Circulating plasma cells predict the outcome of relapsed or refractory multiple myeloma

Pečeliūnas, Valdas; Janiulioniene, Ausra; Matuzeviciene, Reda; Žvirblis, Tadas; Griškevičius, Laimonas

doi:10.3109/10428194.2011.627481

Cited by 39 publications

(40 citation statements)

References 30 publications

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“…8 Interestingly, peripheral blood (PB) MM CTCs (morphologic and phenotypically defined as mature PCs) are also a common event throughout the spectrum of MM. [9][10][11][12][13] CTCs can only be detected in a small fraction of newly diagnosed MM patients (,15%) by conventional morphology.…”

Section: Introductionmentioning

confidence: 99%

“…For any single cell in each 8-color MoAb combination, this included those antigens that were measured directly on it and antigens which were not evaluated directly ("missing values") for that cell in the corresponding tube that it was contained in. Then, the calculation function of the Infinicyt software was used to fill in those "missing values," based on the "nearest neighbor" statistical principle, in a space defined by its unique position in the multidimensional space created by the 5 common (backbone) parameters 3,4,6,8,9,10,11,12,13,14,15) CTCs clustered in a unique area of the whole space occupied by their paired BM clonal PCs, whereas in the remaining cases (patients 2, 5, 7) CTCs were spread throughout the whole BM clonal PC compartment. …”

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confidence: 99%

“…[9][10][11][12][13] CTCs can only be detected in a small fraction of newly diagnosed MM patients (,15%) by conventional morphology.…”

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confidence: 99%

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Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile

Paiva

Paíno

Sayagués

et al. 2013

Blood

143

154

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Key Points• Detailed characterization of myeloma circulating tumor cells shows that these represent a unique subpopulation of BM clonal PCs.• Myeloma CTCs are clonogenic, quiescent, and may represent an ancestral clone potentially driven by circadian rhythms.Circulating myeloma tumor cells (CTCs) as defined by the presence of peripheral blood (PB) clonal plasma cells (PCs) are a powerful prognostic marker in multiple myeloma (MM). However, the biological features of CTCs and their pathophysiological role in MM remains unexplored. Here, we investigate the phenotypic, cytogenetic, and functional characteristics as well as the circadian distribution of CTCs vs paired bone marrow (BM) clonal PCs from MM patients. Our results show that CTCs typically represent a unique subpopulation of all BM clonal PCs, characterized by downregulation (P < .05) of integrins (CD11a/CD11c/CD29/CD49d/CD49e), adhesion (CD33/CD56/CD117/CD138), and activation molecules (CD28/CD38/CD81). Fluorescence in situ hybridization analysis of fluorescence-activated cell sorter-sorted CTCs also unraveled different cytogenetic profiles vs paired BM clonal PCs. Moreover, CTCs were mostly quiescent and associated with higher clonogenic potential when cocultured with BM stromal cells. Most interestingly, CTCs showed a circadian distribution which fluctuates in a similar pattern to that of CD34 1 cells, and opposite to stromal cell-derived factor 1 plasma levels and corresponding surface expression of CXC chemokine receptor 4 on clonal PCs, suggesting that in MM, CTCs may egress to PB to colonize/metastasize other sites in the BM during the patients' resting period. (Blood. 2013;122(22):3591-3598) IntroductionIn the late 2000s, 2 pivotal studies elegantly showed that monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM) in most, if not all myeloma patients. 1,2End-organ damage is the most important criterion to classify therapyrequiring MM patients, and the most common CRAB (hyperCalcemia, Renal failure, Anemia, Bone lesions) symptom is the presence of bone lesions detectable on a skeletal survey.3 Extramedullary disease is present in ;10% of newly diagnosed symptomatic patients, but it increases up to 20% in the relapse/refractory setting, 4 and typically anticipates a dismal outcome. Plasma cell (PC) leukemia is one of the most aggressive forms of the disease and even with novel drugs, the outcome is very poor with both short remission and survival rates.5 This landscape does not greatly differ from that of most solid tumors, in which the presence of metastasis is a key prognostic factor. 6 In fact, recent observations suggest that tumor cell dissemination is often an early event, 7 and the clinical sequel of circulating tumor cells (CTCs) has been the focus of extensive research. 8Interestingly, peripheral blood (PB) MM CTCs (morphologic and phenotypically defined as mature PCs) are also a common event throughout the spectrum of MM. [9][10][11][12][13] CTCs can only be detected in a small fraction of newly diagn...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile

Paiva

Paíno

Sayagués

et al. 2013

Blood

143

154

View full text Add to dashboard Cite

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“…46 Importantly, CTCs show a downregulated expression of CD38 when compared to the patients' BM plasma cells. 45 It is, therefore, at least possible that an otherwise effective anti-CD38 therapy might select for clones with an increased potential for spreading to other sites in the BM or even peripheral tissues.…”

Section: Cd38 Expression In Normal and Tumor Tissuesmentioning

confidence: 99%

“…45 Functionally, CTCs seem to be mostly quiescent, these cells are associated with a higher clonogenic potential, 45 and they seem to be more chemotherapy-resistant than conventional myeloma cells. 46 Importantly, CTCs show a downregulated expression of CD38 when compared to the patients' BM plasma cells.…”

Section: Cd38 Expression In Normal and Tumor Tissuesmentioning

confidence: 99%

Immunotherapies targeting CD38 in Multiple Myeloma

et al. 2016

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Recently, the monoclonal antibody daratumumab was approved as a single agent for the treatment of patients with relapsed/refractory Multiple Myeloma (MM). Daratumumab is an antibody targeting surface molecule CD38 on myeloma cells and the agent is already widely being used based on its good tolerability and proven efficacy. We believe, however, that the efficacy of this drug and other anti-CD38 monoclonal antibodies can be further improved by combining it with other types of immunotherapies. Furthermore, surface molecule CD38 can be used as a target for immunotherapies other than just naked monoclonal antibodies. In this report, we review the expression pattern of CD38 among normal tissues and in different types of plasma cell dyscrasias including their progenitor cells, minimal residual disease, and circulating tumor cells. We summarize the physiological role of CD38 as well as its role in the pathophysiology of MM and we present the most recent clinical trials using CD38 as a target. In addition, we highlight possible combination immunotherapies incorporating anti-CD38 monoclonal antibodies and we demonstrate alternative immunotherapeutic approaches targeting the same antigen such as CD38-specific chimeric antigen receptor (CAR) T cells.

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Single‐cell RNA sequencing reveals chemokine self‐feeding of myeloma cells promotes extramedullary metastasis

et al. 2019

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In this study, we aimed to determine the mechanisms underlying the initial extramedullary translocation of myeloma cells from bone marrow into peripheral blood. We found that clonal circulating plasma cells (cPCs) are more frequently detected by flow cytometry in extramedullary plasmacytoma (EMP) patients and worsen their prognosis. It is technically much easier to collect single cPCs using FACS than it is to perform EMP biopsy. Therefore, combining EMP imaging with cPC detection may be a promising strategy for prognostic stratification. Here, using single‐cell transcriptome analysis, we found that the chemokine CXCL12, a key molecule involved in CXCR4‐dependent cell retention in the bone marrow, is abnormally upregulated in cPCs and might initially enable cPCs to evade bone marrow retention and translocate into the bloodstream.

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Circulating plasma cells predict the outcome of relapsed or refractory multiple myeloma

Cited by 39 publications

References 30 publications

Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile

Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile

Immunotherapies targeting CD38 in Multiple Myeloma

Single‐cell RNA sequencing reveals chemokine self‐feeding of myeloma cells promotes extramedullary metastasis

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