Hematogenous extramedullary relapse in multiple myeloma ‐ a multicenter retrospective study in 127 patients

Avivi, Irit; Cohen, Yaël; Suska, Anna; Shragai, Tamir; Mikala, Gábor; Garderet, Laurent; Seny, Gueye M; Glickman, Sophia; Jayabalan, David; Niesvizky, Rubén; Gozzetti, Alessandro; Wiśniewska-Piąty, Katarzyna; Waszczuk‐Gajda, Anna; Usnarska−Zubkiewicz, Lidia; Hus, Iwona; Guzicka, Renata; Radocha, Jakub; Milunović, Vibor; Dávila, Julio C.; Gentile, Massimo; Castillo, Jorge J.; Jurczyszyn, Artur

doi:10.1002/ajh.25579

Cited by 24 publications

(18 citation statements)

References 35 publications

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“…At the beginning, patients with EMD may respond to the initial treatment of bortezomib and other new drugs, but they may not avoid the development of escape of apoptosis and therapeutic resistance. Furthermore, they tend to acquire a more aggressive disease in later stages ( 24 , 25 ), which is consistent with the clinical treatment response observed in the real world.…”

Section: Discussionsupporting

confidence: 83%

Serum Abnormal Metabolites for Evaluating Therapeutic Response and Prognosis of Patients With Multiple Myeloma

et al. 2022

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AimsTo evaluate abnormal metabolites related to treatment response and prognosis of multiple myeloma (MM) patients through ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS).MethodsForty-six symptomatic MM patients were included in this study who had a prior high level of positive monoclonal proteins before receiving targeted therapy with bortezomib-based regimens. UPLC-MS along with traditional immunofixation was performed on MM diagnostic samples and effective serum samples, and UPLC-MS was used to target valuable metabolic markers related to M protein.MM patients were segregated into pre-therapy (pre-T) and post-therapy (post-T) groups according to the response after chemotherapy. A monoclonal protein could be detected at baseline in 33 newly diagnosed MM (NDMM), 13 refractory and relapsed MM (RRMM) patients and 20 healthy controls (HC) by immunofixation.ResultsBetween pre-T and post-T patients, the data showed that 32, 28 and 3 different metabolites were significantly correlated with M protein in IgG, IgA and light chain-type MM, respectively. These identified metabolites were significantly enriched in arginine and proline metabolism as well as glycerophospholipid metabolism pathways. Among them, PC (19:0/22:2) was displayed to increase significantly and consistently with M protein in each subtype of MM after treatment, which obviously indicated that it was related to the treatment response of MM. Further survival analysis of metabolic markers found that aspartic acid, LysoPE (16:0), SM (d18:1/17:0), PC (18:0/24:1), PC (16:0/16:0), TG (18:1/18:1/22:5) and LysoPE (18:2) reaching a certain cutoff value may be associated with shorter progression free survival (PFS). Finally, Cox multivariate regression analysis identified three factors were independent prognostic factors of MM. Moreover, there were significantly different in PC (19:0/22:2) and in aspartic acid between MM patients and healthy people.ConclusionThis work identified significant metabolic disorders in 46 pairs off pre- and post-therapy MM patients, specifically in arginine, proline and glycerophospholipid pathways. The abnormal metabolites have the potential to serve as new biomarkers for evaluating treatment response and prognosis, as well as early monitoring of disease activity. Therefore, these systematic studies on abnormal metabolites as biomarkers for diagnosis and treatment will provide the evidence for future precise treatment of MM.

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Section: Discussionsupporting

confidence: 83%

Serum Abnormal Metabolites for Evaluating Therapeutic Response and Prognosis of Patients With Multiple Myeloma

et al. 2022

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“…In our own series, the median survival of 29 patients with EMD disease at diagnosis was significantly shorter than that of 191 patients with PS plasmacytomas (1·8 vs. 3·5 years) 33 . A multicentre study of 127 patients with EMD disease also showed dismal outcome 78 . The prognosis is particularly poor in patients with CNS involvement who have a median survival of <3 months, 38,39 and even when novel agents are used outcomes to date have been dismal 41,79,80 .…”

Section: Prognosismentioning

confidence: 62%

Expert review on soft‐tissue plasmacytomas in multiple myeloma: definition, disease assessment and treatment considerations

et al. 2021

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In this review, two types of soft-tissue involvement in multiple myeloma are defined: (i) extramedullary (EMD) with haematogenous spread involving only soft tissues and (ii) paraskeletal (PS) with tumour masses arising from skeletal lesions. The incidence of EMD and PS plasmacytomas at diagnosis ranges from 1Á7% to 4Á5% and 7% to 34Á4% respectively. EMD disease is often associated with high-risk cytogenetics, resistance to therapy and worse prognosis than in PS involvement. In patients with PS involvement a proteasome inhibitor-based regimen may be the best option followed by autologous stem cell transplantation (ASCT) in transplant eligible patients. In patients with EMD disease who are not eligible for ASCT, a proteasome inhibitor-based regimen such as lenalidomide-bortezomib-dexamethasone (RVD) may be the best option, while for those eligible for high-dose therapy a myeloma/lymphoma-like regimen such as bortezomib, thalidomide and dexamethasone (VTD)-RVD/cisplatin, doxorubicin, cyclophosphamide and etoposide (PACE) followed by SCT should be considered. In both EMD and PS disease at relapse many strategies have been tried, but this remains a high-unmet need population.

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“…The presence of extramedullary myeloma, namely EMM, usually portends inferior outcomes for MM patients, even in the era of novel agents and stem cell transplantation (2,(29)(30)(31). Driven by multiple genetic and microenvironmental mechanisms, certain MM subclones are predisposed to survive outside the BM niche (5,32).…”

Section: Discussionmentioning

confidence: 99%

Intratumor Heterogeneity of MIF Expression Correlates With Extramedullary Involvement of Multiple Myeloma

Zhao

et al. 2021

Front. Oncol.

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Macrophage migration inhibitory factor (MIF) has been shown to promote disease progression in many malignancies, including multiple myeloma (MM). We previously reported that MIF regulates MM bone marrow homing and knockdown of MIF favors the extramedullary myeloma formation in mice. Here, based on MIF immunostaining of myeloma cells in paired intramedullary and extramedullary biopsies from 17 patients, we found lower MIF intensity in extramedullary MM (EMM) versus intramedullary MM (IMM). Flow cytometry and histology analysis in xenograft models showed a portion of inoculated human MM cells lost their MIF expression (MIFLow) in vivo. Of note, IMM had dominantly MIFHigh cells, while EMM showed a significantly increased ratio of MIFLow cells. Furthermore, we harvested the extramedullary human MM cells from a mouse and generated single-cell transcriptomic data. The developmental trajectories of MM cells from the MIFHigh to MIFLow state were indicated. The MIFHigh cells featured higher proliferation. The MIFLow ones were more quiescent and harbored abundant ribosomal protein genes. Our findings identified in vivo differential regulation of MIF expression in MM and suggested a potential pathogenic role of MIF in the extramedullary spread of disease.

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Hematogenous extramedullary relapse in multiple myeloma ‐ a multicenter retrospective study in 127 patients

Cited by 24 publications

References 35 publications

Serum Abnormal Metabolites for Evaluating Therapeutic Response and Prognosis of Patients With Multiple Myeloma

Serum Abnormal Metabolites for Evaluating Therapeutic Response and Prognosis of Patients With Multiple Myeloma

Expert review on soft‐tissue plasmacytomas in multiple myeloma: definition, disease assessment and treatment considerations

Intratumor Heterogeneity of MIF Expression Correlates With Extramedullary Involvement of Multiple Myeloma

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