Primary Plasma Cell Leukemia Patients Research Articles

Development of a clinical prognostic model for primary plasma cell leukemia patients treated with novel agents: a multicenter retrospective cohort study.

The prognosis of primary plasma cell leukemia (pPCL) is poor, and the relevant prognostic factors are incompletely understood. We aimed to explore the prognostic factors and develop a validated prognostic prediction model for pPCL patients in the new era. This multicenter retrospective study was conducted across 16 hospitals in China. Cox proportional hazards regression analysis was used to develop a prediction model. The predictive performance of the model was assessed using multiple metrics. Internal validation was conducted using bootstrap resampling. A total of 102 pPCL patients were included in this study, and 57 (55.9%) were male. The 12-month, 24-month, and 36-month OS rates for pPCL patients were 75.4%, 58.3%, and 47.6%, respectively. An overall survival prognostic nomogram for pPCL patients was established by integrating independent prognostic factors, including age, B2MG, and del17p. The nomogram exhibited good performance, with a C-index of 0.720 (95% CI 0.642-0.797) and an AUC of 0.653. Bootstrap validation yielded a C-index of 0.721 (95% CI 0.629-0.787) and an AUC of 0.653 (95% CI 0.546-0.759), indicating a relatively good fit of the calibration curve. A nomogram incorporating age, B2MG grade, and del17p were developed and validated to accurately and consistently predict the prognosis of pPCL patients.

Single-Cell RNA Sequencing Identifies Distinct Immune Microenvironment in Patients with Primary Plasma Cell Leukemia

Background: Primary plasma cell leukemia (PCL) is a highly aggressive form of multiple myeloma (MM). While recent advances in cellular immunotherapy have significantly improved the outcome of patients with MM, these benefits have been limited for PCL patients, and their survival remains poor. This is in partly attributable to our limited understanding of the dysregulated immune microenvironment in PCL. Furthermore, distinct biological features of PCL compared with MM have not been clearly defined. In this regard, we performed single-cell RNA sequencing of bone marrow (BM) immune cells and tumor cells from patients with MM and PCL at diagnosis and compared them with BM immune cells from healthy donors. Methods: Single-cell analysis was performed using 10X Genomics with BM mononuclear cells (BMMCs) isolated from healthy donors (n=3), MM patients (n=2), PCL patients with lower circulating plasma cells (5-20%) (PCL-1) (n=2), and PCL patients with higher circulating plasma cells (>20%) (PCL-2) (n=2) at diagnosis. Sequencing files were processed with CellRanger (10x Genomics) and the data were analyzed with the Seurat toolkit. Cell types were annotated with SingleR based on the Human Primary Cell Atlas built-in references. Pre-B cells, B cells, plasmablasts, plasma cells, granulocyte/macrophage progenitors (GMPs), hematopoietic stem and progenitor cells (HSPCs), myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs), classical monocytes, non-classical monocytes, T cells, natural killer (NK) cells, and stromal cells between healthy donors, MM, PCL-1, and PCL-2 were annotated. Results: We sequenced a total of 85,268 BMMCs to analyze the heterogeneity and transcriptomic features of BMMCs from healthy, MM, and PCL patients. We characterized changes in the transcriptomic features of T cells, NK cells, monocytes, and DCs between healthy, MM, PCL-1, and PCL-2. We examined CD8 + and CD4 + T cell subsets based on differentiation status, including CCR7 + CD45RA + naïve (TN), CCR7 + CD45RA − central memory T (TCM), CCR7 − CD45RA − effector memory (TEM), and CCR7 − CD45RA + terminally differentiated effector memory T (TEMRA) cells. The proportion of CD8 + TN was decreased in MM, PCL-1, and PCL-2 compared with healthy, while the proportion of TEM was increased in MM and PCL-2 compared with healthy. Of note, the proportion of CD8 + NKG7 + cells was highest in PCL-2, followed by PCL-1 and MM, which were minimally detected in healthy. Among CD4 + T cells, the proportion of regulatory T cells did not differ between the groups. However, cytotoxic CD4 + T cells was increased in MM, PCL-1, and PCL-2 compared with healthy. Analysis of NK cells revealed that the proportion of immature NK cells was decreased, while the proportion of mature NK cells was increased in patients with MM, PCL-1, and PCL-2 compared with healthy. We also examined the plasma cells and observed that diversity in plasma cell types is increased in PCL-1 and PCL-2 compared with MM, indicating that the PCL clone is heterogeneous. Conclusion: We demonstrate the characteristics of BM immune cells in PCL by single-cell RNA sequencing. Additional analyses are ongoing to uncover the association between PCL burden and BM immune cell composition and to gain insight into PCL heterogeneity and define high-risk PCL. Our work should improve our understanding to decipher therapeutic options for PCL.

Plasma Cell Leukemia-Clinicopathological Profile from a Tertiary Care Center in Western India.

Poornima ManimaranIntroduction Plasma cell leukemia (PCL) is very uncommon and aggressive neoplasm constituting 2 to 4% of all plasma cell dyscrasias. By definition, clonal plasma cells should make up 20% of peripheral blood or have an absolute plasma cell count of 2 × 10 9 cells/cu.mm. PCL can be primary or secondary. In this study, the clinicohematological features of PCL, and correlation of immunophenotypic profile and conventional therapies with overall survival was analyzed. Materials and Methods This retrospective study involved PCL patients who were diagnosed across a 12-year period, from 2010 to 2021, at a tertiary care center in western India. Clinical, biochemical, peripheral smear, bone marrow aspirate, immunophenotyping, and molecular analysis were performed. Results Total 39 PCL patients were included in the study among which 36 were primary PCL patients. Splenomegaly (10/27), hepatomegaly (6/26), and lymphadenopathy (5/23) were noted. At presentation, all patients had anemia (<11g/dL), thrombocytopenia (33/39), hypercalcemia (>11mg/dl) 10/33 (30.3%) and lytic lesions was noted in 18/26 (69.2%). Immunophenotype of these patients showed CD 38 positivity, CD 138 positivity, CD56 positivity, and CD 117 negativity were 100, 62, 41.6, and 89%, respectively. Overall survival of our patients was 4.1 months and overall survival of patients treated with VTD (bortezomib, thalidomide, dexamethasone) and VCD (bortezomib, cyclophosphamide, dexamethasone) regimen was 3.4 and 4.1 months, respectively, which was not statically significant ( p -value 0.816). CD117 and CD56 markers were also not having any prognostic significance ( p -value 1.000 and 0.873, respectively). Conclusion Because of rarity of the disease, prospective studies are very limited and hence management and outcome of the disease are difficult to analyze. The current treatment protocols have no survival advantage and hence newer therapeutic approach is mandatory to attain better outcome.

MM-066: Primary Plasma Cell Leukemia: A Rare Entity with Four Cases

Context Primary plasma cell leukemia (PPCL) is a rare hematological malignancy with an incomprehensible pathogenesis and a very aggressive course. Objectives Determining the risk factors that can cause the development of PPCL and affect its course was aimed. Design Four PPCL patients diagnosed at Gulhane Training and Research Hospital between March 2019 and June 2020 were evaluated in terms of laboratory and clinical course retrospectively. Patients or Other Participants The mean age of the patients at the time of diagnosis was 66 years (44–76), and males/females:1/1. None of the patients had a history of multiple myeloma (MM). Results Two patients presented with leukocytosis. Mean WBC was 59.625x103/mL (3800–197,000), average plasma cell in smear was 54.5% (20–100), mean plasma cell was 55,500x103/mL (600–188,000). Leukapheresis was applied to one patient. Anemia was detected in all, mean Hb was 9.9 g/dL. Thrombocytopenia was detected in 3 patients and mean platelet was 101x103m/L. Immunofixation results were IgG lambda in two, free lambda in one, and free kappa in 1 patient. Genetic results could not be reached. One patient was lost to follow-up and 3 patients were given bortezomib-cyclophosphamide-dexamethasone (VCD) in first-line treatment. Two patients died during follow-up, and mean survival was 77 days. One patient who was given 1 cycle VCD and 1 cycle lenalidomide-dexamethasone was lost to follow-up. ASCT could not be planned due to the short life span of the patients. Conclusion Incidence of PPCL is 0.4–1.2/million, progression from MM is seen in 0.5% cases. There is no difference between MM and PPHL in terms of CD38 and CD138 positivity, but CD56 is more frequently positive in MM and CD20 in PCL. CD27 positivity in PCL indicates increased anti-apoptotic activity. Discussion Approximately 150 multiple myeloma patients were followed up in our clinic between the same dates. Secondary PCL cases were not detected, and the fact that all of the diagnosed cases were PPCL created a picture incompatible with the incidence rates reported in the literature. Lambda monoclonality was shown in three of our patients, so it constitutes a feature for PPCL, unlike myeloma. Absence of genetic results is an important lack of our patients. More patients are needed for determination of risk factors in PPCL. It is necessary to identify poor prognostic indicators and urgently undergo transplantation in eligible patients using bortezomib-based treatment regimens.

Primary Plasma Cell Leukemia in China: A Retrospective Single Center Study

Background: Primary plasma cell leukemia (PPCL) is a rare and aggressive malignancy, with a peculiar clinical and biological features and very poor prognosis. It differs from secondary PCL (SPCL), a leukemic transformation from a previously diagnosed multiple myeloma (MM). Although a few studies have suggested that use of novel agents and performing autologous stem cell transplantation (ASCT) has prolonged survival time of PPCL patients, the prognosis is still poor compared with MM, and the optimal therapy remains unclear.Materials and methods: 50 patients with PPCL were enrolled in Blood Diseases Hospital, Chinese Academy of Medical Sciences in China from June 1999 to June 2016. We analyzed the clinical and cytogenetic characteristics of these patients, survival analysis was conducted by Kaplan-Meier estimates and compared using the log-rank test.Results: Median age of 50 cases was 58 years (range between 26 and 86 years), 76% patents were less than 60 years old. There were 34 males and 16 females. The most common immunoglobulin type was IgG (42%), 26% of patients had light chain type. Regarding the ISS, 2 (4.0%) patients were stage I, 7(14.0%) were stage II, and 41 (82.0%) were stage III. 44 patients (88%) was diagnosed with anemia, 5(10%)patients were found leukopenia, while 23 (46%) patients with leukocytosis. 38(76.0%) patients had thrombocytopenia at diagnosis. 14 (28%) patients were found with renal dysfunction. 42(84%) patients showed elevated LDH level.39 (78%) patients had high β-2microglobulin levels (> 5.5 mg/L). 20(40.0%) patients had low serum albumin levels (< 3.5 g/dL) . There were 33(66.0%) patients with hypercalcemia. Organomegaly (liver, spleen and etc.) was detected in 25 (50.0%) patients and osteolytic bone lesions were present in 34(68.0%) patients. 8(16.0%) patients were involved in extramedullary disease.Cytogenetic analysis has showed that the most common abnormalities were complex karyotype (58.3%), while 50% patients with hypodiploid were found in 24 cases. FISH analysis showed that 13 patients with del13q, 15 patients with del17p, and 6 patients with t(4;14), while 12 patients with t(11;14). 14 patients were found at least 2 abnormalities of 30 patients.All patients were treated in our hospital, 36 cases were treated with novel agent-based chemotherapy , such as bortezomib, cyclophosphamide, and dexamethasone(BCD), or bortezomib, doxorubicin, and dexamethasone (PAD), or thalidomide, melphalan, and prednisolone (MPT), or thalidomide ,cyclophosphamide, dexamethasone (TCD), or thalidomide and dexamethasone (TD), or bortezomib,dexamethasone,cis-platin,doxorubicin,cyclophosphamide,etoposide (VDPACE).8 patients were treated with conventional chemotherapy including vincristine, doxorubicin, and dexamethasone(VAD), or cyclophosphamide, etoposide, dexamethasone(CED), or melphalan and prednisolone(MP), or M2 regimen. 6patients received hematopoietic stem cell transplantation (HSCT) after initial induction chemotherapy, 4 of them received ASCT, 2 patients with allogeneic stem cell transplantation (allo-SCT).Three patients achieved complete remission (CR), while 6 patients received very good partial remission (VGPR) after novel agent therapy. In the conventional chemotherapy group, only one patient received VGPR, and 3 patients received partial remission (PR). In the HSCT group, there were one with CR, and 2 patients with VGPR. Overall response rates (ORR) were significantly higher in patients with novel agent-based regimens compared with those treated with conventional chemotherapy (72% vs. 50%, P < 0.05). (Table 3)Take the total cohort as a whole, the median PFS and OS were 6 months (95% CI 0-15.67), and 12 months (95% CI 5.08-18.09). In total, 5 (10%) patients died within less than 1 month. The major causes of early mortality were disease progression and infection. The median OS was lower in patients who were initially treated with conventional agents (12 months, 95%CI 0-26.4) compared with those treated with novel agents (24 months, 95% CI 8.9-39.5, P = 0.15), but the difference was not statistically significant. Additionally, patients with complex karyotypes showed a trend with poor survival compared to those with normal one.Conclusion: Plasma cell leukemia has a higher incidence in cytogenetic aberrations. Novel agent-based chemotherapy combined with SCT could deepen the response rate, and improve the survival time. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Management of Primary Plasma Cell Leukemia Remains Challenging Even in the Era of Novel Agents.

Primary plasma cell leukemia (PCL) is a rare and aggressive variant of multiple myeloma (MM). PCL is characterized by peripheral blood involvement by malignant plasma cells and an aggressive clinical course leading to poor survival. There is considerable overlap between MM and PCL with respect to clinical, immunophenotypic, and cytogenetic features, but circulating plasma cell count exceeding 20% of peripheral blood leukocytes or an absolute plasma cell count of >2000/mm3 distinguishes it from MM. After initial stabilization and diagnosis confirmation, treatment of PCL in a fit patient typically includes induction combination chemotherapy containing novel agents typically, with proteasome inhibitors (such as bortezomib) and immunomodulatory drugs (eg, lenalidomide), followed by autologous hematopoietic stem cell transplant (HSCT) and multidrug maintenance therapy using novel agents post-HSCT. Long-term outcomes have improved employing this strategy but the prognosis for non-HSCT candidates remains poor and new approaches are needed for such PCL patients not eligible for HSCT. Here, we report a case of primary PCL, and a comprehensive and up to date review of the literature for diagnosis and management of PCL. We also present the findings of Positron Emission Tomography (PET) scan. Since PCL is often associated with extra-medulary disease, including PET scan at the time of staging and restaging may be a novel approach particularly to evaluate the extra-medullary disease sites.

Preclinical Activity of JNJ-7957, a Novel BCMA×CD3 Bispecific Antibody for the Treatment of Multiple Myeloma, Is Potentiated by Daratumumab.

Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action. We evaluated the anti-MM activity of the fully human BCMA×CD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor- and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated. We show that JNJ-7957 has potent activity against 4 MM cell lines, against tumor cells in 48 of 49 BM samples obtained from MM patients, and in 5 of 6 BM samples obtained from primary plasma cell leukemia patients. JNJ-7957 activity was significantly enhanced in patients with prior daratumumab treatment, which was partially due to enhanced killing capacity of daratumumab-exposed effector cells. BCMA expression did not affect activity of JNJ-7957. High T-cell frequencies and high effector:target ratios were associated with improved JNJ-7957-mediated lysis of MM cells. The PD-1/PD-L1 axis had a modest negative impact on JNJ-7957 activity against tumor cells from daratumumab-naïve MM patients. Soluble BCMA impaired the ability of JNJ-7957 to kill MM cells, although higher concentrations were able to overcome this negative effect. JNJ-7957 effectively kills MM cells ex vivo, including those from heavily pretreated MM patients, whereby several components of the immunosuppressive BM microenvironment had only modest effects on its killing capacity. Our findings support the ongoing trial with JNJ-7957 as single agent and provide the preclinical rationale for evaluating JNJ-7957 in combination with daratumumab in MM.

Primary Plasma Cell Leukemia: A Retrospective Study of a Rare Disease From Tertiary Cancer Centre From India.

Plasma cell leukemia (PCL) is an aggressive rare leukemic variant of multiple myeloma (MM). We aim to present 4years data on clinical profile and treatment outcomes of Primary PCL (PPCL) patients treated at tertiary care cancer centre from Northern India. To analyse response and safety profile of a PPCL with or without stem cell transplantation. Retrospectively reviewed and analysed PPCL patient's data at our centre from January-2013 to June-2017. Total 11 PPCL patients diagnosed among 240 MM patients during study period. Eight were males. Only 10 patients were started on treatment. Four (n = 4/10) patients underwent stem cell transplantation. Overall response rate was 70% (n = 7). Eleven culture positive bacterial infections (bloodstream = 2, urinary tract = 3; pulmonary = 6) were recorded. Four patients had fungal infections. One patient had Herpes Zoster infection. Relapse rate of entire cohort was 50% (n = 5). Median PFS and OS of entire cohort was 11months (95% confidence interval 6.3-15.6) and 21months (95% C.I. 1-49.8) respectively. The estimated PFS and OS at 1year of transplanted versus nontransplanted patients were 71% + 24% versus 0% (P = 0.96) and 71% + 24% versus 15% + 19% (P = 0.234) respectively. Treatment with PIs + IMAs followed by transplants (single/double) might improve depth and duration of remission and OS. Patients should be treated with indefinite maintenance therapy to control disease.

Primary plasma cell leukemia in the era of novel agents for myeloma – a multicenter retrospective analysis of outcome

Primary plasma cell leukemia (PPCL) is a rare form of multiple myeloma with a dismal prognosis. This retrospective multi-center study examines the national experience of PPCL in the era of novel agents. During 2002–2016, thirty-nine patients with PPCL were identified in 11 Israeli centers. One-fifth of them died in the first 2 months after diagnosis. The overall survival (OS) of those who survived the first 3 months was 22.5 months. About 70% of patients received at least one type of immunomodulatory drug (IMiD) and similarly proteasome inhibitor (PI) during treatment. There was a survival advantage for those who received IMiD but not for those who received PI or other type of standard dose chemotherapy. In multivariate analysis, low performance status and increased uric acid were also associated with shorter OS. In conclusion, this study demonstrates favorable impact of treatment with IMiDs and hematopoietic cell transplantation on the survival of PPCL patients.

Advances in the Diagnosis and Therapy of Primary Plasma Cell Leukemia -Review

Primary plasma cell leukemia (PPCL) is an uncommon and very aggressive hematological disease, which has different cytogenetic abnormalities, special molecular and biological characteristics, compared with multiple myeloma(MM). The clinical course is unfavorable with short remissions and reduced overall survival(OS). Intensive chemotherapy regimens and bortezomib-based regimens, immunoregulatory drugs(IMiDs) as well as stem cell transplantation may be beneficial to PPCL patients. This review summarizes the recent advances of this malignant disease, including clinical and biochemical characteristics of PPCL, therapy and prognosis of PPCL, new drugs for PPCL and so on.

Primary Plasma Cell Leukemia Has a Poor Prognosis Even in the Era of Novel Agents - a Multicenter Case Series

Introduction: Primary plasma cell leukemia (PPCL) is a rare and aggressive variant of multiple myeloma (MM), characterized by the presence of 20% and/or 2X109/L plasma cells (PCs) in the peripheral blood (PB) of the patient. Data regarding this entity are scarce and based on case reports and few retrospective case series. Most of the reports are dated prior to the incorporation of novel agents into MM treatment. The aim of this multicenter retrospective study was to evaluate the response and survival of PPCL patients in the era of the novel agents.Methods: We searched for the diagnosis of PPCL, during the years 2002-2016, in the medical summaries of 16 medical centers in Israel which routinely treat patients with MM. Patients with the presence of plasma cells in the blood during the course of MM (secondary plasma cell leukemia) were excluded.Results: 40 PPCL patients were identified in 11 of the 16 medical centers. It is probable that several patients were recorded as MM and thus not identified as PPCL. The characteristics of the patients and their disease are available for 35 patients and are summarized in table 1. One third of the patients presented with light chain disease and over two thirds had hypercalcemia at diagnosis. The median age was 60 and 3 patients were aged less than 35 years at diagnosis. The median number of treatments was 2. 83% of the patients received at least one IMiD or proteosome inhibitor (PI), 51% received both IMiD and PI. 17% of the patients received more than one line of IMiDs and a similar number of patients received more than one line of PIs (Fig. 1). The type of novel agents that were used are shown in figure 2. 45.7% of the patients underwent hematopoietic stem cell transplant (HSCT), of those, 4 patients (11%) have undergone tandem auto-allo HSCT and 1 (3%) - tandem auto-auto HSCT.29% of the patients did not responded to induction therapy and 57% achieved PR or better response. 13 out of 35 patients (37%) are still alive and one is lost to follow-up. The median overall survival (OS) was 11 months.7 patients (20%) survived less than 2 months while 13 (37%) survived more than 24 months, including 7 who survived more than 48 months.Among the 16 patients who underwent HSCT, all the 4 who underwent tandem auto-allo-transplant survived more than 32 months.Conclusions: Despite the modest size of this patient cohort, several inferences may be made. Patients with PPCL have unique characteristics compared to MM patients; lower median age, more frequent light chain disease and hypercalcemia at presentation. Extreme leukocytosis or leukopenia are rare. Despite intensive use of novel agents, the median OS of this cohort remains poor - 11 months. The best results were seen in patients who received tandem auto-allo HSCT, suggesting that the immunotherapeutic graft-versus-myeloma effect may offer the best hope for long-term survival to patients with PPCL. [Display omitted] [Display omitted] [Display omitted] DisclosuresAvivi:Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche.

Plasma cell leukemia in North India: retrospective analysis of a distinct clinicohematological entity from a tertiary care center and review of literature.

BackgroundPlasma cell leukemia (PCL) is a rare and aggressive plasma cell neoplasm. In PCL, clonal plasma cells comprise ≥20% of the peripheral blood (PB) leukocytes and/or the absolute clonal PB plasma cell count is ≥2×109/L. Primary PCL (PPCL) originates de novo, whereas, secondary PCL (SPCL) evolves from pre-existing multiple myeloma.MethodsClinicohematological features, immunophenotypic profile, and survival of PCL patients were analyzed retrospectively.ResultsBetween January 2007 and December 2014, ten PPCL and four SPCL patients were investigated (8 PPCLs and 3 SPCLs had complete clinical data). All were North Indians, sharing common geography and ethnicity. Our cohort showed less frequent renal failure, more frequent hepatomegaly, and non-secretory type disease. In contrast to western literature, flow cytometric immunophenotyping of our cohort revealed altered expression of CD138 (67%), CD56 (33%), and CD20 (0%). With novel therapeutic agents, these PPCL patients had a median overall survival of 15 months.ConclusionWe highlight that our PPCL patients from North India had distinct clinicohematological and immunophenotypic profiles. The significance of our findings must be tested in a larger patient cohort and must be supported by molecular and cytogenetic investigations to unmask possible significant effects on pathogenesis.

Multiple myeloma patients with low proportion of circulating plasma cells had similar survival with primary plasma cell leukemia patients.

The common features shared by primary plasma cell leukemia (pPCL) and multiple myeloma (MM) with circulating plasma cells (CPCs) are peripheral blood invasion and expansion of plasma cells independent of the protective bone marrow (BM) microenvironment niche. However, few studies have addressed the relationship between pPCL and MM with CPCs. Here, we quantitated the number CPCs by conventional morphology in 767 patients with newly diagnosed MM; their clinic features were compared with those of 33 pPCL cases. When the presence of CPCs was defined as more than 2% plasma cells per 100 nucleated cells on Wright-Giemsa stained peripheral blood smears, the incidence of MM with CPCs was 14.1% in newly diagnosed MM. Patients with CPCs shared many clinical features with pPCL, especially clinical parameters related to tumor burden. However, no commonalities were found in immunophenotyping and cytogenetics. The prognosis of pPCL was poor, with a median progression free survival (PFS) of 12months and an overall survival (OS) of 15months. MM patients with CPCs had a clearly inferior PFS and OS as compared with the control cohort. Most interestingly, although the CPCs were not high enough to meet the diagnostic criteria for pPCL, the survival of MM patients with CPCs was comparable with that of pPCL, with a median PFS of 17months and an OS of 25months.

Lenalidomide and Low Dose Dexamethasone As First Line Therapy for Newly Diagnosed Patients with Primary Plasma Cell Leukemia

AbstractAbstract 729 Introduction:The prognosis of primary plasma cell leukemia (PPCL) remains poor. The “novel agents” have recently shown promising results in PPCL patients in case reports or small retrospective series. Here we describe the first prospective, multicenter, phase II clinical trial of PPCL, where lenalidomide in combination with low dose dexamethasone (Ld) was tested as initial therapy in newly diagnosed patients fulfilling the IMWG diagnostic criteria of PPCL. Patients and methods:Ld regimen consisted of lenalidomide 25 mg/d for 21 days and oral dexamethasone 40 mg on days 1, 8, 15, and 22 for each 28-day cycle. After 4 cycles, responding patients not eligible for stem cell transplantation (SCT) continued until 8 cycles of full-dose Ld, followed by a maintenance dose of single agent lenalidomide equal to 10 mg/d on days 1–21 of each 28-day cycle. Patients responding after 4 cycles and eligible for SCT proceeded according to the treatment centre’s transplant policy. Patients not responding after 4 cycles or progressing during this treatment were considered off-study. Appropriate dose reductions (in particular for patients with reduced renal function at baseline), double contraception methods and anti-thrombotic/anti-infective prophylaxis were recommended. The primary end-point was early response rate according to IMWG uniform response criteria. Secondary end-points were PFS, OS, feasibility and efficacy of SCT, safety. Results:According to the Simon optimal two-stage adaptive design, twenty-three patients were enrolled in between March 2009 and May 2011. The male/female ratio was 1.1, and median age was 60 years (range 44–80). The median absolute number and percentage of circulating plasma cells were 4.280/μl (range 1.500–114.660) and 34% (range 21–90) respectively. Fifteen patients (65.2%) had abnormal renal function at presentation. Twenty-one patients (91.3%) were tested by FISH analysis and cytogenetic abnormalities were detected in all of them, del13q being the most frequently found (16 patients). Seventeen patients showed multiple chromosomal lesions. Involvement of chromosome 14 was observed in 18 patients, three of whom showed t(4;14). Chromosome 1q gain and del17p were detected in 10 and 7 patients, respectively. In the intention-to-treat (ITT) population, overall response rate (ORR) after at least one Ld cycle was 73.9% (17/23), with 8 patients (34.7%) achieving partial remission (PR), 5 (21.7%) very good PR (VGPR), 3 (13%) complete response (CR), and 1(4.3%) near CR (nCR) (VGPR or better: 39%). In the efficacy-evaluable (EE) population, 14 out of 15 patients who received the initially planned 4 Ld cycles (65.2% of the ITT population) responded (ORR 93.3%), achieving 5 PR (33.3%), 5 VGPR (33.3%), 1 near-CR (6.6%) and 3 CR (20%) (VGPR or better: 59.9%). The maintenance phase was reached and safely performed in 4 responding patients not eligible for SCT, 3 of whom relapsed after 2, 8 and 22 months, respectively. After Ld induction therapy, 8 patients received single (n. 4) or double (n. 4) autologous SCT (ASCT); another patient underwent a sequence of ASCT followed by non-myeloablative allogeneic SCT (AlloSCT). Six eligible patients did not receive ASCT frontline, due to initial Ld failure or adverse events; three of them underwent single ASCT (n. 2) or tandem ASCT/non-myeloablative AlloSCT (n. 1) after a bortezomib-based salvage therapy, achieving 2 CR and 1 PR. After a median follow-up of 23 months, median OS and PFS in ITT population were not reached and 22 months, respectively. All transplanted patients remained alive, although three of them relapsed and started salvage treatments; OS was 12 months in the 11 patients who did not receive ASCT (p < 0.001). The correspondent figures for PFS were 29 and 16 months, respectively (p < 0.01). Considering ITT population, multivariate analyses showed that SCT was positively correlated to both OS and PFS. There were 17 episodes of grade 3/4 non hematological toxicity, which occurred in 13 patients (5 infections, 3 renal, 3 metabolic, 2 gastro-intestinal, 2 skin, 1 fatigue, 1 thromboembolic), causing early interruption of Ld treatment in 4 patients. Grade 3/4 hematological toxicity (mainly neutropenia) occurred in 11 patients (47.8%). Conclusions:Ld may be a feasible and effective initial therapeutic option for PPCL, particularly in patients who receive ASCT after a short course of induction treatment. Disclosures:Musto:Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide as first line therapy of plasma cell leukemia. Petrucci:Celgene: Honoraria. Cascavilla:Celgene: Honoraria. Di Raimondo:Celgene: Honoraria. Caravita:Celgene: Honoraria. Morabito:Celgene: Honoraria. Offidani:Celgene: Honoraria. Bringhen:Celgene: Honoraria. Boccadoro:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Celgene: Consultancy, Honoraria.

Frontline chemotherapy with bortezomib-containing combinations improves response rate and survival in primary plasma cell leukemia: a retrospective study from GIMEMA Multiple Myeloma Working Party

The best therapeutic approach for primary plasma cell leukemia (PPCL) remains unknown so far. In very limited studies, the poor clinical outcome of this aggressive variant of multiple myeloma seemed to be ameliorated by the use of the proteasome inhibitor bortezomib. Aiming to provide more consolidated data, this multicenter retrospective survey focused on unselected and previously untreated PPCL patients who had received bortezomib as frontline therapy. Twenty-nine patients with PPCL were collected. Bortezomib was given at standard doses and schedules, in various combinations with dexamethasone, thalidomide, doxorubicin, melphalan, prednisone, vincristine, and cyclophosphamide. An overall response rate of 79% was observed, with 38% of at least very good partial remission. Grade 3-4 hematological, neurological, infectious, and renal toxic effects occurred in 20%, 21%, 16%, and 4% of patients, respectively. After a median follow-up of 24 months, 16 patients were alive (55%), 12 of whom were in remission phase and 4 relapsed. The best long-term results were achieved in patients who received stem-cell transplantation after bortezomib induction. Bortezomib, used as initial therapy, is able to increase the percentage and the quality of responses in PPCL patients, producing a significant improvement of survival.

High incidence of cryptic translocations involving the Ig heavy chain gene in multiple myeloma, as shown by fluorescence in situ hybridization.

Cytogenetic studies have shown rearrangements of the Ig heavy chain (IGH) gene at 14q32 in 10-60% of patients with multiple myeloma (MM) or primary plasma cell leukemia (PCL). Analysis of MM patients and human myeloma cell lines (HMCL) using interphase fluorescence in situ hybridization (FISH) and molecular techniques has shown IGH rearrangements in 75% of MM cases and in up to 100% of HMCL. A review of the literature revealed at least 18 different partner chromosomal regions. To investigate whether some of these translocations were recurrent and possibly to identify new partner regions, we developed a set of FISH probes to detect every IGH recombination. We analyzed 28 MM and 4 primary PCL patients with abnormal karyotypes and 12 HMCL. Whereas conventional cytogenetics detected a 14q32 abnormality in only 15% of the patients, FISH detected it in 47% of patients and in 75% of HMCL. The partner chromosome was identified in 10 of 15 patients with a 14q32 rearrangement. Interestingly, the same t(4; 14)(p16;q32) was detected in five patients and three HMCL, i.e., 33% of patients and HMCL with an IGH rearrangement. New partner chromosomal regions have also been identified, i.e., 9p13, 12p11, 12p13, and Xq28, besides the previously reported 8q24, 11q13, 12q24, and 16q24 rearrangements. The genes involved in these new translocations are not known, except for 9p13, where PAX5 was shown to be the partner gene. We conclude that: I) IGH recombinations are frequent but not constant in MM, 2) these rearrangements often occur through cryptic translocations, and 3) the t(4;14)(p16;q32) is one of the most frequent translocations, but many other chromosomal regions may be involved.