Search

A 71-year-old female with relapsed IgA lambda myeloma developed progressive cytopenia. The peripheral blood film showed 5% blastoid cells. Flow cytometry analysis was indicative of plasma cells. The bone marrow smear was packed with plasmablasts. Target CD138-cell FISH and molecular karyotyping identified a complex genome. NGS identified high-risk mutations. Bone marrow histology confirmed myeloma with no evidence of acute leukaemia. The patient was diagnosed with plasmablastic progression of myeloma and secondary PCL. Secondary PCL patients have a poor prognosis. It is essential to recognize this subtype and explore a novel treatment approach., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Plasma cell leukemia (PCL) is a rare and aggressive plasma cell disorder, exhibiting a more unfavorable prognosis than multiple myeloma. PCL is classified into pPCL and sPCL. Recently, the IMWG has recommended new PCL definition criteria, which require the presence of ≥5% circulating plasma cells in peripheral blood smears. Due to its low incidence, research on pPCL and sPCL is limited., Methods: We conducted a retrospective study and analyzed clinical and cytogenetic data of pPCL and sPCL patients. Overall survival (OS) and progression-free survival (PFS) were assessed by the Kaplan-Meier method, and survival distributions were compared using the log-rank test., Results: This is a small cohort comprising 23 pPCL and 9 sPCL patients. Notably, sPCL patients showed a higher incidence of extramedullary infiltration and a higher percentage of bone marrow plasma cells ( p  = 0.015 and 0.025, respectively). Although no significant difference was found between the two groups in OS and PFS, a trend emerged suggesting a superior survival outcome for pPCL patients, with a higher cumulative 1-year PFS rate (38.3% vs. 13.3%) and a lower early mortality rate (mortality rate at 3 months: 15% vs. 33%). We also suggested that pPCL patients carrying t(11;14) may have a longer median survival time than individuals with other cytogenetic abnormalities, but this was not confirmed due to the small sample size., Conclusion: Our study revealed clinical and cytogenetic features of pPCL and sPCL patients according to the new diagnostic criteria. The findings suggested a generally better prognosis for pPCL than sPCL and the likelihood of t(11;14) translocation acting as a favorable prognostic factor in pPCL. It is important to note that our study had a limited sample size, which may lead to bias. We hope well-designed studies can be conducted to provide more results.

Background: Plasma cell leukemia (PCL) is one of the rare cancer which is characterized by the uncontrolled proliferation of plasma cells in peripheral blood and bone marrow. The aggressive behavior of the disease and high mortality rate among PCL patients makes it a thirst area to be explored., Methods: The dataset for PCL was obtained from the GEO database and was analyzed using GEO2R for differentially expressed genes. Further, the functional enrichment analysis was carried out for DEGs using DAVID. The protein-protein interactions (PPI) for DEGs were obtained using STRING 11.5 and were analyzed in Cytoscape 3.7.2. to obtain the key hub genes. These key hub genes were investigated for their interaction with suitable drug candidates using DGIdb, DrugMAP, and Schrodinger's version 2022-1., Results: Out of the total of 104 DEGs, 39 genes were up-regulated whereas 65 genes were down-regulated. A total of 11 biological processes, 2 cellular components, and 5 molecular functions were enriched along with the 7 KEGG pathways for the DEGs. Further, a total of 11 hub genes were obtained from the PPI of DEGs of which TP53, MAPK1, SOCS1, MBD3, and YES1 were the key hub genes. Oxaliplatin, mitoxantrone, and ponatinib were found to have the highest binding affinity towards the p53, MAPK1, and YES1 proteins respectively., Conclusion: TP53, MAPK1, SOCS1, MBD3, and YES1 are the signature hub genes that might be responsible for the aggressive prognosis of PCL leading to poor survival rate. However, p53, MAPK1, and YES1 can be targeted with oxaliplatin, mitoxantrone, and ponatinib., Competing Interests: Declaration of competing interest All the authors of this manuscript have no conflict of interest in any financial or non-financial means to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The aim of the study was to investigate the clinical and laboratory characteristics of IgM primary plasma cell leukemia., Methods: We retrospectively analyzed a case of clinical and laboratory characteristics of IgM primary plasma cell leukemia and review related literature of patient with primary plasma cell leukemia., Results: Laboratory tests: Alanine aminotransferase 128 U/L, Aspartate aminotransferase 245 U/L, Globulin 47.8 g/L, Lactate dehydrogenase 1,114 U/L, Creatinine 111.7 mol/L, Serum calcium 2.47 mmol/L, β2 microglobulin 8.52 µg/mL, Immunoglobulin G 31.41 g/L, D-dimer 2.34 mg/L, Prothrombin time 13.6 seconds Fibrinogen 2 g/L, White blood cell 7.38 x 109/L, Red blood cell 3.46 x 1012/L, Hemoglobin 115 g/L, Platelet 7 x 109/L, and 12% Primitive naive cells can be seen in peripheral blood smear. Bone marrow smear: Accounted for 52% of original cells, the cell size, shape is irregular, the edge is not neat, the cell quality is rich, stained gray blue, cytoplasmic staining uneven, some devouring blood cells can be seen in the cytoplasm or unknown substance, the nucleus shape is irregular, visible distortion and fold, is visible on the part of the nuclei cavitation sample inclusions, chromatin is meticulous, partly visible large nucleoli. Flow cytometry results showed abnormal cell group held 23.85% of nuclear cells, expression of CD38, CD138, CD117, cKappa, partly CD20, weak expressing CD45, not express CD27, CD19, CD56, CD200, CD81, cLambda. It was a monoclonal plasma cell with an abnormal phenotype, consistent with a plasma cell tumor. Immunofixation electrophoresis results showed that the serum M protein was 22.80 g/L, which was IgG-κ type, the serum free KAP light chain was 232.69 mg/L, the serum free LAM light chain was 5.37 mg/L, and the rFLC (κ-FLC: λFLC) was 43.33. The diagnosis was primary plasmacytic leukemia of light chain type., Conclusions: Primary plasma cell leukemia (pPCL) is a rare and highly aggressive plasma cell malignancy. Laboratory staff should pay more attention to and recognize the pleomorphic morphology of neoplastic plasma cells, which can enable timely clinical development of bone marrow smear, biopsy, flow cytometry, and cytogenetic tests providing help in early diagnosis and treatment.

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.

Heavy chain deposition disease (HCDD) is characterized by the deposition of truncated monoclonal immunoglobulin heavy chains along glomerular basement membranes. Truncated heavy chains are thought to be associated with plasma cell disease (PCD), but previous bone marrow cytology tests showed that only 30% of HCDD cases are related to PCDs. We report the first known use of immunoglobulin heavy chain (IGH) gene rearrangement to diagnose a patient with γ3-HCDD, although bone marrow morphology test identified no abnormalities. Our findings provide strong evidence for a correlation between PCDs and HCDD, which could help understand the genetic background underlying abnormal heavy chains and assess disease prognosis. Further, concordant with previous findings, bortezomib-based chemotherapy had a good therapeutic effect in our patient. We summarize the experience of diagnosing and treating a case of HCDD, and combine this with a literature review to further explore the correlation between PCDs and HCDD, which has important clinical value.

Plasma cell leukemia (PCL) is clinically and genetically distinct from multiple myeloma (MM), despite controversies regarding the disease definition. To determine the distinct features of PCL, the genetic property of primary PCL (pPCL) was compared with that of secondary PCL (sPCL) and MM. In patients with pPCL, Eighty-nine non-synonymous mutations were observed in 68 genes. The most frequently mutated genes were TP53 , TSC2 , and TYK2. In comparison with genetic abnormalities of sPCL and MM, 45 genes were present only in pPCL while 28 genes were only in sPCL and 22 genes only in MM. Among the common genes between pPCL and MM, a higher prevalence of TP53 was observed in pPCL, compared to MM ( p  < 0.05), while similar, compared to sPCL ( p =  0.64). In summary, pPCL patients showed a higher level of genetic heterogeneity and distinctive genetic signature in their mutational profile compared to patients with MM and sPCL.

Background: Secondary plasma cell leukaemia (sPCL) is an aggressive form of multiple myeloma (MM), but the mechanism underlying MM progresses into PCL remains unknown., Methods: Gene expression profiling of MM patients and PCL patients was analysed to identify the molecular differences between the two diseases. Cox survival regression and Kaplan-Meier analysis were performed to illustrate the impact of integrin subunit alpha 6 (ITGA6) on prognosis of MM. Invasion assays were performed to assess whether ITGA6 regulated the progression of MM to PCL., Results: Gene expression profiling analyses showed that cell metastasis pathways were enriched in PCL and ITGA6 was differentially expressed between PCL and MM. ITGA6 expression was an independent prognostic factor for event-free survival (EFS) and overall survival (OS) of MM patients. Moreover, the stratification ability of the International Staging System (ISS) of MM was improved when including ITGA6 expression. Functional studies uncovered that increased ITGA6 reduced the myeloma cell invasion. Additionally, low expression of ITGA6 resulted from epigenetic downregulating of its anti-sense non-coding RNA, ITGA6-AS1., Conclusion: Our data reveal that ITGA6 gradually decreases during plasma cell dyscrasias progression and low expression of ITGA6 contributes to myeloma metastasis. Moreover, ITGA6 abundance might help develop MM prognostic stratification.

Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the clinical treatment of hematological malignancies due to the prominent anti-tumor effects. B cell maturation antigen (BCMA) CAR-T cells have demonstrated promising effects in patients with relapsed/refractory multiple myeloma. However, the dynamics of CAR-T cell proliferation and cytotoxicity in clinical patients remains unexplored. Here, we longitudinally profiled the transcriptomes of 55,488 T cells including CAR-T products, CAR-T cells, and endogenous T cells at the peak and remission phases in a plasma cell leukemia (PCL) patient treated with BCMA CAR-T cells by single-cell transcriptomic analysis. Our results showed distinct CAR-T and endogenous T cell subsets indicating stage-specific expression in proliferation, cytotoxicity, and intercellular signaling pathways. Furthermore, we found that CAR-T cells at peak phase gradually convert to a highly cytotoxic state from a highly proliferative state along a development trajectory. Moreover, re-analysis of a single cell study from CD8 + CD19 CAR-T confirmed our findings. These commonalities suggest conserved mechanisms for CAR-T treatment across hematological malignancies. Taken together, our current study provides insight into CAR-T cell dynamics during CAR-T therapy and proves that both BCMA CAR-T and CD19 CAR-T have similar transcriptional characteristics, especially at the CAR-T peak phase., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

We analyzed variations in terms of chromosomal abnormalities (CA) by fluorescence in situ hybridization (FISH) analysis on purified bone marrow plasma cells throughout the progression from monoclonal gammopathy of undetermined significance/smoldering multiple myeloma (MGUS/SMM) to newly diagnosed MM/plasma cell leukemia (NDMM/PCL) at diagnosis and from diagnostic samples to progressive disease. High risk was defined by the presence of at least del(17p), t(4;14), and/or t(14;16). 1p/1q detection (in the standard FISH panel from 2012 onward) was not available for all patients. We analyzed 139 MM/PCL diagnostic samples from 144 patients, with a median follow-up of 71 months: high-risk CA at diagnosis (MGUS/SMM or NDMM) was present in 28% of samples, whereas 37-39% showed high-risk CA at relapse. In 115 patients with NDMM who evolved to relapsed/refractory MM, we identified 3 different populations: (1) 31/115 patients (27%) with gain of new CA (del13, del17p, t(4;14), t(14;16) or 1q CA when available); (2) 10/115 (9%) patients with loss of a previously identified CA; and (3) 74 patients with no changes. The CA gain group showed a median overall survival of 66 months vs. 84 months in the third group (HR 0.56, 95% CI 0.34-0.92, p = 0.023). Clonal evolution occurs as disease progresses after different chemotherapy lines. Patients who acquired high-risk CA had the poorest prognosis. Our findings highlight the importance of performing FISH analysis both at diagnosis and at relapse.

A 70-year-old man with medical history of IgG kappa multiple myeloma, initially diagnosed in 2017, underwent induction therapy with carfilzomib, lenalidomide and dexamethasone followed by autologous haematopoietic stem cell transplantation. Nine months following transplant, disease relapsed in the form of plasma cell leukaemia. Fluorescent in situ hybridisation of malignant plasma cells revealed t(11;14). A combination therapy including venetoclax was used based on efficacy data for Bcl-2 inhibitor venetoclax from available early-phase clinical trials in patients with relapsed multiple myeloma with t(11;14) and other published case studies. Unfortunately, the disease was primary refractory, and after further ineffective therapies, the patient did not have a successful outcome., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the clinical characteristics, genetic abnormalities, treatment efficacy and prognostic factors in patients with plasma cell leukemia(PCL)., Methods: 30 patients diagnosed as PCL in our hospital from January 1993 to December 2019 were enrolled, and the clinical characteristics, laboratory findings, therapeutic regimes, and survival data of the patients were retrospectively analyzed., Results: The median age of the 30 patients was 56.5 (28-80) years old, among them, 25 patients were primary plasma cell leukemia, and 5 patients were secondary plasma cell leukemia. Complex karyotypes and subdiploids were most common in cytogenetic abnormalities. Among the 20 cases of chromosome G banding, 11 (55%) cases were complex karyotypes and 8 (40%) cases were hypodiploid. Fluorescent in situ hybridization (FISH) test showed that among 11 cases, 6 cases showed 17p13 deletion, 8 cases showed at least two kinds of abnormalities, which including t (14; 16), t (8; 14), t (11;14), 17p13 deletion, and 13q14 deletion. The median overall survival (OS) time was 10.5 months for all patients. The median OS time of the patients in ECOG score ≤ 2 group was 21.5 months, which was significantly longer than those in the ECOG score>2 group(1.2 months) (P=0.017). The median OS time of the patients treated with novel agents (including proteasome inhibitor and/or immunomodulator) was 24.9 months, which was significantly longer than the patients treated with traditional chemotherapy group(10.5 months) (P＜0.001). For the patients treated with novel agents, the median OS time of patients accepted two novel agents combination was 30.9 months, which was longer than those of single novel agent(11.5 months) (P=0.021). The effect of genetic abnormolity to the OS of the patients showed no statistical difference. Multivariate statistical analysis showed that ECOG score>2 was the independent prognostic factor of plasma cell leukemia patients. There were two patients underwent allogeneic hematopoietic stem cell transplantation in the study,but died due to the pulmonary infection within 6 months after transplantation., Conclusion: In the era of novel agents, ECOG score is an independent prognostic factor of plasma cell leukemia. Multiple novel agents treatment should be underwent as soon as possible to improve the prognosis of the patients. Pulmonary infection is a common factor that cause the death of the patients after allogeneic hematopoietic stem cell transplantation.

Background: Previous studies have pointed out the role of dickkopf-related protein 1 (DKK 1) - Wnt inhibitor, which is essential for osteoblast functioning, in the development of osteolytic lesions in multiple myeloma (MM)., Aim: To assess the DKK 1 expression displayed by myeloma cells in bone marrow trephine biopsies of patients with and without osteolytic lesions, and in different malignancy grades of the disease., Methods: The expression level of DKK 1 was assessed immunohistochemically in bone marrow of 49 MM patients presented with and without osteolytic lesions (the 1 st and the 2 nd group, respectively)., Results: Levels of weak, moderate, and strong DKK 1 expression were distributed - as 43.33, 27.78 and 25.56%, and 63.91, 18.80, and 1.50%, respectively when evaluating the samples obtained from the 1 st and the 2 nd group. Statistically significant differences were found when the levels of DKK 1 expression in the 1 st and the 2 nd group were compared (χ 2  = 51; df = 3; p < 0.001)., Conclusions: DKK 1 contributes to the development of osteolytic lesions in MM. The present study provides morphological evidence that inhibition in Wnt signaling may lead to bone damage observed in the advanced stage of the disease.

Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by the presence of ≥20% circulating plasma cells. Overall survival remains poor despite advances of anti-MM therapy. The disease biology as well as molecular mechanisms that distinguish pPCL from non-pPCL MM remain poorly understood and, given the rarity of the disease, are challenging to study. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype, we performed whole-exome sequencing and gene expression analysis in 23 and 41 patients with newly diagnosed pPCL, respectively. The results reveal an enrichment of complex structural changes and high-risk mutational patterns in pPCL that explain, at least in part, the aggressive nature of the disease. In particular, pPCL patients with traditional low-risk features such as translocation t(11;14) or hyperdiploidy accumulated adverse risk genetic events that could account for the poor outcome in this group. Furthermore, gene expression profiling showed upregulation of adverse risk modifiers in pPCL compared to non-pPCL MM, while adhesion molecules and extracellular matrix proteins became increasingly downregulated. In conclusion, this is one of the largest studies to dissect pPCL on a genomic and molecular level.

In multiple myeloma (MM), MYC rearrangements that result in increased MYC expression are associated with an aggressive form of MM and adverse outcome. However, the consequences of MYC amplification in MM remain unclear. Here, we describe an unusual case of plasma cell leukemia (PCL) harboring MYC amplification on double minute chromosomes (dmin). A 79-year-old woman was initially diagnosed as having BJP-κ type MM with bone lesions. After seven months, the disease progressed to secondary PCL: leukocytes 49.1 × 10 9 /L with 77% plasma cells showing lymphoplasmacytic appearance. The bone marrow was infiltrated with 76% plasma cells immunophenotypically positive for CD38 and negative for CD45, CD19, CD20, and CD56. The karyotype by G-banding and spectral karyotyping was 48,XX,der(14)t(11;14)(q13;q32),+der(14)t(14;19)(q32;q13.1),+18,6~95dmin[15]/46,XX[5]. Fluorescence in situ hybridization detected multiple MYC signals on dmin and double IGH/CCND1 fusion signals on der(14)t(11;14) and der(14)t(14;19). Most plasma cells were diffusely and strongly positive for MYC and CCND1 by immunohistochemistry. The patient died of progressive disease after one week. MYC amplification led to high expression of MYC and rapid disease progression, indicating its clinical significance in the pathogenesis of MM/PCL. MYC amplification on dmin may be a very rare genetic event closely associated with the progression to PCL and coexistence of IGH/CCND1 fusions., Competing Interests: Declaration of Competing Interest Dr. Minami reports honoraria from Janssen, Novartis, and Ono, and research grant from Ono. Other authors have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Primary plasma cell leukemia (pPCL) is a highly aggressive plasma cell dyscrasia characterised by short remissions and very poor survival. Although the 17p deletion is associated with poor outcome and extramedullary disease in MM, its presence does not confer the degree of aggressiveness observed in pPCL. The comprehensive exploration of isoform expression and RNA splicing events may provide novel information about biological differences between the two diseases. Transcriptomic studies were carried out in nine newly diagnosed pPCL and ten MM samples, all of which harbored the 17p deletion. Unsupervised cluster analysis clearly distinguished pPCL from MM samples. In total 3584 genes and 20033 isoforms were found to be deregulated between pPCL and MM. There were 2727 significantly deregulated isoforms of non-differentially expressed genes. Strangely enough, significant differences were observed in the expression of spliceosomal machinery components between pPCL and MM, in respect of the gene, isoform and the alternative splicing events expression. In summary, transcriptome analysis revealed significant differences in the relative abundance of isoforms between pPCL and MM, even when they both had the 17p deletion. The mRNA processing pathway including RNA splicing machinery emerged as one of the most remarkable mechanisms underlying the biological differences between the two entities.

Light-chain plasma cell myeloma (LC-PCM) is a PCM subtype in which only immunoglobulin light-chain is secreted. However, the absence of immunoglobulin heavy-chain (IGH) production in this condition has not been fully elucidated. To address this issue, we retrospectively analyzed patients at our center with LC-PCM and found a group who had only split signals of IGH gene derived from 14q32/IGH translocations by fluorescence in situ hybridization (FISH). Six patients were identified with only split signals of the IGH gene derived from 14q32/IGH translocations. Five of these patients were newly diagnosed, while one had IgG-λ PCM at presentation, which transformed to λ LC-PCM after treatment. The translocation partners were identified in four patients: two cases of (11;14)(q13;q32) and two cases of (4;14)(p16;q32). The development of LC-PCM appears to be explained by the application of allelic exclusion in these patients, such that 14q32/IGH translocation in one allele contributes to the pathogenesis of PCM and the subsequent loss of the other allele is responsible for the loss of IGH production. These findings suggest that a FISH pattern of IGH with "split and loss" may constitute a unique subgroup of LC-PCM.

Background: Primary plasma cell leukemia (pPCL) is uncommon, aggressive and has a different biology than multiple myeloma (MM)., Aim: To report the features of patients with pPCL., Material and Methods: Review of databases of the Hematology Department and the Hematology laboratory., Results: Of 178 patients with monoclonal gammopathies, five (2.8%) patients aged 33 to 64 years (three females) had a pPCL. The mean hemoglobin was 7.3 g/dL, the mean white blood cell count was 52,500/mm3, with 58% plasma cells, and the mean platelet count was 83,600/mm3. The mean bone marrow infiltration was 89%, LDH was 2,003 IU/L, serum calcium was 13 mg/dL, and creatinine 1.5 mg/dL. Two patients had bone lesions. Three were IgG, one IgA lambda and one lambda light chain. CD20 was positive in one, CD56 was negative in all and CD117 was negative in 3 cases. By conventional cytogenetic analysis, two had a complex karyotype. By Fluorescence in situ Hybridization, one was positive for TP53 and another for t (11; 14). One patient did not receive any treatment, three patients received VTD PACE and one CTD. None underwent transplant. Three patients are alive. The mean survival was 14 months., Conclusions: These patients with pPCL were younger and had a more aggressive clinical outcome than in multiple myeloma.

Primary plasma cell leukemia (pPCL) is a rare and very aggressive variant of multiple myeloma (MM). Specific clinical, biological and molecular patterns distinguish pPCL from MM. Here, we performed a genome-wide methylation analysis by high-density array in 14 newly diagnosed pPCL patients along with 60 MMs, and 5 patients affected by monoclonal gammopathy of uncertain significance (MGUS). Our analysis revealed a global hypomethylation profile associated with pPCL. Additionally, differential methylation patterns were found related to distinct chromosomal aberrations and DIS3 mutations, affecting genes with roles in bone metabolism, cell migration, transcription regulation or DNA damage response. When compared with MM patients, pPCL showed a distinct methylation profile mostly characterized by hypomethylated probes specific for genes involved in several processes like cell adhesion and migration. Furthermore, decreasing methylation levels were evidenced for genes significantly modulated in the progressive phases of plasma cell dyscrasias, from MGUS to MM and pPCL. Overall, our data provide new insights into the molecular characterization of pPCL, thus being potentially useful in the prognostic stratification or identification of novel molecular targets., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Primary plasma cell leukemia (pPCL) is the most aggressive form of the plasma cell (PC) malignancy, multiple myeloma (MM). It has been commonly associated with the presence of a chromosome translocation involving the immunoglobulin heavy chain (IgH) locus on 14q32, that is t (11;14). Results from early phase clinical trials utilizing the selective Bcl-2 inhibitor, venetoclax, as a single agent in patients with relapsed MM have had remarkable efficacy among patients with t (11;14) abnormality. The present case demonstrates the ability of a combination regimen incorporating Bcl-2 inhibition with daratumumab, bortezomib, venetoclax, and dexamethasone to induce a rapid and very deep hematologic response in a pPCL patient with t (11;14), even in a setting of very refractory disease. This case highlights the need to further study Bcl-2 inhibition-based therapy as an option for therapy in patients with pPCL with t (11;14)., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Primary nonsecretory plasma cell leukemia (PCL) is an extremely rare type of multiple myeloma. Here, we report a case of nonsecretory PCL with no previous history of multiple myeloma. The case exhibited extremely low levels of serum immunoglobulin and light chain, no detectable serum M-protein or free light chain restriction, no urine BJP, and no cytoplasmic light chain expression in flow cytometry. In fluorescence in situ hybridization, tumor cells exhibited fusion genes for IgH/BCL1 and IgH/cMyc, disappearance of the p53 signal, and a split signal for IgK(2p11), but no split signal for IgL (22q11). Therefore, we diagnosed primary nonsecretory PCL with multiple chromosomal abnormalities., (2018 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Plasma cell leukemia is a rare and aggressive plasma cell neoplasm that may either originate de novo (primary PCL) or by leukemic transformation of multiple myeloma (MM) to secondary PCL (sPCL). The prognosis of sPCL is very poor, and currently no standard treatment is available due to lack of prospective clinical studies. In an attempt to elucidate factors contributing to transformation, we have performed super-SILAC quantitative proteome profiling of malignant plasma cells collected from the same patient at both the MM and sPCL stages of the disease. 795 proteins were found to be differentially expressed in the MM and sPCL samples. Gene ontology analysis indicated a metabolic shift towards aerobic glycolysis in sPCL as well as marked down-regulation of enzymes involved in glycan synthesis, potentially mediating altered glycosylation of surface receptors. There was no significant change in overall genomic 5-methylcytosine or 5-hydroxymethylcytosine at the two stages, indicating that epigenetic dysregulation was not a major driver of transformation to sPCL. The present study constitutes the first attempt to provide a comprehensive map of the altered protein expression profile accompanying transformation of MM to sPCL in a single patient, identifying several candidate proteins that can be targeted by currently available small molecule drugs. Our dataset furthermore constitutes a reference dataset for further proteomic analysis of sPCL transformation.

Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL).

Primary plasma cell leukemia (pPCL) is a rare and aggressive form of plasma cell dyscrasia and may represent a valid model for high-risk multiple myeloma (MM). To provide novel information concerning the mutational profile of this disease, we performed the whole-exome sequencing of a prospective series of 12 pPCL cases included in a Phase II multicenter clinical trial and previously characterized at clinical and molecular levels. We identified 1, 928 coding somatic non-silent variants on 1, 643 genes, with a mean of 166 variants per sample, and only few variants and genes recurrent in two or more samples. An excess of C > T transitions and the presence of two main mutational signatures (related to APOBEC over-activity and aging) occurring in different translocation groups were observed. We identified 14 candidate cancer driver genes, mainly involved in cell-matrix adhesion, cell cycle, genome stability, RNA metabolism and protein folding. Furthermore, integration of mutation data with copy number alteration profiles evidenced biallelically disrupted genes with potential tumor suppressor functions. Globally, cadherin/Wnt signaling, extracellular matrix and cell cycle checkpoint resulted the most affected functional pathways. Sequencing results were finally combined with gene expression data to better elucidate the biological relevance of mutated genes. This study represents the first whole-exome sequencing screen of pPCL and evidenced a remarkable genetic heterogeneity of mutational patterns. This may provide a contribution to the comprehension of the pathogenetic mechanisms associated with this aggressive form of PC dyscrasia and potentially with high-risk MM.

Plasma cell leukemia (PCL) is a very aggressive and rare form of malignant monoclonal gammopathy characterized by the presence of plasmocytes in peripheral blood. It is classified as primary PCL occuring 'de novo', or as secondary PCL in patients with relapsed/refractory multiple myeloma. Primary PCL is a distinct clinicopathological entity from myeloma with different cytogenetic abnormalities and molecular findings, which are usually found only in advanced multiple myeloma. The clinical course is aggressive with short remissions and reduced overall survival. The diagnostic criteria are based on the percentage (>20%) and absolute number (2 × 10(9) /L) of plasma cells in peripheral blood. After establishing diagnosis, induction therapy should begin promptly which is aimed to rapid disease control and to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens, followed by high-dose therapy with autologous stem cell transplantation, are recommended. Allogeneic transplantation can be considered in younger patients. This article reviews recent knowledge of this hematological malignancy that is associated with a very poor prognosis., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Plasma cell leukemia (PCL) is a rare hematologic malignancy with very poor outcome. It is defined by the presence of >2 × 10(9)/L plasma cells or >20% plasmacytosis of the differential white cell count in the peripheral blood. Primary PCL is first diagnosed in the leukemic phase, while secondary PCL corresponds to the leukemic transformation of a previously diagnosed multiple myeloma (MM). The incidence of PCL ranges between 2-4% of patients with MM and 0.9% of patients with acute leukemia. In this case series, we describe the clinicopathologic, immunophenotypic, and cytogenetic findings of four patients diagnosed with PCL within a ten-year period (2002-2012) at King Faisal Specialist Hospital and Research Centre (General Organization), Riyadh, Saudi Arabia., (Copyright © 2015 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.)

Background: Plasma cell leukemia (PCL) is an uncommon and aggressive disease caused by the clonal proliferation of atypical plasma cells with phenotypical abnormalities similar to those seen in multiple myeloma (MM), although at different rates. Here, we report a case of IgD PCL with a very unusual CD138-/CD19+/CD4+ phenotype., Methods: Peripheral blood and bone marrow samples from a 37-year-old patient afflicted by an aggressive plasma cell dyscrasia were examined and analyzed by conventional morphology, flow cytometry, and immunohistochemistry., Results: Analysis of peripheral blood fulfilled criteria for PCL (more than 20% and more than 2 × 10e9 cells/L). However, flow cytometry and immunohistochemistry phenotyping revealed that the cells were CD138-/CD38+/CD19+/CD4+/CD56-/CD117-., Conclusions: PCL is diagnosed on peripheral blood smear. Immunophenotyping is a tool that can be helpful in diagnosing difficult cases but its atypical findings should not prevent the appropriate PCL diagnosis in clinically and morphologically unquestionable cases. © 2014 International Clinical Cytometry Society., (© 2014 Clinical Cytometry Society.)

Multiple myeloma can be categorized into hyperdiploid or non-hyperdiploid myeloma based on the number of chromosomes found in the tumor clone. Among the non-hyperdiploid myelomas, the hypodiploid subtype has the most aggressive clinical phenotype, but the genetic differences between groups are not completely defined. In order to understand the genetic background of hypodiploid multiple myeloma better, we compared the genomic (array-based comparative genomic hybridization) and transcriptomic (gene expression profiling) background of 49 patients with hypodiploid myeloma with 50 other non-hyperdiploid and 125 hyperdiploid myeloma patients. There were significant chromosomal and gene expression differences between hyperdiploid patients and non-hyperdiploid and hypodiploid patients. Non-hyperdiploid and hypodiploid patients shared most of the chromosomal abnormalities; nevertheless a subset of these abnormalities, such as monosomies 13, 14 and 22, was markedly increased in hypodiploid patients. Furthermore, deletions of 1p, 12p, 16q and 17p, all associated with poor outcome or progression in multiple myeloma, were significantly enriched in hypodiploid patients. Molecular risk-stratification indices reinforce the worse prognosis associated with hypodiploid multiple myeloma compared with non-hyperdiploid multiple myeloma. Gene expression profiling clustered hypodiploid and non-hyperdiploid subgroups closer than hyperdiploid myeloma but also highlighted the up-regulation of CCND2, WHSC1/MMSET and FGFR3 in the hypodiploid subtype. In summary, hypodiploid multiple myeloma is genetically similar to non-hyperdiploid multiple myeloma but characterized by a higher prevalence of genetic alterations associated with poor outcome and disease progression. It is provocative to hypothesize that hypodiploid multiple myeloma is an advanced stage of non-hyperdiploid multiple myeloma.

The objective of this study was to describe co-expression correlations of cell cycle regulatory genes in multiple myeloma (MM) and plasma cell leukemia (PCL). Our results highlight the presence of dynamic equilibrium between co-expression of activator and inhibitor gene sets. Moreover inhibitor set is more sensitive to the activator changes, not vice versa. We have shown that CDKN2A expression is associated with short-term survival in newly diagnosed MM patients (survival was 30.3 ± 3.9 months for 'low' expressed and 7.5 ± 5.6 months for 'high' expressed group, p<0.0001). Moreover low-expression CDKN2A group showed time-to-progression benefit in newly diagnosed patients (remission was 20.8 ± 3.6 months for 'low' and 8.4 ± 2.7 months for 'high' expressed group, p<0.0001) as well as in whole studied cohort of MM patients (remission was 20.8 ± 2.8 months for 'low' and 9.8 ± 1.1 months for 'high' expressed group, p<0.0001). The overexpression of inhibitors can be explained as a compensatory reaction to growing "oncogenic stress"., (© 2013 Elsevier Inc. All rights reserved.)

Purpose: Primary plasma cell leukemia (pPCL) is a rare and very aggressive form of plasma cell dyscrasia. To date, no information on microRNA (miRNA) expression in pPCL has been reported. This study aimed at investigating the involvement of miRNAs in pPCL and their possible relationship with higher tumor aggressiveness., Experimental Design: Global miRNA expression profiles were analyzed in highly purified malignant plasma cells from 18 pPCL untreated patients included in a prospective clinical trial. MiRNA expression patterns were evaluated in comparison with a representative series of multiple myeloma patients, in relation to the most recurrent chromosomal abnormalities (as assessed by fluorescence in situ hybridization and single-nucleotide polymorphism-array analysis), and in association with clinical outcome. MiRNA expression was also integrated with gene expression profiles in pPCL and multiple myeloma samples., Results: We identified a series of deregulated miRNAs in pPCL (42 upregulated and 41 downregulated) in comparison with multiple myeloma. Some of them, on the basis of their reported functions and putative target genes computed by integrative analysis, might have a role in the pathobiology of pPCL. As regards chromosomal aberrations, the expression of some miRNAs mapped to hotspot altered regions was associated with DNA copy number of the corresponding loci. Finally, 4 miRNA (miR-497, miR-106b, miR-181a*, and miR-181b) were identified as having expression levels that correlated with treatment response, and 4 (miR-92a, miR-330-3p, miR-22, and miR-146a) with clinical outcome., Conclusions: Overall, our study provides insights into the possible contribution of miRNAs in the pathogenesis of pPCL and suggests targets for future therapeutic investigations.

Primary plasma cell leukemia (pPCL) is a rare, yet aggressive form of de novo plasma cell tumor, distinct from secondary PCL (sPCL) which represents a leukemic transformation of pre-existing multiple myeloma (MM). Herein, we performed a comprehensive molecular analysis of a prospective series of pPCLs by means of FISH, single nucleotide polymorphism (SNP) array and gene expression profiling (GEP). IGH@ translocations were identified in 87% of pPCL cases, with prevalence of t(11;14) (40%) and t(14;16) (30.5%), whereas the most frequent numerical alterations involved 1p (38%), 1q (48%), 6q (29%), 8p (42%), 13q (74%), 14q (71%), 16q (53%), and 17p (35%). We identified a minimal biallelic deletion (1.5 Mb) in 8p21.2 encompassing the PPP2R2A gene, belonging to a family of putative tumor suppressors and found to be significantly down-regulated in deleted cases. Mutations of TP53 were identified in four cases, all but one associated with a monoallelic deletion of the gene, whereas activating mutations of the BRAF oncogene occurred in one case and were absent in N- and K-RAS. To evaluate the influence of allelic imbalances in transcriptional expression we performed an integrated genomic analysis with GEP data, showing a significant dosage effect of genes involved in transcription, translation, methyltransferase activity, apoptosis as well as Wnt and NF-kB signaling pathways. Overall, we provide a compendium of genomic alterations in a prospective series of pPCLs which may contribute to improve our understanding of the pathogenesis of this aggressive form of plasma cell dyscrasia and the mechanisms of tumor progression in MM., (Copyright © 2012 Wiley Periodicals, Inc.)

To further contribute to the understanding of multiple myeloma, we have focused our research interests on the mechanisms by which tumour plasma cells have a higher survival rate than normal plasma cells. In this article, we study the expression profile of genes involved in the regulation and protection of telomere length, telomerase activity and apoptosis in samples from patients with monoclonal gammopathy of undetermined significance, smouldering multiple myeloma, multiple myeloma (MM) and plasma cell leukaemia (PCL), as well as several human myeloma cell lines (HMCLs). Using conventional cytogenetic and fluorescence in situ hybridization studies, we identified a high number of telomeric associations (TAs). Moreover, telomere length measurements by terminal restriction fragment (TRF) assay showed a shorter mean TRF peak value, with a consistent correlation with the number of TAs. Using gene expression arrays and quantitative PCR we identified the hTERT gene together with 16 other genes directly involved in telomere length maintenance: HSPA9, KRAS, RB1, members of the Small nucleolar ribonucleoproteins family, A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins, and 14-3-3 family. The expression levels of these genes were even higher than those in human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), which have unlimited proliferation capacity. In conclusion, the gene signature suggests that MM tumour cells are able to maintain stable short telomere lengths without exceeding the short critical length, allowing cell divisions to continue. We propose that this could be a mechanism contributing to MM tumour cells expansion in the bone marrow (BM)., (© 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

To determine whether primary plasma cell leukemia (PPCL) remains a high-risk multiple myeloma feature in the context of contemporary therapy and gene-expression profiling (GEP), we reviewed records of 1474 patients with myeloma, who were enrolled in Total Therapy protocols or treated identically off protocol. A total of 27 patients (1.8%) were classified as having PPCL. As a group, these patients more often had low hemoglobin, high beta-2-microglobulin, high lactate dehydrogenase, low albumin and cytogenetic abnormalities. Among 866 patients with GEP results, the PPCL group more often had disease that was classified as high risk, and in CD-1 and MF molecular subgroups. Regardless of the therapeutic protocol, patients with PPCL had shorter median overall survival (OS; 1.8 years), progression-free survival (PFS; 0.8 years) and complete response duration (CRD; 1.3 years) than the remainder, whose clinical outcomes had improved markedly with successive protocols. Multivariate analyses of pretreatment parameters showed that PPCL was a highly significant independent adverse feature linked to OS, PFS and CRD. In GEP analyses, 203 gene probes distinguished PPCL from non-PPCL; the identified genes were involved in the LXR/RXR activation, inositol metabolism, hepatic fibrosis/hepatic stellate-cell activation and lipopolysaccharide/interleukin-1-mediated inhibition of RXR function pathways. Different treatment approaches building on these genomic differences may improve the grave outcome of patients with PPCL.

Aberrant DNA methylation plays a relevant role in multiple myeloma (MM) pathogenesis. MicroRNAs (miRNAs) are a class of small non-coding RNAs that recently emerged as master regulator of gene expression by targeting protein-coding mRNAs. However, miRNAs involvement in the regulation of the epigenetic machinery and their potential use as therapeutics in MM remain to be investigated. Here, we provide evidence that the expression of de novo DNA methyltransferases (DNMTs) is deregulated in MM cells. Moreover, we show that miR-29b targets DNMT3A and DNMT3B mRNAs and reduces global DNA methylation in MM cells. In vitro transfection of MM cells with synthetic miR-29b mimics significantly impairs cell cycle progression and also potentiates the growth-inhibitory effects induced by the demethylating agent 5-azacitidine. Most importantly, in vivo intratumor or systemic delivery of synthetic miR-29b mimics, in two clinically relevant murine models of human MM, including the SCID-synth-hu system, induces significant anti-tumor effects. All together, our findings demonstrate that aberrant DNMTs expression is efficiently modulated by tumor suppressive synthetic miR-29b mimics, indicating that methyloma modulation is a novel matter of investigation in miRNA-based therapy of MM.

In this issue of Blood, Keats et al,(1) Egan et al,(2) and Walker et al(3) provide a genome-wide snapshot of the clonal landscape in multiple myeloma(MM)illustrating the complexity of the evolutionary process and the dynamics of clonal evolution over time.

The longitudinal evolution of a myeloma genome from diagnosis to plasma cell leukemia has not previously been reported. We used whole-genome sequencing (WGS) on 4 purified tumor samples and patient germline DNA drawn over a 5-year period in a t(4;14) multiple myeloma patient. Tumor samples were acquired at diagnosis, first relapse, second relapse, and end-stage secondary plasma cell leukemia (sPCL). In addition to the t(4;14), all tumor time points also shared 10 common single-nucleotide variants (SNVs) on WGS comprising shared initiating events. Interestingly, we observed genomic sequence variants that waxed and waned with time in progressive tumors, suggesting the presence of multiple independent, yet related, clones at diagnosis that rose and fell in dominance. Five newly acquired SNVs, including truncating mutations of RB1 and ZKSCAN3, were observed only in the final sPCL sample suggesting leukemic transformation events. This longitudinal WGS characterization of the natural history of a high-risk myeloma patient demonstrated tumor heterogeneity at diagnosis with shifting dominance of tumor clones over time and has also identified potential mutations contributing to myelomagenesis as well as transformation from myeloma to overt extramedullary disease such as sPCL.

Bone morphogenetic proteins (BMPs), which belong to the transforming growth factor-β superfamily, are multifunctional signaling molecules that have become of increasing interest in cancer research. Recent observations suggest that alterations in BMPs and BMP signaling are associated with tumorigenesis and disease progression in various types of malignancies. This study investigated the methylation status of the BMP6 gene promoter in various types of plasma cell proliferative disorders by combined bisulfite restriction analysis. While BMP6 methylation was not detected in any samples from monoclonal gammopathies of undetermined significance, intramedullary multiple myeloma (MM), plasma cell leukemia or solitary plasmacytoma, both case studies and cell line studies showed that multiple extramedullary plasmacytoma (MEP) consistently carried a methylated BMP6 promoter. The BMP6 methylation-positive MEP was an aggressive form of MM with extremely high levels of serum lactate dehydrogenase (LDH). Bisulfite sequencing analysis confirmed intensive methylation at CpG sites of the BMP6 promoter region. The methylation of BMP6 was correlated with decreased levels of mRNA transcripts. Expression of BMP6 was restored by the demethylating agent 5-aza-2'-deoxycytidine, suggesting that the methylation is associated with transcriptional silencing. Our study implied that BMP6 promoter methylation is not a common event in MMs, but occurs in aggressive MEP. These findings warrant further investigation to clarify whether BMP6 methylation together with elevated LDH could be a marker of poor prognosis in MEP patients who should be considered for early intensive treatment.

Bone marrow specimens from 185 patients with plasma cell disorders (PCD) were investigated by fluorescence in situ hybridization (FISH) in order to determine the temporal sequence of cytogenetic aberrations. In 25 cases combined FISH analysis has also been performed at single cell level. Clonal evolution was observed in 16% of cases. The Δ13 was preceded by t(4;14)(p16;q32) and t(14;16)(q32;q23) translocations. Deletion of p53 gene was a secondary aberration compared to Δ13 and t(11;14)(q13;q32) translocation. In 22% of all cases with recurrent IGH translocation, this aberration was presented only in a subset of purified plasma cells questioning its initiating role., (Copyright © 2011 Elsevier Ltd. All rights reserved.)