Plasma cell neoplasia after kidney transplantation: French cohort series and review of the literature

Kormann, Raphaël; Harel, François; Moles, Thibault; Dantal, Jacques; Kamar, Nassim; Moreau, Karine; Bachelet, Thomas; Heng, Anne-Élisabeth; Garstka, A.; Colosio, Charlotte; Ducloux, Didier; Sayegh, Johnny; Savenkoff, Benjamin; Viglietti, Denis; Sberro, Rebecca; Rondeau, Éric; Peltier, Julie

doi:10.1371/journal.pone.0179406

Cited by 8 publications

(5 citation statements)

References 45 publications

(56 reference statements)

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“…Prior studies have reported a younger age of presentation of PT‐PCNs (median 56‐60 years) 41,42 compared to MM (median 68‐71 years), 53,54 although many included extraosseus plasmacytomas, which tend to occur in young patients 30 . The median age of diagnosis of PT‐PCMs in our series (68 years) was similar to MM, however, the incidence of bone disease (18%) was lower than that reported in MM (78%) 55 .…”

Section: Discussioncontrasting

confidence: 37%

“…enabled ruling out all the differential diagnostic considerations in the current study.The pathogenetic mechanisms underlying PT-PCM development have not been clarified. Most studies did not evaluate EBV infection of the neoplastic plasma cells [41][42][43]. On analysis of the Transplant Cancer Match Study data, Engels et al found 4/8 (50%) PT-PCMs with available information to be EBV+, but results of imaging studies were not provided and other sites of disease were not mentioned 8.…”

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confidence: 99%

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The clinical and pathological features of plasma cell myeloma post solid organ transplantation

et al. 2020

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Plasma cell neoplasms (PCNs), comprising plasma cell myelomas (PCMs) and plasmacytomas, which occur after solid organ transplantation, represent rare subtypes of monomorphic post-transplant lymphoproliferative disorders (M-PTLDs). Data regarding the clinical and pathological features of post-transplant (PT)-PCMs are limited. To gain a better understanding of disease biology, we performed comprehensive immunophenotypic analysis, reviewed cytogenetic analysis results and evaluated clinical outcomes of PT-PCMs diagnosed and treated at our institution. Fifteen PT-PCM (M: F-4:1) and two PT-MGUS (two males) cases were identified. The median age of PT-PCM patients was 68 years (29-79 years) and PCMs presented at a median of 9.7 years (0.5-24.7 years) after transplantation. The PT-PCMs accounted for 11.6% of all M-PTLDs and the period prevalence was 9/3108 (0.29%), 3/1071 (0.28%), 2/1345 (0.15%) and 1/878 (0.11%) post kidney, heart, liver and lung transplantation. Lytic bone disease was observed in 1/11 (9%) patients. Marrow plasma cell infiltration ranged from 10%-70% (median 20%), with 10/15 (67%) and 5/15 (33%) cases manifesting immature and plasmablastic morphology. The immunophenotype of all cases and cytogenetic abnormalities, identified in 60% of cases, were similar to multiple myeloma (MM) of immunocompetent individuals. All PT-PCMs were EBER negative. Ten of 11 (91%) patients with active MM were treated, all with proteasome inhibitor-based therapy. Treatment response and 5-year overall survival (54.5%) was comparable to MM of immunocompetent individuals. However, the survival of patients with plasmablastic PCMs was inferior to those with immature PCMs. 0ur findings indicate PT-PCMs to be predominantly late onset PTLDs that have similar clinicopathologic characteristics as conventional MM.

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Section: Discussioncontrasting

confidence: 37%

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confidence: 99%

The clinical and pathological features of plasma cell myeloma post solid organ transplantation

et al. 2020

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“…The development of cancers in general following transplantation is quite common [ 73 ]. Some studies have found a trend of lower risk of getting multiple myeloma after a kidney transplant, compared with the general population [ 74 , 75 ], whereas other studies found a higher incident of multiple myeloma following kidney transplantation [ 76 , 77 ]. Overall, it seems that giving tacrolimus to patients is safe, but that the patients might have an increased rate of infection.…”

Section: Discussionmentioning

confidence: 99%

FKBP12 is a major regulator of ALK2 activity in multiple myeloma cells

et al. 2023

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Background The immunophilin FKBP12 binds to TGF-β family type I receptors, including the BMP type I receptor ALK2. FKBP12 keeps the type I receptor in an inactive state and controls signaling activity. Removal of FKBP12 with drugs such as the FKBP-ligand FK506 enhances BMP activity in various cell types. In multiple myeloma cells, activation of SMAD1/5/8 leads to apoptosis. We hypothesized that removing FKBP12 from ALK2 in myeloma cells would potentiate BMP-induced ALK2-SMAD1/5/8 activity and in consequence cell death. Methods Multiple myeloma cell lines were treated with FK506, or other FKBP-binding compounds, combined with different BMPs before analyzing SMAD1/5/8 activity and cell viability. SMAD1/5/8 activity was also investigated using a reporter cell line, INA-6 BRE-luc. To characterize the functional signaling receptor complex, we genetically manipulated receptor expression by siRNA, shRNA and CRISPR/Cas9 technology. Results FK506 potentiated BMP-induced SMAD1/5/8 activation and apoptosis in multiple myeloma cell lines. By using FKBP-binding compounds with different affinity profiles, and siRNA targeting FKBP12, we show that the FK506 effect is mediated by binding to FKBP12. Ligands that typically signal via ALK3 in myeloma cells, BMP2, BMP4, and BMP10, did not induce apoptosis in cells lacking ALK3. Notably, BMP10 competed with BMP6 and BMP9 and antagonized their activity via ALK2. However, upon addition of FK506, we saw a surprising shift in specificity, as the ALK3 ligands gained the ability to signal via ALK2 and induce apoptosis. This indicates that the receptor complex can switch from an inactive non-signaling complex (NSC) to an active one by adding FK506. This gain of activity was also seen in other cell types, indicating that the observed effects have broader relevance. BMP2, BMP4 and BMP10 depended on BMPR2 as type II receptor to signal, which contrasts with BMP6 and BMP9, that activate ALK2 more potently when BMPR2 is knocked down. Conclusions In summary, our data suggest that FKBP12 is a major regulator of ALK2 activity in multiple myeloma cells, partly by switching an NSC into an active signaling complex. FKBP12 targeting compounds devoid of immunosuppressing activity could have potential in novel treatment strategies aiming at reducing multiple myeloma tumor load.

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“…5,10 Therefore, it is not surprising that immunodeficiency increases the risk of EBV-associated lymphoproliferative disorders. 11 EBV-positive plasma cell neoplasms are usually reported in post-transplant patients [12][13][14][15][16][17][18] and less commonly in HIV-positive patients, 3,[19][20][21][22][23] with the prevalence dramatically lower in immunocompetent individuals. 20 HIV predisposes infected individuals to many cancers, including several hematolymphoid malignancies.…”

Section: Introductionmentioning

confidence: 99%

The Prevalence of Epstein-Barr Virus in Plasma Cell Neoplasms is Higher in HIV-Positive Individuals

2022

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Aims. Epstein-Barr virus (EBV) is causally associated with many hematolymphoid malignancies. This laboratory-based study aimed to establish the prevalence of EBV in plasma cell neoplasms in a large South African cohort and to determine whether there is any correlation between EBV-positivity and human immunodeficiency virus (HIV) status in patients with plasma cell neoplasms, including plasma cell myeloma and plasmacytoma (solitary plasmacytoma of bone and extraosseous plasmacytoma). Methods. This single-institution retrospective study included all patients with a histopathologic diagnosis of plasma cell neoplasm between 2003 and 2020. EBV-expression in the plasma cell neoplasms was assessed by EBV-encoded RNA (EBER) in situ hybridization (ISH) and correlated with HIV status. HIV status was determined by retrieving prior serologic results. Formalin-fixed paraffin-embedded tissue from HIV-unknown patients underwent HIV-1 p24 antibody testing. Results. Sixteen of 89 plasma cell neoplasms (18%) were EBV-positive. There was a significant correlation between EBV and HIV infection in plasma cell neoplasms, with 6/10 tumors from HIV positive patients showing EBV-positivity in tumor cells. The EBV-positive cohort was significantly younger than the EBV-negative group. Conclusion. EBV-positivity in plasma cell neoplasms in this study is higher than previously reported. The significant occurrence of EBV in plasma cell neoplasms from HIV-positive patients suggests a co-carcinogenic relationship between the two viruses.

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Plasma cell neoplasia after kidney transplantation: French cohort series and review of the literature

Cited by 8 publications

References 45 publications

The clinical and pathological features of plasma cell myeloma post solid organ transplantation

The clinical and pathological features of plasma cell myeloma post solid organ transplantation

FKBP12 is a major regulator of ALK2 activity in multiple myeloma cells

The Prevalence of Epstein-Barr Virus in Plasma Cell Neoplasms is Higher in HIV-Positive Individuals

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