More Than 2% of Circulating Tumor Plasma Cells Defines Plasma Cell Leukemia-Like Multiple Myeloma

Abstract

Purpose: Primary plasma cell leukemia (PCL) is the most aggressive monoclonal gammopathy. It was formerly characterized by ≥ 20% circulating plasma cells (CTCs) until 2021, when this threshold was decreased to ≥ 5%. We hypothesized that primary PCL is not a separate clinical entity, but rather that it represents ultra-high-risk multiple myeloma (MM) characterized by elevated CTC levels.

Methods: We assessed the levels of CTCs by multiparameter flow cytometry in 395 patients with newly diagnosed transplant-ineligible MM to establish a cutoff for CTCs that identifies the patients with ultra-high-risk PCL-like MM. We tested the cutoff on 185 transplant-eligible patients with MM and further validated on an independent cohort of 280 transplant-ineligible patients treated in the GEM-CLARIDEX trial. The largest published real-world cohort of patients with primary PCL was used for comparison of survival. Finally, we challenged the current 5% threshold for primary PCL diagnosis.

Results: Newly diagnosed transplant-ineligible patients with MM with 2%-20% CTCs had significantly shorter progression-free survival (3.1 v 15.6 months; P < .001) and overall survival (14.6 v 33.6 months; P = .023) than patients with < 2%. The 2% cutoff proved to be applicable also in transplant-eligible patients with MM and was successfully validated on an independent cohort of patients from the GEM-CLARIDEX trial. Most importantly, patients with 2%-20% CTCs had comparable dismal outcomes with primary PCL. Moreover, after revealing a low mean difference between flow cytometric and morphologic evaluation of CTCs, we showed that patients with 2%-5% CTCs have similar outcomes as those with 5%-20% CTCs.

Conclusion: Our study uncovers that ≥ 2% CTCs is a biomarker of hidden primary PCL and supports the assessment of CTCs by flow cytometry during the diagnostic workup of MM.

Trial registration: ClinicalTrials.gov NCT02575144.

FIG 1.

The optimal cutoff for identification of ultra-high-risk PCL-like multiple myeloma is 2% of CTCs. Kaplan-Meier curves for (A) PFS and (B) OS for transplant-ineligible patients with NDMM (N = 395); and (C) PFS and (D) OS for transplant-eligible patients with NDMM (N = 185) with < 2% (blue line) and 2%-20% (red line) of CTCs. CTC, circulating tumor plasma cell; HR, hazard ratio; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PCL, plasma cell leukemia; PFS, progression-free survival.

FIG 2.

Basic clinical characteristics and level of CTCs for the transplant-ineligible cohort: the level of CTCs, ISS stage, cytogenetic risk, LDH, sex, and median PFS. ^aSignificantly different distribution between multiple myeloma groups according to Fisher's exact test (Data Supplement). CTC, circulating tumor plasma cell; ISS, International Staging System; LDH, lactate dehydrogenase; PFS, progression-free survival.

FIG 3.

Validation of 2% cutoff on independent cohort of transplant-ineligible patients with NDMM treated in the GEM-CLARIDEX trial. Kaplan-Meier curves for PFS of transplant-ineligible patients from the GEM-CLARIDEX trial stratified according to < 2% (blue line) or 2%-20% (red line) of CTCs. CTC, circulating tumor plasma cell; NDMM, newly diagnosed multiple myeloma; PFS, progression-free survival.

FIG 4.

Patients with NDMM with 2%-20% of CTCs have comparable prognosis with pPCL. Kaplan-Meier curves for OS of (A) transplant-ineligible patients and (B) transplant-eligible patients with < 2% (blue line) and 2%-20% (red line) of CTCs together with patients with pPCL from the case series by Jurczyszyn et al (teal line). CTC, circulating tumor plasma cell; NDMM, newly diagnosed multiple myeloma; OS, overall survival; pPCL, primary plasma cell leukemia.

FIG 5.

Patients with 2%-5% display similar PFS as those with 5%-20% of CTCs. Kaplan-Meier curves for PFS of patients from the transplant-ineligible cohort merged with the patients from the GEM-CLARIDEX trial stratified according to < 2% (blue line), 2%-5% (red line), and 5%-20% (teal line). CTC, circulating tumor plasma cell; PFS, progression-free survival.