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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.

Background: Multiple myeloma (MM) usually follows a clinical course leading to refractoriness and limited treatment options in advanced stages, which might need bridge therapies to either autologous stem cell transplantation or novel therapies. We report our experience with the high-dose chemotherapy mCBAD (modified cyclophosphamide, bortezomib, doxorubicin, and dexamethasone) regimen in newly diagnosed MM (NDMM), relapsed/refractory MM (RRMM), and plasma cell leukemia (PCL) patients., Patients and Methods: We searched our electronic records database for MM patients who received mCBAD from 2010 to 2016 for 28-day cycles of cyclophosphamide 350 mg/m 2 intravenously (I.V.) twice daily with mesna 400 mg/m 2 I.V. daily (days 1-4), bortezomib 1.3 mg/m 2 subcutaneously/I.V. (days 1, 4, 8, 11), doxorubicin 9 mg/m 2 daily continuous infusion (days 1-4), dexamethasone 40 mg orally daily (on days 1-4, 9-12, 17-20). International Myeloma Working Group (IMWG) criteria were used for response assessment and diagnosis. Descriptive statistics, Fisher exact test, χ 2 , Wilcoxon rank sum, and Kaplan-Meier were used for statistical purposes., Results: One hundred forty patients met the inclusion criteria. A median of 2 cycles of therapy was administered. The overall response rate was 85% in patients with RRMM (n = 116) and 100% in NDMM (n = 13) and PCL (n = 11) patients. Respective median progression-free survival (mPFS) for NDMM, PCL, and RRMM were 19.61 months (95% confidence interval [CI], 5.26 to not applicable [NA]), 7.56 months (95% CI, 4.7 to NA), and 4.64 months (95% CI, 3.75-6.73). Patients with RRMM who used mCBAD as a bridge to autologous transplant (36.2%) had mPFS (11.48 months; 95% CI, 7.52-15.9 months) compared with those who did not (mPFS: 3.19 months; 95% CI, 2.4-3.75 months). Cytopenias occurred in more than 90% of patients, and febrile neutropenia was noted in 26%. All cases of treatment-related mortality (8%) occurred in patients with RRMM, except for 1 patient with PCL., Conclusion: mCBAD results in high response rates in myeloma and PCL, however, with high treatment-related mortality. Its use in RRMM should be limited to patients who have immediate need for therapy without other treatment options and who have good performance status (score of 0-1) or NDMM if novel agents are not available depending on practice setting. mCBAD can be a treatment option for patients with PCL., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This multicenter retrospective study included 101 patients (median age 62 years) with secondary plasma cell leukemia (sPCL). The median time from initial multiple myeloma diagnosis to sPCL was 31 months. Fifty-five out of 72 patients (75%) who received any therapy were treated with immunomodulators (IMiDs) and/or proteasome inhibitors (PIs), and 14/72 (19%) underwent salvage autologous stem cell transplantation (ASCT). The overall response rate in patients who received ASCT or PI (either alone or in combination) was higher than in those who did not (93% vs. 36% and 60% vs. 30%, respectively). The median overall survival (OS) in patients who received therapy was 4.2 months (95% CI: 1.3; 8.0) with a 1-year OS of 19%. Platelet count ≤100 × 10 9 /L at sPCL diagnosis was the only independent predictor of a poorer OS in treated patients (HR = 3.98, p = .0001). These findings suggest that patients with sPCL may benefit from salvage ASCT- and PI-based regimens.

The presence of circulating plasma cells in patients with multiple myeloma is considered a marker for highly proliferative disease. In the study herein, the impact of circulating plasma cells assessed by cytology on survival of patients with multiple myeloma was analyzed. Wright-Giemsa stained peripheral blood smears of 482 patients with newly diagnosed myeloma or plasma cell leukemia were reviewed and patients were classified into 4 categories according to the percentage of circulating plasma cells: 0%, 1-4%, 5-20%, and plasma cell leukemia with the following frequencies: 382 (79.2%), 83 (17.2%), 12 (2.5%) and 5 (1.0%), respectively. Median overall survival according to the circulating plasma cells group was 47, 50, 6 and 14 months, respectively. At multivariate analysis, the presence of 5 to 20% circulating plasma cells was associated with a worse overall survival (relative risk 4.9, 95% CI 2.6-9.3) independently of age, creatinine, the Durie-Salmon system stage and the International Staging System (ISS) stage. Patients with ≥5% circulating plasma cells had lower platelet counts (median 86×10 9 /L vs 214×10 9 /L, P <0.0001) and higher bone marrow plasma cells (median 53% vs 36%, P =0.004). The presence of ≥5% circulating plasma cells in patients with multiple myeloma has a similar adverse prognostic impact as plasma cell leukemia., (Copyright© Ferrata Storti Foundation.)

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.)

Introduction: Bortezomib-based therapy is commonly used in treatment for relapsed or refractory multiple myeloma (MM). Unfortunately, many patients show relapse or progression in heterogeneous patterns., Patients and Methods: In this study, we retrospectively evaluated patterns of relapse or progression after bortezomib-based salvage therapy in patients with MM and analyzed prognostic significance according to patterns of relapse or progression. One hundred forty-eight patients were treated with bortezomib-based therapy between November 2004 and April 2012. Of these patients, 104 (70.3%) patients relapsed or progressed after bortezomib-based salvage therapy. We divided the patterns of relapse or progression to the 2 groups: (1) the isoform relapse or progression (group A) in 89 (85.6%) patients as disease findings at initiation of bortezomib-based therapy; and (2) transformed relapse or progression (group B) in 15 (14.4%) patients (plasmacytoma, n = 7; light chain escape, n = 6; and plasma cell leukemia, n = 2) different from initial disease findings., Results: Median overall survival in group A and group B were 32.7 months (95% confidence interval [CI], 21.3-44.1) and 10.7 months (95% CI, 2.0-19.4) (P < .001), respectively., Conclusion: MM patients who relapsed or progressed as the transformed pattern for bortezomib-based salvage therapy have an extremely poor prognosis and might require new innovative approaches., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Secondary monoclonal gammopathy of undetermined significance (MGUS) is a special phenomenon that occurs during the treatment of multiple myeloma (MM). The incidence, biological characteristics, and prognostic value of secondary MGUS in patients with MM remain undefined. We proceed with a retrospective systematic review of serum immunofixation electrophoresis studies performed in 438 cases of patients with plasma cell dyscrasias, including 409 cases of newly diagnosed MM and 29 cases of primary plasma cell leukemia. Secondary MGUS was more common in patients with myeloma who had undergone stem cell transplantation than in those who had not (17 [29.8%] of 57 versus 5 [1.4%] of 352, P < .001). The clinical parameters and cytogenetic characteristics in patients with or without secondary MGUS were comparable. The complete response rates in patients with or without secondary MGUS were 81.8% and 21.8% respectively (P < .01). For the cohort as a whole, secondary MGUS was associated with significantly prolonged progression-free survival (median, 52.0 months versus 22.5 months; P = .002) and overall survival (median, not reached versus 35.0 months; P < .001). The presence of secondary MGUS retained independent prognostic value with a moderate impact on overall survival (hazard ratio .128 [95% confidence interval .018 to .922]; P = .041) in the multivariate Cox regression model. However, when analysis was restricted to patients undergoing stem cell transplantation, no statistical differences in progression-free survival and overall survival were found. In conclusion, we observe that secondary MGUS was frequently observed in MM patients after transplantation and conferred a survival prolongation. The favorable survival in patients with secondary MGUS may be explained by beneficial effect from myeloablative therapy., (Copyright © 2014 American Society for Blood and Marrow Transplantation. All rights reserved.)

Background: Reduced-intensity conditioning allogeneic transplantation for myeloma is associated with lower non-relapse mortality and higher relapse rates in comparison with myeloablative conditioning transplants., Patients and Methods: We have retrospectively audited 19 patients with myeloma or primary plasma cell leukemia who received allogeneic transplantation with a uniform alemtuzumab-based reduced-intensity conditioning protocol. These patients had not been treated with bortezomib or lenalidomide before transplantation., Results: The treatment-related mortality at 1 year was (4/19) 21% with low incidence of graft-versus-host disease (6%) and 2-year progression-free survival and overall survival rates of 35% and 42%, respectively., Conclusion: Progression-free survival in this cohort of patients is comparable to previously published data of reduced-intensity conditioning allogeneic transplantation in myeloma. However, there is no plateau observed on the survival curves with a significant transplant-related mortality of 21%. Therefore, alemtuzumab-based allogeneic transplantation cannot be recommended as standard practice outside of clinical trials for treatment of myeloma., (2011 Elsevier Inc. All rights reserved.)

We analysed the clinical impact of epigenetic dysregulation of the Wnt pathway in malignant plasma cell disorders. In multiple myeloma (MM) cell lines, aberrant promoter hypermethylation of the secreted Frizzled-related protein (SFRP) genes was a common event, and hypermethylation of SFRP1,-2 and -5 was associated with transcriptional silencing. Among 76 primary patient samples, the frequency of aberrant methylation was 35.5% for SFRP1, 52.6% for SFRP2, 1.3% for SFRP4 and 6.9% for SFRP5. Hypermethylation of SFRP1 and -2 genes was detected in monoclonal gammopathy of undetermined significance and all MM stages including plasma cell leukaemia (PCL), while SFRP5 methylation was restricted to advanced MM stages and PCL. Our data indicate that epigenetic silencing of Wnt antagonists is an early event in MM pathogenesis and that SFRP5 hypermethylation may play a role in disease progression.

Plasma cell leukemia (PCL) is a rare variant of multiple myeloma (MM). Patients may either present de novo (primary PCL), or PCL may occur during the course of MM (secondary PCL). We compared the laboratory and clinical findings of both primary and secondary PCL and MM to elucidate their natural history and the relationship among these entities. Ten cases of PCL (7 cases of primary PCL and 3 cases of secondary PCL) and 20 sex- and age-matched cases of MM were compared. The patients with primary PCL showed significantly lower platelet and neutrophil counts in peripheral blood and higher cellularity in bone marrow than patients with MM (p = 0.002, < 0.001 and 0.027, respectively). Immunophenotypic studies showed a different expression of HLA-DR and CD117 antigens among the 3 groups. There was a significant difference in survival between the 3 groups (median survival of primary PCL, secondary PCL and MM = 22.2, 1.3 and 36.4 months, respectively; p = 0.048). The patients with primary PCL showed better prognosis than those with secondary PCL. Primary PCL might be a differently developed disease from MM. In diagnosing PCL, it is important to differentiate primary PCL from secondary PCL for the prediction of prognosis., (2007 S. Karger AG, Basel)

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.

The most common chromosomal translocation in multiple myeloma (MM) is t(11;14)(q13;q32). Here, we describe the clinical characteristics of patients with MM who have this translocation. We have identified 24 patients at our institution who had t(11;14)(q13;q32) as determined by standard cytogenetic analysis (CC). Seven patients had the translocation detected at the time of original diagnosis and 17 at the time of relapse. Median survival in all patients after original diagnosis was 43 months; median survival after the translocation was detected was 11.9 months. Four patients had a clinical diagnosis of plasma cell leukemia. Most patients had an elevated beta2-microglobulin (13/20 had >4 microg/ml). The bone marrow (BM) labeling index (LI) of patients, at the time of translocation detection, was elevated in most (median 1.4%, 17/23 patients had BMLI > or = 1%). Of the 24 patients, 19 (79%) died of disease progression and 5 (21%) were alive with disease at last follow-up. Lytic lesions, bone pain, or compression fractures eventually developed in all patients. Patients with MM who have t(11;14)(q13;q32) detected by standard cytogenetics seem to have an aggressive clinical course.

In this study, we analyzed 69 plasma cell neoplasms, including 54 multiple myelomas (MMs), 3 cases of plasma cell leukemia, and 12 plasmacytomas, for expression of cyclin D1 protein using an immuno-histochemical method applied to routinely fixed, paraffin-embedded tissue sections. Cyclin D1 was expressed in 18 (26%) of 69 plasma cell neoplasms, including 16 (30%) of 54 MMs and 2 (17%) of 12 plasmacytomas. Three cases of plasma cell leukemia were negative. Cyclin D1 expression correlated with the cytologic differentiation and histologic stage of MM. Twelve (75%) of 16 MMs had intermediate or immature cytologic features and were histologic Stage III. With use of a polymerase chain reaction assay, we also analyzed six cases (three cyclin D1 positive, three cyclin D1 negative) for the t(11;14); one MM carried the t(11;14) and expressed cyclin D1 protein. We conclude that cyclin D1 expression occurs in approximately one-quarter of plasma cell neoplasms and correlates with the degree of cytologic differentiation and histologic stage. The relatively high frequency of cyclin D1 expression, compared with the less than 5% incidence of the t(11;14) detected by conventional cytogenetics reported in the literature, suggests that upregulation of cyclin D1 protein might be the result of mechanisms other than the t(11;14).

In patients with advanced multiple myeloma (MM) there is an excess of production of interleukin-6 (IL-6) in vivo, and elevated serum levels are associated with plasmablastic proliferative activity and short survival. These data prompted us to perform a clinical trial with a murine anti-IL-6 monoclonal antibody (MoAb) to neutralize the excess of this putatively deleterious factor in these patients. Ten MM patients with extramedullary involvement frequently were treated with anti-IL-6 MoAb. The MoAb was administered intravenously to 9 patients; 1 patient with malignant pleural effusion received intrapleural therapy. Of the 3 patients who succumbed to progressive MM after less than 1 week of treatment (including the only 1 treated locally), 2 with evaluable data exhibited marked inhibition of plasmablastic proliferation. Among the 7 patients remaining more homogeneous receiving the anti-IL-6 MoAb for more than 1 week, 3 had objective antiproliferative effect marked by a significant reduction of the myeloma cell labelling index within the bone marrow. One of these 3 patients achieved a 30% regression of tumor mass. However, none of the patients studied achieved remission or improved outcome as judged by standard clinical criteria. Of major interest, objective antiproliferative effects were associated with complete inhibition of C-reactive protein (CRP) synthesis and low daily IL-6 production in vivo. On the other hand, the lack of effect in 4 patients was associated with a higher IL-6 production and inability of the MoAb to neutralize it. Anti-IL-6 was also associated with resolution of low-grade fever in all the patients and with worsening thrombocytopenia and mild neutropenia. The generation of human antibodies to Fc fragment of the murine anti-IL-6 MoAb observed in 1 patient was associated with dramatic progression. These data show that anti-IL-6 MoAb can suppress the proliferation of myeloma cells and underscore the biologic role of IL-6 for myeloma growth in vivo. Furthermore, suppression of CRP and worsening of neutropenia/thrombocytopenia both indicate that IL-6 is critically involved in acute-phase responses and granulopoiesis/thrombopoiesis.

Between October 1988 and October 1991, 104 patients with multiple myeloma and 6 with plasma cell leukaemia were studied cytogenetically. Abnormal karyotypes were found in bone marrow cells of 33 patients (30%). Most pathological karyotypes were complex with numerous modal and structural anomalies. Numerical anomalies most frequently involved chromosome 11 and structural aberrations occurred most often in chromosomes 1, 11 and 14. The most consistent structural aberration was a 14q+ chromosome (10 patients) resulting from a t(11;14)(q13;q32) in 4 patients and a t(8;14)(q24;q32) in 1 patient. Sequential cytogenetic studies were performed in 15 patients. In 5 of 8 cases with a normal karyotype at diagnosis, chromosomal anomalies were detected when disease progressed. In concomitant cytogenetic/cytological studies it was found that in the majority of patients with normal karyotype the mitoses originated from contaminating normal bone marrow cells. Pathological karyotypes were detected more frequently in pretreated than in untreated patients, in patients with plasma cell leukaemia than in patients with multiple myeloma, in patients with stage III and dense bone marrow infiltration than in patients with stage I. Patients with abnormal karyotype, irrespective if pretreated or not, had a significantly shorter median survival than those with normal karyotype. These findings suggest that karyotype is an independent prognostic factor in multiple myeloma.

Three patients, one with plasma cell leukemia and clinically asymptomatic hypernephroma and meningioma, and two others with multiple myeloma, had M-components of IgD/lambda type. In the first case, IgD globulin was found in the serum, ascitic and pleural fluids. Including our patients, 50 cases of IgD myeloma have been reported in the literature. A review of this group showed some significant differences from the other classes of multiple myeloma. IgD myeloma seems to involve a larger proportion of younger people, 66% being less than 59 years of age. The involvement of internal organs and renal damage were more frequent in IgD myeloma than in other classes. Serum total protein was frequently not increased, the relative concentration of M-component was often low and in 12% there was no spike in electrophoresis. The diagnosis therefore was sometimes difficult. In a quarter of the cases Bence Jones proteinemia was found and in 15% there were multiple spikes, both these manifestations being rare in IgG or IgA classes of myeloma. In 89%, IgD globulin had lambda type light chain, clearly contrasting with the figure of approximately 30% in other classes. Bence Jones protein was found in the urine in 91%. The survival time seemed to be shorter than in other myelomas.