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

Davine Hofste Op Bruinink*, Rowan Kuiper, Mark van Duin, Tom Cupedo, Vincent H J van der Velden, Remco Hoogenboezem, Bronno van der Holt, H Berna Beverloo, Erik T Valent, Michael Vermeulen, Francesca Gay, Annemiek Broijl, Hervé Avet-Loiseau, Nikhil C Munshi, Pellegrino Musto, Philippe Moreau, Sonja Zweegman, Niels W C J van de Donk, Pieter Sonneveld

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)3132-3150
Number of pages19
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume40
Issue number27
Early online date31 Mar 2022
DOIs
Publication statusPublished - 20 Sept 2022

Bibliographical note

SUPPORT:
Supported by the European Union's Horizon 2020 research and innovation program under grant agreement no. 701143, the Dutch Cancer Foundation under grant agreement no. 2010-4798, a grant from the European Myeloma Network, and unrestricted grants from Janssen and Celgene.

© 2022 by American Society of Clinical Oncology

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