Form Of Plasma Cell Dyscrasia Research Articles

MYEOV gene overexpression in primary plasma cell leukemia with t(11;14)(q13;q32).

Primary plasma cell leukemia (pPCL) is an uncommon form of plasma cell dyscrasia, and the most aggressive of the human monoclonal gammopathies. The t(11;14)(q13;q32) rearrangement is the most common alteration in pPCL, promoting cyclin D1 (CCND1) gene overexpression caused by its juxtaposition with the immunoglobulin heavy locus chromosome region. The myeloma overexpressed (MYEOV) gene maps very close to the CCND1 gene on chromosome 11, but its overexpression is rarely observed in multiple myeloma. The present study describes a case of pPCL with t(11;14) characterized by a breakpoint on der(11), unlike the one usually observed. Droplet digital polymerase chain reaction analysis revealed overexpression of CCND1 and MYEOV. To the best of our knowledge, MYEOV gene overexpression has never been previously described in pPCL.

Clinical Features and Prognostic Factors in Solitary Plasmacytoma: A Single Center Retrospective Study

Background: Solitary plasmacytoma (SP) is a rare form of plasma cell dyscrasia that represents 2.8-5% of all plasma cell disorders. It is characterized by a localized accumulation of neoplastic monoclonal plasma cells, without evidence of systemic disease, such as multiple myeloma (MM). It can be classified into two groups according to the localization: SP of the bone (SBP) and extramedullary plasmacytoma (EMP). The common presentation of the SBP is in the axial skeleton, whereas the EMP is usually seen in the head and neck. The clinical course and prognosis are quite different between these two entities. Here we present the clinical features, treatment strategies and relative prognostic factors of a series of SP patients followed at a single center over four decades. Methods: A retrospective study was carried out in 53 patients with SP referred at our Institution between 1976 and 2012. Patients’ characteristics are shown in Table 1. The median follow-up was 8.9 years (range 0.5-38.1). Thirty-five patients had SBP and 18 patients EMP. The median age was 56.8 years (range 27-80). The male to female ratio was 1.18:1 and 2.6:1 in SBP and EMP, respectively. The vertebral column (48% of cases) and the upper respiratory tract (50% of cases) were the most common sites of involvement SBP and EMP, respectively. Serum M-protein was detected in 62.8% and 27.7% of the SBP and EMP cases (P=0.0156). The tumor sizes were larger in the SBP group than in the EMP group (P=0.0039). Treatment consisted of local radiotherapy (n=26), combined radiotherapy + chemotherapy (n=15), surgery alone (n=4) and chemotherapy alone (n=8). The radiation dose was available for 35 patients and the median radiation dose administered was 41 Gy (range 21-88 Gy). Results: All patients were evaluable for treatment response and outcome. We found no differences between treatment approaches in terms of response rate, progression-free survival (PFS) and overall survival (OS). The local control rate was 94.3% and there was no statistically significant difference between the two groups. Progression to MM was recorded in 20/35 (57.1%) patients with SBP and in 1/18 (5.5%) patients with EMP. The median time to progression was 2.5 years (range 0.6-11). The 5-year PFS rate for all patients was 66.3% (95% CI: 53.9-81.4). Patients with SBP showed a worse PFS rate than EMP patients (53.0% vs 88.5%), with a statistically significant difference (P=0.0003). The total 5-year OS rate was 78.4% (95% CI: 67.3-91.3). Patients with SBP had a significantly worse OS rate than patient with EMP (71.9% vs 88.2%, respectively) (P=0.0290). Univariate analysis revealed that SBP and a larger tumor size (≥5 cm) were adverse prognostic factors affecting PFS (P=0.0027 and P=0.0498, respectively). SBP had an adverse effect also on OS (P=0.0405). In multivariate analysis, bone localization was the only independent worse prognostic factor for both PFS (P=0.0041) and OS (P=0.0216). Conclusions: Patients with SBP have a significantly worse prognosis than patients with EMP, underlining that they are indeed two different entities within the spectrum of plasma cells dyscrasias. The use of modern testing is mandatory to better characterize the patients’ risks of progression and to exclude an occult MM, especially in SBP. There is also a need for further prospective studies with large series of patients evaluating SBP and EMP separately, to elucidate the role of prognostic factors and treatment options for these conditions.Table 1CharacteristicsPatient (number)Sex, mean (%)Male Female33 (62.3)20 (37.7)Age (years)Median (range) ≤ 60 years, mean (%)56.81 (27-80)33 (62.3)Histological typeSBP mean, % EMP mean, %35 (66)18 (34)Tumor size atDiagnosis, number (%)≤5 cm >5 cm N/A19 (35.8)20 (37.7)14 (26.5)Serum M protein (%)Positive Negative27 (50.9)26 (49.1)Urinary B-J proteinPositive Negative6 (11.3)47 (88.7)SBP Anatomic siteVertebral column Long tubal bone Sternum Ribs Craniofacial bone Scapula17 (48)5 (14)4 (11)3 (8.5)3 (8.5)3 (8.5)EMP Anatomic siteUpper respiratory tract Paranasal sinus Lymph nodes GI tract testis9 (50)4 (22)2 (11)2 (11)1 (6) DisclosuresPetrucci:Jansse-Cilag: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria.

Breast involvement in immunolymphoproliferative disorders: Report of a case of multiple myeloma of the breast

Summary: Breast involvement by immunolymphoproliferative disordersis rare. Primary and secondary malignant lymphomas of the breast are much more common than multiple myeloma, of which only a few cases have been described. We report a case of a patient with an established diagnosis of multiple myeloma in whom breast involvement appeared after the completion of the treatment. We underline diagnostic difficulties caused by the lack of clinical and radiological features which allow us to differentiate between breast carcinoma and breast involvement by lymphoproliferative disease. Only fine needle aspiration and/or excisional biopsy can differentiate between immunolymphoproliferative disorders and epithelial or mesenchymal tumors of the breast. I. Introduction Multiple myeloma(MM) is the most frequent lympho-immunoproliferative disorders, but their localization in the breast is quite rare. MM is a disseminated malignant B-cell lineage neoplasm, characterized by clonal proliferation of plasma cells in the bone marrow, associated with the overproduction of structurally homogeneous immunoglobulins (M-component). They represent the most frequent form of plasma cell dyscrasias and about 1% of all types of tumors [1]. The incidence increases progressively with age and the mean age at diagnosis is about 65 years, while the onset in children [2] and young adults before 40 years is very rare [3]. Impaired hemopoiesis, renal failure, osteolytic bone lesions, recurrent infections, hypercalcemia are the most common features of the disease. Clinically apparent extraosseous manifestation are present in less than 5% of patients with multiple myeloma and are usually associated with more aggressive behaviour, resistance to treatment and shorter survival.

Polyclonal Gamma Globulin Suppression and Risk Of MGUS Progression Into Multiple Myeloma

Monoclonal gammopathy of undetermined significance (MGUS) is the most common form of plasma cell dyscrasia, with a prevalence of 3% in the general population above age of fifty. MGUS has a malignant evolution rate of 1% per year. Large longitudinal studies have suggested that virtually all patients diagnosed with multiple myeloma (MM) had a preceding MGUS, with 75 % having detectible Monoclonal (M) protein ≥8 years prior to diagnosis. It is important to identify the features at diagnosis that can predict neoplastic transformation to MM. PurposeWe identified 239 patients at our institute in whom MGUS was diagnosed between 2000 and 2010. The presenting clinico-hematologic features were correlated with the frequency of evolution into MM to identify early predictors of evolution. The primary end point was progression to MM. ResultsThe patients' mean age was 70.7 years. The Male/Female ratio was 0.7. The mean concentration of the M component (MC) was 0.7 g/dL. IgG was the most frequent MC (77%), followed by IgA (13%). The median ratio of MC protein to total protein was 0.5. Single or multiple background polyclonal (PC) suppression was noted in 36% of patients. PC suppression of 50% or more was noted in 20.1% of patients, 49.8% had < 50% and 30.1% had no suppression. Mean bone marrow plasma cell percentage was 4.5 percent and mean hemoglobin was 12.4 g/dL.Eighteen of the 239 patients with MGUS progressed into MM over ten years of follow up.Univariate comparisons of all variables between those who progressed and those who did not, showed that the initial concentration of the serum M protein, ratio of M protein to the total protein, number of PC gamma globulins suppressed, degree of PC suppression and IgM gamma globulin suppression were statistically significant risk factors that correlated with progression into MM. Fourteen out of eighteen patients with progressive disease had either PC suppression or background IgM suppression. ConclusionsMonoclonal protein concentration, ratio of M protein to the total protein and abnormal serum free light chain ratio are simple variables that have been shown in multiple previous studies to predict the progression of MGUS into MM. In our study, we additionally found that number of PC suppressed, degree of suppression and IgM suppression are also key risk factors that can predict progression.We believe that these variables can be potentially applied into an approach that uses a detailed risk stratification system to predict which cases of MGUS will progress into MM and to provide more intensive monitoring for patients more likely to progress.Table 1descriptive statistics on all variablesVariableResponseAll patients/(N=239)AgeN Mean (SD)239 70.7 (11.7)GenderMale99 ( 41%)Female140 ( 59%)RaceCaucasian108 ( 45%)AA113 ( 47%)Hispanic2 ( 1%)Other16 ( 7%)MC typeIgG184 ( 77%)IgA30 ( 13%)IgM16 ( 7%)Kappa3 ( 1%)Lambda6 ( 3%)MC levelN Mean (SD)238 0.7 (0.8)No of Ig suppressed0154 ( 64%)157 ( 24%)228 ( 12%)IgA suppressedNo207 ( 87%)Yes32 ( 13%)IgG suppressedNo219 ( 92%)Yes20 ( 8%)IgM suppressedNo178 ( 74%)Yes61 ( 26%)Level of suppression>50%48 (20.1%)<50%119 (49.8%)None72 (30.1%)M/totalN Mean (SD)229 0.5 (0.5)SFLRN Mean (SD)57 19.0 (73.3)UPEPNo119 ( 59%)Yes82 ( 41%)% plasma cellsN Mean (SD)Median (Min, Max)59 4.5 (3.4)4.0 (0.5, 16)HbN Mean (SD)230 12.4 (2.1)ProgressionNo221 ( 92%)Yes18 ( 8%)Table 2Univariate comparisons of all variables between those who progressed and those who did not. Bold p-value is statistically significant.VariableResponseNo progression(N= 221)Progression(N= 18)p-valueAge70.5 ± 11.972.4 ± 8.90.663GenderMale91 ( 41%)8 ( 44%)0.787Female130 ( 59%)10 ( 56%)RaceCaucasian96 ( 43%)12 ( 67%)0.289AA108 ( 49%)5 ( 28%)Hispanic2 ( 1%)0 ( 0%)Other15 ( 7%)1 ( 6%)MC typeIgG170 ( 77%)14 ( 78%)0.480IgA26 ( 12%)4 ( 22%)IgM16 ( 7%)0 ( 0%)Kappa3 ( 1%)0 ( 0%)Lambda6 ( 3%)0 ( 0%)MC level0.7 ± 0.81.4 ± 0.8<.001No of PC suppressed0148 ( 67%)6 ( 33%)0.016149 ( 22%)8 ( 44%)224 ( 11%)4 ( 22%)IgA suppressionNo193 ( 87%)14 ( 78%)0.252Yes28 ( 13%)4 ( 22%)IgG suppressionNo204 ( 92%)15 ( 83%)0.186Yes17 ( 8%)3 ( 17%)IgM suppressionNo169 ( 76%)9 ( 50%)0.013Yes52 ( 24%)9 ( 50%)Level of suppression>50%40 (18.1%)8 (44.4%)0.047<50%113 (51.1%)6 (33.3%)None68 (30.8%)4 (22.2%)M/total0.5 ± 0.50.7 ± 0.20.001SFLR18.1 ± 74.733.6 ± 45.70.033UPEPNo108 ( 59%)11 ( 65%)0.629Yes76 ( 41%)6 ( 35%)% plasma cells3.7 ± 2.99.5 ± 1.9<.001Hb12.4 ± 2.111.9 ± 1.90.320Time to progressionN/A30 (12, 51) Disclosures:No relevant conflicts of interest to declare.

Transcriptional Characterization of a Prospective Series of Primary Plasma Cell Leukemia Revealed Signatures Associated with Tumor Progression and Poorer Outcome

Plasma cell leukemia (PCL) is a rare form of plasma cell dyscrasia that presents either as a progression of previously diagnosed multiple myeloma, namely secondary PCL, or as initial manifestation of disease, namely primary PCL (pPCL). Although the presenting signs and symptoms include those seen in multiple myeloma, pPCL is characterized by several aspects that define a more aggressive course. Here, we have investigated the transcriptome of pPCLs and correlated differential expression profiles with outcome to provide insights into the biology of the disease. The expression profiles of 21 newly diagnosed pPCLs included in a multicenter prospective clinical trial were generated using high-density microarray, then evaluated in comparison with a representative series of patients with multiple myeloma and in association with clinical outcome. All but one of the pPCLs had one of the main immunoglobulin heavy-chain locus translocations, whose associated transcriptional signatures resembled those observed in multiple myeloma. A 503-gene signature distinguished pPCL from multiple myeloma, from which emerged 26 genes whose expression trend was associated with progressive stages of plasma cells dyscrasia in a large dataset from multiple institutions, including samples from normal donors throughout PCL. Finally, 3 genes were identified as having expression levels that correlated with response to the first-line treatment with lenalidomide/dexamethasone, whereas a 27-gene signature was associated with overall survival independently of molecular alterations, hematologic parameters, and renal function. Overall, our data contribute to a fine dissection of pPCL and may provide novel insights into the molecular definition of patients with poorer prognosis.

Biological and Clinical Relevance of miRNA Expression Signatures in Primary Plasma Cell Leukemia

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. 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. 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. Overall, our study provides insights into the possible contribution of miRNAs in the pathogenesis of pPCL and suggests targets for future therapeutic investigations.

Plasmacytoma cases with unfamiliar clinical features

Plasmacytoma is a relatively rare form of plasma cell dyscrasias with indolent clinical features. Major localizations are in the upper airways and the region of head. Since it represents only a minority of all plasma cell neoplasms, careful histological review should be addressed to the specimens of these patients. In this paper the authors report three cases, developing plasmacytoma with uncommon clinical features. First patient had an unfamiliar localization of plasmacytoma in the cerebellopontine angle which was first meant to be malignant meningioma and later a large subcutaneous mass was detected in the gluteal region. Second patient developed plasmacytoma after a prostate adenocarcinoma as a secondary malignancy. Third patient, developed plasmacytoma and definite plasma cell myeloma with a coexistence of systemic sclerosis. Treating patients with chemo-radiotherapy, and irradiating the one with localized disease resulted in complete remission in two out of the three patients. Imaging techniques such as positron emission tomography combined with computed tomo- graphy (PET-CT) proved to be useful as tumor exploration tool, however multidisciplinary cooperation is recommended in these cases.

Outcomes of Patients with POEMS Syndrome Treated Initially with Radiation

AbstractAbstract 448 Background:POEMS syndrome is a rare form of plasma cell dyscrasia that presents with polyneuropathy and various other systemic findings. Patients with 1–3 lesions and bone marrows without clonal plasma cells have been given targeted radiation as the initial and potentially definitive therapy. Outcomes of patients treated thus have not been systematically studied. Patients and Methods:One hundred and forty-six patients with POEMS syndrome were seen at the Mayo Clinic in Rochester, MN between January 1999 and September 2011. Charts of patients with research authorization were reviewed with IRB approval. Patients who had been given targeted radiation as their initial primary therapy were eligible for this study. Thirty-eight patients satisfied criteria and comprise the study population. Three patients had either short or poorly documented follow-up and were excluded from the response and time to next treatment analyses. Patients were categorized by systems that were involved at diagnosis, time of radiation, response after radiation, and the need for further therapy. Statistical analyses were performed using JMP statistical software (SAS, Carey, NC). Results:The median age was 50, with 76% of the population being male. Median time from diagnosis to radiation was 0.7 months, ranging from 0 to 9.4 months. 20, 14, 11 and 2 patients had immunosuppressive therapy with corticosteroids, IVIG, plasmapheresis, or rituximab, respectively, directed at a prior presumptive, but incorrect, diagnosis of CIDP. Five patients had one cycle or less of alkylator, lenalidomide, or bortezomib, prior to receiving what was hoped to be definitive radiation therapy. The median number of bone lesions was 1, range 1–6. In total 55 lesions of the possible 64 were irradiated being mostly found in the pelvic bones including the sacrum, ileum, ischium, and pubis. The median dose of radiation given was 45 Gy range 35 Gy to 54 Gy.Forty-nine percent had clinical improvement, 26% had a mixed clinical picture, 3% merely stabilized, and 23% had a clinical worsening. 29% had a complete hematologic response, 9% had a very good partial hematologic response, 9% had a partial hematologic response, 26% had no hematologic response, and the remaining were either non- or oligo-secretory or undocumented. 11% had a complete FDG-PET response, 11% had a partial FDG-PET response, 11% had no FDG-PET response, and the remaining had no documented FDG-PETs to analyze. 11% had a complete VEGF response, 3% had partial VEGF response, 14% had no VEGF response, and the rest were either not documented or unevaluable.The median follow up of living patients is 30 months, and the 4-year OS is 95%. Forty-eight percent of patients went on to receive additional therapy after their radiation (Figure). The median time to next therapy (TTNT) for these patients was 7.6 months (range 2.2 –73 months). Subsequent therapies included high dose chemotherapy with autologous hematopoietic stem cell transplant (n=10), low dose alkylator (n=2), thalidomide/lenalidomide (n=3), and more radiation (n=3). None of the baseline characteristics predicted for whether a patient would receive (or require) subsequent therapy, including the number of bone lesions at baseline. Conclusion:The results show that radiation is sufficient to produce clinical improvements and hematologic and radiographic responses approximately 50% of patients, even those with as many as 3 lesions. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Genome‐wide analysis of primary plasma cell leukemia identifies recurrent imbalances associated with changes in transcriptional profiles

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.

Clinico-Pathological Spectrum of Primary Plasma Cell Leukemia Diagnosed at a Tertiary Care Centre in South India Over 5 Year Period

Plasma cell leukemia (PCL) represents a rare and aggressive form of plasma cell dyscrasia which can be primary (pPCL) or secondary (sPCL). It is diagnosed based on absolute plasma cell count of more than 2.0×10(9)/l or a relative proportion of greater than 20% of the peripheral blood leukocyte count. Although pPCL and sPCL share several clinical features, important differences exist. Patients with pPCL are younger; often have extra osseous organ involvement (liver, spleen and other extramedullary sites), increased frequency of renal failure, fast declining performance status and rapid progression to the terminal stage. Patients with sPCL have advanced bone disease. Presented in this article is India data of a short series of five cases of PCL diagnosed at a tertiary care centre from south India over last 5years. All cases were de novo and had varied spectrum of presentation and so were not suspected to be plasma cell dyscrasia clinically. Detailed hemato-pathological evaluation clinched the diagnosis in all the cases.

IgG Myeloma Presenting as a Large Mediastinal Mass and Pleural Effusion

Plasmacytoma, a rare form of plasma cell dyscrasia, refers to a neoplastic proliferation of plasma cells. Although the upper aerodigestive tract is the most common site for extramedullary plasmacytoma, mediastinal and pleural involvement is extremely rare. We report the case of a patient who presented with a large mediastinal mass and pleural effusion. Diagnosis was challenging and subsequently made as mediastinal extramedullary plasmacytoma with simultaneous myelomatous pleural effusion. Further investigations revealed multiple myeloma.

Primary plasma cell leukemia with light chain secretion and multiple chromosomal abnormalities: How successfully treated? - A case report with review of literature

Primary plasma cell leukemia is a rare form of plasma cell dyscrasia. We present a case which had leukocytosis with numerous circulating plasma cells in the peripheral blood. Flow cytometry revealed an unusual CD117 expression. Free light chain analysis in the serum showed a markedly elevated level of free lambda light chains. Radiography did not reveal any lytic lesions. Fluorescent in-situ hybridization analysis revealed deletion of 13q14.3 and t(4;14)/t(11;14), while the cytogenetic analysis was normal. The patient was given chemotherapy and was subjected to autologous stem cell transplant, after which she is in complete remission till date.

From standard radiography to whole-body MRI: 30 years of progress in multiple myeloma imaging

Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells within the bone marrow. It is the most serious form of plasma cell dyscrasias, whose complications—hypercalcemia, renal failure, anemia, and lytic bone lesions—are severe and justify the therapeutic management. Imaging of bone lesions is a cardinal element in the diagnosis, staging, study of response to therapy, and prognostic evaluation of patients with MM. Historically, the skeletal radiographic workup (SRW), covering the entire axial skeleton, has been used to detect bone lesions. Over time, new imaging techniques that are more powerful than SRW have been evaluated. Low-dose and whole-body computed tomography (CT) supplants SRW for the detection of bone involvement, but is of limited value in assessing therapeutic response. Bone marrow MRI, initially studying the axial pelvic-spinal skeleton and more recently the whole body, is an attractive alternative. Beyond its non-irradiating character, its sensitivity for the detection of marrow damage, its capacity to evaluate the therapeutic response and its prognostic value has been demonstrated. This well-established technique has been incorporated into disease staging systems by many health systems and scientific authorities. Along with positron emission tomography (PET)-18 fluorodeoxyglucose CT, it constitutes the current imaging of choice for MM. This article illustrates the progress of the MRI technique over the past three decades and situates its role in the management of patients with MM.

Response of primary plasma cell leukemia to the combination of bortezomib and dexamethasone: Do specific cytogenetic and immunophenotypic characteristics influence treatment outcome?

Plasma cell leukemia (PCL) is a rare and aggressive form of plasma cell dyscrasias. Its special biological characteristics may play an important role in the poor outcome when treated with conventional therapy or even with stem cell transplantation. New treatment approaches based on the biology of this disease are mandatory. Here we present three cases of primary PCL with adverse cytogenetics (deletion 13q14 and translocation 4;14) and specific immunophenotypic features (CD27 antigen strong expression) in which excellent response and sustained remission was achieved with the combination of bortezomib and dexamethasone. The possible role of these biological characteristics is been analyzed.

Role of osteoblast suppression in multiple myeloma

Multiple myeloma is the most common form of plasma cell dyscrasia and virtually all cases of myeloma exhibit osteolytic lesions, which result in bone pain, pathological fractures, spinal cord compression, and hypercalcaemia. Malignant plasma cells disrupt the delicate balance between bone formation and bone resorption, which ultimately leads to the debilitating osteolytic lesions. This review focuses principally on mechanisms of osteoblast inhibition by malignant plasma cells with emphasis placed on our experimental findings, which support a model for abnormal Wnt signaling in osteoblast suppression. We describe how excessive amounts of soluble Wnt inhibitors secreted by malignant plasma cells in multiple myeloma could promote osteolytic lesions, tumor growth, suppress hematopoiesis, prevent proper engraftment, and expansion of transplanted stem cells. Finally, we detail current therapies shown to disrupt the interaction between the myeloma cell and the microenvironment, leading to activation of osteoblasts.

Gene expression profiling of plasma cell dyscrasias reveals molecular patterns associated with distinct IGH translocations in multiple myeloma

Multiple myeloma (MM) is the most common form of plasma cell dyscrasia, characterized by a marked heterogeneity of genetic lesions and clinical course. It may develop from a premalignant condition (monoclonal gammopathy of undetermined significance, MGUS) or progress from intramedullary to extramedullary forms (plasma cell leukemia, PCL). To provide insights into the molecular characterization of plasma cell dyscrasias and to investigate the contribution of specific genetic lesions to the biological and clinical heterogeneity of MM, we analysed the gene expression profiles of plasma cells isolated from seven MGUS, 39 MM and six PCL patients by means of DNA microarrays. MMs resulted highly heterogeneous at transcriptional level, whereas the differential expression of genes mainly involved in DNA metabolism and proliferation distinguished MGUS from PCLs and the majority of MM cases. The clustering of MM patients was mainly driven by the presence of the most recurrent translocations involving the immunoglobulin heavy-chain locus. Distinct gene expression patterns have been found to be associated with different lesions: the overexpression of CCND2 and genes involved in cell adhesion pathways was observed in cases with deregulated MAF and MAFB, whereas genes upregulated in cases with the t(4;14) showed apoptosis-related functions. The peculiar finding in patients with the t(11;14) was the downregulation of the alpha-subunit of the IL-6 receptor. In addition, we identified a set of cancer germline antigens specifically expressed in a subgroup of MM patients characterized by an aggressive clinical evolution, a finding that could have implications for patient classification and immunotherapy.

Gene Expression Profiling of Plasma Cell Dyscrasias: The Role of IGH Translocations in the Heterogeneity of Multiple Myeloma.

Multiple Myeloma (MM) is the most common form of plasma cell dyscrasia, characterized by a marked heterogeneity of genetic lesions and clinical course. It may develop from a premalignant condition (monoclonal gammopathy ofundetermined significance, MGUS) or progress from intra-medullary to extra-medullaryforms (plasma cell leukemia, PCL). To provide insights into the molecular characterization of plasma cell dyscrasias and to investigate the contribution of specific genetic lesions to the biological and clinical heterogeneity of MM, we analyzed the gene expression profiles of plasma cells isolated from 7 MGUS, 39 MM and 6 PCL patients by means of DNA microarrays. MMs resulted highly heterogeneous at transcriptional level, whereas the differential expression of genes mainly involved in DNA metabolism and proliferation distinguished MGUS from PCLs and the majority of MM cases. The clustering of MM patients was mainly driven by the presence of the most recurrent translocations involving the immunoglobulin heavy-chain locus. Distinct signatures have been found to be associated with different lesions: the overexpression of CCND2 and genes involved in cell adhesion pathways was observed in cases with deregulated MAF and MAFB, whereas genes upregulated in cases with the t(4;14) showed apoptosis related functions. In addition, we identified a set of cancer germ-line antigens specifically expressed in a sub-group of MM patients characterized by an aggressive clinical evolution, a finding that could have implications for patient classification and immunotherapy.

Solitary extramedullary plasmacytoma of tonsil — a rare location

Extramedullary plasmacytoma is a rare form of plasma cell dyscrasia, in which plasmacell tumours arise outside the bone marrow. The tumor may arise in any part of the body but the vast majority occur in head and neck, primary in the nasal cavity, paranasal sinuses or upper airway. We present here a rare case of extramedullary plasmacytoma arising from the tonsil The clinical, histolopathology, immunohistochemical findings are reviewed and the management discussed.

Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients.

Fifty-seven cases of Ig light chain-associated Fanconi syndrome (FS) have been reported so far, mostly as isolated reports. The pioneering work by Maldonado and associates (35), who reviewed the first 17 cases in 1975, led to the unifying concept that patients with FS and Bence Jones proteinuria have a special form of plasma cell dyscrasia characterized by slow progression of the tumor and by prominent crystal formation in proximal tubule cells, in the absence of myeloma casts in the distal tubule. We carefully reappraised these characteristics in a series of 11 patients. Ten renal biopsy specimens were available for electron microscopy, adding to the 15 previously reported cases with ultrastructural studies. Moreover, 10 of the kappa light chains could be entirely or partially sequenced and tested for their resistance to cathepsin B, a lysosomal protease present in proximal tubule cells. Our series showed an unexpected clinicopathologic heterogeneity. Seven patients presented with the typical clinical and pathologic features of FS and low-mass myeloma or monoclonal gammopathy of undetermined significance (MGUS), in keeping with Maldonado et al's description. Crystals in bone marrow cells were detected in patients of this group, only. Three patients who presented with full-blown FS exhibited, however, the characteristic features of myeloma cast nephropathy in the setting of high-mass myeloma. One patient of this group also had numerous crystals in proximal tubule cells. The eleventh patient had complete FS with MGUS, but no crystals in proximal tubule cells even after electron microscopy. Contrasting with the clinicopathologic heterogeneity, genetic and biochemical analyses of the light chains showed a striking homogeneity. First, they all were of the kappa type. Second, 8 of 9 belonged to the V kappa I variability subgroup, which indicates that FS light chains are related by the sequence of their variable regions. Third, the 8 V kappa I light chain sequences most likely originated from only 2 germline genes, LCO2/012 and LCO8/018. Fourth, all 5 LCO2/012-derived sequences presented an unusual hydrophobic or nonpolar residue at position 30. These sequence peculiarities may account for unusual physicochemical properties of the light chains including the resistance of their variable domain V kappa to proteolysis by cathepsin B, observed in 7 of 9 patients in our series, while light chains isolated from patients with myeloma cast nephropathy are completely digested. Resistance of V kappa to proteolysis in FS patients can explain the accumulation of the light chain in the endocytotic compartment of the proximal tubule cells, leading to impairment of proximal tubule functions.

NONSECRETORY MYELOMA, IMMUNOGLOBULIN D MYELOMA, AND PLASMA CELL LEUKEMIA

Nonsecretory myeloma, which accounts for 1% to 5% of all myelomas, is characterized by the absence of detectable M-protein in serum and urine. The presenting features of nonsecretory myeloma are similar to those in patients with a detectable M-protein, except for the absence of renal function impairment. The response to therapy and survival of patients with nonsecretory myeloma are similar to those of patients with measurable M-protein. Immunoglobulin D myeloma represents 2% of all myelomas. Patients with IgD myeloma usually present with a small band or no evident M-spike on serum electrophoresis and heavy light-chain proteinuria. Thus, IgD myeloma can be considered a variant of Bence Jones myeloma; the presence of the IgD M-protein and the predominance of the lambda light chain are the only distinctive features. The median survival of patients with IgD myeloma is almost 2 years, with one fifth of them surviving for more than 5 years. Plasma cell leukemia is also a rare form of plasma cell dyscrasia (2% to 4% of all myelomas). The primary form accounts for 60% of the cases. In primary PCL, the constellation of adverse biologic prognostic factors in patients with advanced aggressive myeloma is already present at diagnosis. In fact, primary PCL has a more aggressive clinical presentation than MM, with a higher frequency of extramedullary involvement, anemia, thrombocytopenia, hypercalcemia, and renal failure. Treatment with a single alkylating agent plus prednisone is not appropriate. Combination chemotherapy with VAD, cyclophosphamide and etoposide, or VCMP/VBAP is a better initial option. Given the poor prognosis of primary PCL, intensification with high-dose therapy followed by stem cell rescue should be offered to affected patients.