Research into risk classification of patients with multiple myeloma is gaining momentum. To this end, various scientists focus on circulating tumor cells in the blood, each with their own approach. Doctor-researcher Davine Hofste op Bruinink explains the developments.
Traditionally, newly diagnosed multiple myeloma (NDMM) has been viewed as a disease localized to the bone marrow, while primary plasma cell leukemia (pPCL) is also found in the blood. However, using newer techniques, such as flow cytometry and next-generation sequencing, it appears that most NDMM patients also have malignant plasma cells, or circulating tumor cells (CTC), in the blood. A high CTC burden – in other words having a PCL-like gene expression profile – is associated with a worse prognosis in NDMM, independent of classical risk factors. These findings may have an impact on the staging of NDMM.
Distinguish less black and white
It Journal of Clinical Oncology recently published five articles1-5an editorial6 and an ‘Oncology Grand Rounds’7 all of which go deeper into this issue. The first in this series was the article by first author physician-researcher Davine Hofste on Bruinink (Erasmus MC). “NDMM and pPCL used to be seen as 2 separate diseases,” she says. “Since the publication of Prof. Kyle in 1974, it was agreed: with less than 20% CTCs it is NDMM and above that pPCL. Thanks to the introduction of more sensitive detection methods, we now know that CTCs can be measured in almost all NDMM patients and that NDMM and pPCL are therefore not 2 separate syndromes, but are part of a continuum. High CTC levels are associated with a poorer prognosis. However, it is still unclear which cut-off value can best be used for high-risk NDMM.”
Cut-off values as a risk factor
In addition to Hofste’s article on Bruinink1 the editor discusses articles from a Spanish group2 and an Italian group3. The Spanish group found an association between progression-free survival (PFS) and CTCs in 374 NDMM patients. The researchers suggest that the presence of ≥ 0.01% CTCs may act as an independent risk factor in NDMM patients eligible for transplant. The Italian group found an association between PFS and overall survival (OS) in 401 NDMM patients. These researchers suggest a cut-off value of ≥ 0.07% CTCs as a new independent risk factor in NDMM patients.
1,700 genes
Hofste’s approach to Bruinink1 and colleagues differs from these 2 publications. “pPCL represents highly aggressive disease within MM, but no molecular marker existed yet. Within our research, we wanted to develop a classifier for a ‘PCL-like’ gene expression profile of MM cells and investigate whether this marker had independent prognostic value in the context of classical risk factors in NDMM.” For the development and validation of the classifier, the researchers, including bioinformatician Dr. Rowan Kuiper (Erasmus MC, SkylineDx), used CTC levels, tumor burden and tumor gene expression profiles of 154 NDMM patients from the Cassiopeia and HO143 trials and 29 pPCL- patients from the EMN12/HO129 trial. “We saw that CTC levels not only depended on tumor burden, but were also independently associated with the expression of 1,700 genes.”
PCL-like classifier
From this large number of genes, the researchers selected 54, which together formed the basis for a classifier for PCL-like MM. “In the validation cohort, the classifier not only showed a sensitivity of 93% for pPCL, but also classified 10% of the NDMM tumors as PCL-like,” says Hofste op Bruinink. “We then looked at the prognostic value of PCL-like status in an independent cohort of 2,139 NDMM patients from 7 different studies.” PCL-like MM patients were found to fare worse than patients without PCL-like status, also referred to as intramedullary MM (i-MM). “This was true both in univariate survival analyzes and in the context of known prognostic factors in NDMM, such as ISS/R-ISS/R2-ISS staging, high-risk FISH markers, and the SKY92 and UAMS70 gene expression classifiers.”8
Addition to known risk factors
PCL-like MM patients were similar to pPCL in terms of transcriptome and cytogenetics, but had significantly lower CTC levels and tumor burden than pPCL. The researchers also saw that the relationship between CTCs and PCL like score was not 1-to-1. “If you only look at CTCs, you will classify a different part of the patient population as high risk than on the basis of PCL-like status,” Hofste van Bruinink notes. “We hope that the PCL-like classifier will be used as a new, independent marker for high-risk NDMM to set up risk-based trials, as it is still unclear what the optimal ‘upfront’ treatment strategy is for this group of patients,” she concludes. Hofste op Bruinink will receive her PhD this year under Prof. Pieter Sonneveld for her research into MM.
References:
- Hofste Op Bruinink D, Kuiper R, Van Duin M, et al. Identification of High-Risk Multiple Myeloma With a Plasma Cell Leukemia-Like Transcriptomic Profile. J Clin Oncol. 2022;40:3132-50.
- Garcés JJ, Cedena M-T, Puig N, et al. Circulating Tumor Cells for the Staging of Patients With Newly Diagnosed Transplant-Eligible Multiple Myeloma. J Clin Oncol. 2022;40:3151-61.
- Bertamini L, Oliva S, Rota-Scalabrini D, et al. High Levels of Circulating Tumor Plasma Cells as a Key Hallmark of Aggressive Disease in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2022;40:3120-31.
- Kostopoulos IV, Ntanasis-Stathopoulos I , Rousakis P, et al. Circulating Plasma Cells in Newly Diagnosed Multiple Myeloma: Prognostic and More. J Clin Oncol. 2023;41:708-10.
- Jelinek T, Bezdekova R, Zihala D, et al. More Than 2% of Circulating Tumor Plasma Cells Defines Plasma Cell Leukemia-Like Multiple Myeloma. J Clin Oncol. 2022 Oct 31. Online ahead of print.
- Chakraborty R, Lentzsch S. Circulating Tumor Cell Burden as a Component of Staging in Multiple Myeloma: Ready for Prime Time? J Clin Oncol. 2022;40:3099-102.
- Van de Donk NWCJ. How We Manage Newly Diagnosed Multiple Myeloma With Circulating Tumor Cells. J Clin Oncol. 2022 Nov 30. Online ahead of print.
- Hofste op Bruinink, et al. ASH 2022, abstract 648.