Identification of High-Risk Multiple Myeloma With a Plasma Cell Leukemia-Like Transcriptomic Profile

Abstract

PURPOSE Primary plasma cell leukemia (pPCL) is an aggressive subtype of multiple myeloma, which is distinguished from newly diagnosed multiple myeloma (NDMM) on the basis of the presence of ≥ 20% circulating tumor cells (CTCs). A molecular marker for pPCL is currently lacking, which could help identify NDMM patients with high-risk PCL-like disease, despite not having been recognized as such clinically. METHODS A transcriptomic classifier for PCL-like disease was bioinformatically constructed and validated by leveraging information on baseline CTC levels, tumor burden, and tumor transcriptomics from 154 patients with NDMM included in the Cassiopeia or HO143 trials and 29 patients with pPCL from the EMN12/HO129 trial. Its prognostic value was assessed in an independent cohort of 2,139 patients with NDMM from the HOVON-65/GMMG-HD4, HOVON-87/NMSG-18, EMN02/HO95, MRC-IX, Total Therapy 2, Total Therapy 3, and MMRF CoMMpass studies. RESULTS High CTC levels were associated with the expression of 1,700 genes, independent of tumor burden (false discovery rate < 0.05). Of these, 54 genes were selected by leave-one-out cross-validation to construct a transcriptomic classifier representing PCL-like disease. This not only demonstrated a sensitivity of 93% to identify pPCL in the validation cohort but also classified 10% of NDMM tumors as PCL-like. PCL-like MM transcriptionally and cytogenetically resembled pPCL, but presented with significantly lower CTC levels and tumor burden. Multivariate analyses in NDMM confirmed the significant prognostic value of PCL-like status in the context of Revised International Staging System stage, age, and treatment, regarding both progression-free (hazard ratio, 1.64; 95% CI, 1.30 to 2.07) and overall survival (hazard ratio, 1.89; 95% CI, 1.42 to 2.50). CONCLUSION pPCL was identified on the basis of a specific tumor transcriptome, which was also present in patients with high-risk NDMM, despite not being clinically leukemic. Incorporating PCL-like status into current risk models in NDMM may improve prognostic accuracy.

Circulating Tumor Cell Burden as a Component of Staging in Multiple Myeloma: Ready for Prime Time?

“…Furthermore, in patients with matched bone marrow (BM) and peripheral blood samples, CTCs had a significantly higher PCL-like transcriptomic score compared with BM plasma cells. 14 This is in line with prior data from Paiva et al, 19 who had demonstrated CTCs to have higher clonogenic potential compared with paired BM plasma cells. This further adds to the biological plausibility behind CTCs being an important prognostic factor in myeloma.…”

“…20 Furthermore, CTCs in myeloma are quiescent and express CD44, an antigen associated with cancer stem cells. 19,20 Hofste op Bruinink et al 14 demonstrated that genes related to cell adhesion, tumor suppression, proliferation, RNA splicing, cell migration, and DNA damage control were differentially expressed in patients with high CTC burden. Using a transcriptomic classifier, they identified 10% of patients with newly diagnosed myeloma who presented with PCL-like malignant plasma cells in blood and BM regarding transcriptional, cytogenetics, and clinical features, and had significantly worse outcomes.…”

“…12 Furthermore, the prognostic impact of CTCs was independent of fluorescent in situ hybridization cytogenetics, such that highrisk patients with low CTC burden had superior PFS compared with standard-risk patients with high CTC burden. 12,13 In contrast to the studies by Bertamini et al 13 and Garc és et al, 12 which focused on a CTC threshold for identifying patients with poor prognosis, Hofste op Bruinink et al 14 analyzed the transcriptome to biologically characterize CTCs. It is known that hypoxia and inflammation-related transcriptional programs are upregulated in CTCs, which act as a vehicle for disseminating myeloma to additional BM niche and extramedullary sites.…”

“…11 Although these preliminary results were encouraging regarding the incorporation of CTC quantification as a prognostic marker and for minimally invasive tumor burden assessment, they were plagued with significant limitations such as heterogeneity in treatments, retrospective design, and low sensitivity of flow cytometry assays used to measure CTCs. There are three articles accompanying this editorial (Garc és et al, 12 Bertamini et al, 13 and Hofste op Bruinink et al 14 ) on the prognostic impact of CTC burden and transcriptomic profile in newly diagnosed myeloma in the context of several recent randomized controlled trials. The salient features of these three studies and CTC cutoffs are summarized in Table 1.…”

“…Second, the follow-up duration in the studies by Garc és et al 12 and Bertamini et al 13 was likely insufficient for a robust assessment of the prognostic impact of high CTC burden on OS in multivariable analyses. In the article by Hofste op Bruinink et al, 14 which had pooled data from several trials with an extended follow-up, patients with newly diagnosed myeloma with transcriptomic and cytogenetic features similar to plasma cell leukemia (PCL), or PCL-like myeloma, had worse PFS in 7/8 and worse OS in 6/8 trials compared with those who did not have PCL-like myeloma. Furthermore, in patients with matched bone marrow (BM) and peripheral blood samples, CTCs had a significantly higher PCL-like transcriptomic score compared with BM plasma cells.…”