bone lesion incidence was similar (48.1% vs 45.3%, p=0.74). Induction regimens were comparable between groups; bortezomib- or daratumumab-based doublet/triplet regimens were most commonly used. Upfront autologous stem cell transplantation (ASCT) after induction therapy without regimen change occurred in 19.4% vs 17.2%, respectively. Few patients in either group received CAR-T cell therapy (1 1.3% vs 4 0.5%) or bispecific monoclonal antibodies (4 5.2% vs 12 1.6%). Median overall survival (OS) was 37.9 vs 98.7 months in the ≥1% and 1% CPCs groups, respectively, with 5-year OS of 36.5% vs 65.1%; the ≥1% CPCs group had significantly inferior OS (p0.0001). In multivariate analysis, ≥1% CPCs was independently associated with inferior OS (hazard ratio HR 2.39, 95% CI 1.65–3.45, p0.001) after adjusting for age, renal function, R2-ISS stage III-IV, and t(11;14). Restricted cubic spline analysis demonstrated that mortality risk increased steeply up to approximately 1% CPCs, beyond which the risk plateaued. In the overall cohort, R2-ISS stage III was associated with better prognosis than stage IV (p0.01); however, patients with stage III and ≥1% CPCs had outcomes comparable to stage IV (p=0.625) and significantly worse than stage III with 1% CPCs. Among patients with CPCs ≥1%, those who underwent upfront ASCT showed improved prognosis compared to those who did not (median OS: not reached vs 33.6 months, p=0.048). Although relatively few patients with ≥1% CPCs achieved complete response (CR) or minimal residual disease (MRD) negativity, those who did showed outcomes comparable to patients with 1% CPCs achieving these endpoints (median OS: not reached vs not reached, p=0.19). Conclusion Morphologically identified ≥1% CPCs in peripheral blood confers significantly increased mortality risk in NDMM patients. The mortality risk plateaus beyond this threshold, suggesting 1% CPCs may represent a clinically meaningful cutoff for risk stratification. Upfront ASCT following successful induction therapy remains a key therapeutic approach for patients with CPCs ≥1%. Achieving CR or MRD negativity provides meaningful prognostic benefit regardless of CPC status, underscoring the importance of novel therapeutic approaches including CAR-T cell therapy and bispecific monoclonal antibodies in this high-risk population.