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.

Daratumumab with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma patients – real world evidence analysis

“…Interestingly, RCTs dealing with daratumumab in the front-line setting do not confirm clear benefit of daratumumab treatment in HR-CA patients [36][37][38]. This controversy only highlights necessity to consider HR-CA in a wider context of other highrisk factors, such as high LDH levels [39], extramedullary plasmacytomas [40] or circulating plasma cells [41]. Moreover, methods, such as FISH, may not reveal more complex aberrations (e.g., chromotrypsis or specific gene mutations), which have negative prognostic impact as well.…”

How We Manage Newly Diagnosed Multiple Myeloma With Circulating Tumor Cells

“…Both transplant-eligible and transplant-ineligible patients with 2%-20% CTCs had a very poor prognosis, compared with patients with < 2% CTCs. 9 The clinical outcomes of patients with 2%-20% CTCs was also compared with that of a cohort of patients with pPCL. Both PFS and OS were virtually identical between patients with 2%-20% CTCs and patients with pPCL.…”

“…Therefore, the optimal cutoff of circulating plasma cells for defining pPCL or ultra-high-risk PCL-like MM remained a matter of debate. To address this question, Jelinek et al 9 assessed the levels of CTCs by flow cytometry in a large series of patients with newly diagnosed MM who received treatment in real-world clinical practice. In their article, published in this issue of the Journal of Clinical Oncology , the authors show that approximately 4%-7% of newly diagnosed patients with MM had 2%-20% CTCs.…”

“…Diagnostic workup in patients with suspected multiple myeloma or pPCL. Classification is according to the IMWG criteria 17 with addition of the 2% threshold on the basis of the study by Jelinek et al 9 Myeloma-defining events: biomarker of malignancy (clonal BM plasma cells ≥ 60%; serum free light chain ratio ≥ 100; > 1 focal lesion on MRI [each lesion must be ≥ 5 mm in size]) or end-organ damage (hypercalcemia, renal insufficiency, anemia, and one or more lytic bone lesions [≥ 5 mm in size]). If BM has < 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal BM involvement.…”

“…6,7 Patients with high CTC levels also had a lower probability of achieving a complete response or MRD negativity, compared with those with low CTC levels. 6,7 Although adverse prognostic features such as elevated LDH, ISS stage 3, or poor risk cytogenetic abnormalities are more common in patients with high levels of CTCs, 6,7,9 the presence of elevated CTCs is an independent predictor of impaired PFS and OS. 6,7,9 In the FORTE study, the optimal CTC cutoff to stratify patients with newly diagnosed MM was 0.07%, and in the Spanish study, it was 0.01%.…”