Secondary Plasma Cell Leukemia Research Articles

PARP1-Mediated Alt-NHEJ Repair Is a Therapeutic Target in Multiple Myeloma

Background- Multiple Myeloma (MM) is a hematologic malignancy strongly characterized by genomic instability, which promotes disease progression and drug resistance. We previously demonstrated that LIG3-dependent Alt-NHEJ repair is involved in genomic instability, drug resistance and survival of MM cells. On these premises, we investigated PARP1 as driver component of Alt-NHEJ pathway and new therapeutic target in MM. Materials and methods- Cell proliferation and apoptosis were evaluated with CellTiter-Glo assay and Annexin V staining. Alt-NHEJ repair was evaluated using EJ2-GFP. PARP1, Caspase 3, MYC and DNA Damage Response protein levels were analyzed by Western blot of whole protein extracts. In vivo anti-MM activity was evaluated in NOD-SCID mice bearing subcutaneous H929 and AMO-1 Bortezomib resistant (ABZB) xenografts, daily treated with Olaparib (Selleckchem) via oral gavage. Results - By interrogating public available datasets, we found significant correlation between higher mRNA expression of PARP1 and shorter survival of MM patients. On these findings, we investigated the effect of available PARP inhibitors (PARPi) on MM cell survival. We found that Olaparib, a clinically available PARPi induced a significant reduction of proliferation and clonogenic growth of MM cell lines at low micromolar concentrations. Importantly, Olaparib impaired viability of MM cell lines or primary malignant plasmacells co-cultured with stromal cells, thus overcoming the bone marrow microenvironment supportive effect for MM survival. As result of PARP-mediated Alt-NHEJ repair inhibition, anti-proliferative effects were associated to increase of DNA double-strand breaks (DSBs), activation of DNA damage response, cell cycle arrest and finally apoptosis. To identify predictive biomarkers for PARPi in MM, a published sensitivity gene expression signature was applied to our MM gene expression profiling (GEP) data. Interestingly, this signature was particularly enriched in TC2 MM and secondary plasma cell leukemia (PCL). Therefore, in order to evaluate concordantly modulated sets of genes that were possibly associated to PARPi signature in MM, PARPi-positive and PARPi-negative MM-TC2 cases were compared by GSEA analysis. Interestingly, groups of genes regulated by MYC or involved in DNA repair resulted among the most significantly up-regulated in PARPi-positive versus PARPi-negative MM-TC2 cases. Accordingly, MYC transcript reached the highest median expression levels in sPCL and HMCLs across PC dyscrasia groups, and in MM-TC2 class. Consistently U266 cells, which was quiet insensitive to PARP knockdown or PARP inhibitor Olaparib, were null for c-MYC as compared to multiple myeloma cell lines evaluated in this study. Conversely, as formal proof of our hypothesis, over-expression of c-MYC in U266 cells (MYC-OE) induced cell death upon PARP silencing or PARP inhibitor treatment. Notably, we found that c-MYC-PARP1 loop was also hyper-activated in Bortezomib resistant cells, thus confirming pivotal role of Alt-NHEJ repair in drug resistance development. Remarkably, to demonstrate the in vivo relevance of our findings, we showed that clinically available Parp-inhibitor Olaparib exerted a significant anti-MM activity on both Bortezomib sensitive (H929) and resistant (ABZB) MM cells injected in immunocompromised mice. Conclusion Taken together, our findings indicate that MM cells are dependent on PARP-mediated Alt-NHEJ repair pathway, which therefore represents a novel druggable target pathway in MYC-driven MM cells. Disclosures No relevant conflicts of interest to declare.

High-Throughput Functional Drug Screening and Genomic Analysis to Guide Individualized Therapy for Relapsed/Refractory Multiple Myeloma

Background: The response to treatment for patients with relapsed/refractory multiple myeloma (MM) is highly variable. This may in part be related to the broad genomic heterogeneity that has been reported across individual patients. We hypothesize that in vitro functional drug screening and correlated genomic analyses of patient tumor cells is feasible and may improve clinical treatment response. To address this, we developed a custom high-throughput drug sensitivity (HTS) assay enabling simultaneous testing of 170 chemotherapy drugs and targeted inhibitors, as well as correlative gene expression and mutational analysis by next-generation sequencing. We report on the feasibility of this approach in a clinical trial enrolling patients with relapsed/refractory MM (NCT03389347). Patients and Methods: Twenty patients with relapsed/refractory MM or secondary plasma cell leukemia were enrolled in the study and 15 (9 female, 6 male) had a sufficient number of plasma cells for HTS. The average number of prior treatment regimens among the tested patients was 5.8 (range 3-11) and all had previously received a proteasome inhibitor and immunomodulatory drug and 8 had prior autologous stem cell transplants. Nine patients had stage III disease by the Revised International Staging System (R-ISS) and 4 had stage II disease. Eight patients exhibited high-risk cytogenetics, including 4 patients with del(17p), 5 patients with t(4;14), and 2 patients with t(14;16). The sources of plasma cells utilized for the HTS assay included bone marrow aspirate or core biopsies, soft tissue biopsies of plasmacytomas, and blood samples from patients with circulating plasma cells. Additional blood and bone marrow samples were obtained for RNA sequencing, whole-exome sequencing, and targeted sequencing of circulating tumor DNA. The CLIA approved HTS assay was performed at the Quellos HTS Core at the University of Washington using CD138+plasma cells isolated by magnetic bead separation. Tumor cells were tested against a panel of 170 drugs that includes conventional agents and targeted inhibitors, some FDA approved and others investigational. Cell viability was assessed at 72 hours by a luminescent cell viability assay (Cell Titer Glo, Promega) and drug response was determined using the concentration of experimental compound required to achieve 50% in vitro response inhibition (IC50) and area under the dose-response curve (AUC). Results: We report that the HTS assay can be completed in a median of 5 days from sampling (range 4-6 days), establishing feasibility. The mean percentage of bone marrow plasma cells among patients who could be tested was 56% compared to 5% for patients who had insufficient cells. We observed heterogeneity in patient genomic profiles and in vitro drug responses. The drugs with the highest in vitro response include those commonly used in MM such as bortezomib, ixazomib, carfilzomib, and panobinostat, as well as those under investigation including venetoclax and selinexor. Sensitivity was observed for drugs that have not been investigated for the treatment of MM including alvocidib and omacetaxine. Progression on prior therapy was not consistently predictive of in vitro drug responses and could be a consequence of some myeloma cells retaining sensitivity. Correlative genomic analyses were associated with in vitro drug responses for a subset of compounds. Among the 8 patients who received individualized therapy guided by the assay, 6 had an evaluable response and 5 (83%) achieved effective disease control (stable disease or better). Updated clinical treatment outcomes will be reported at the ASH conference. Conclusions: In this study, we successfully demonstrate the feasibility of a CLIA approved HTS assay capable of delivering actionable results in time to inform individualized treatment decisions for patients with MM. Correlative gene expression and mutational analysis are associated with in vitro drug response. Finally, we demonstrate that some of the patients who received treatment guided by the results of the HTS assay achieved a clinical response. These data suggest that using functional drug screening to predict sensitivity or resistance to both approved and experimental agents warrants further testing. Validation of the HTS assay in a larger population of MM patients holds the potential to improve treatment outcomes. Disclosures Cowan: Cellectar: Consultancy; Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Celgene: Consultancy, Research Funding; Juno: Research Funding; Sanofi: Consultancy. Green:Celgene: Consultancy; Cellectar Biosciences: Research Funding; GSK: Consultancy; Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; Seattle Genetics: Research Funding. Libby:Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy; Akcea: Consultancy. Silbermann:Janssen, Sanofi: Other: Consultant/Advisor. Becker:The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding. OffLabel Disclosure: We will discuss in-vitro sensitivity testing of drugs that have not been approved for the treatment of multiple myeloma.

Molecular Characterization of Bone Marrow and Peripheral Blood Compartments from Patients with Plasma Cell Leukemia in the Mmrf Commpass Study

Plasma cell leukemia (PCL) is rare but represents an aggressive, advanced form of multiple myeloma (MM) where neoplastic plasma cells (PCs) escape the bone marrow (BM) and circulate in the peripheral blood (PB). Traditionally, PCL is defined by the presence of >20% circulating plasma cells (CPCs), however, recent studies have suggested that PCL be redefined as the presence of >5% CPCs. The Multiple Myeloma Research Foundation CoMMpass study (NCT01454297) is a longitudinal, observational clinical study with 1143 newly diagnosed MM patients. BM-derived MM samples were characterized using whole genome (WGS), exome (WES), and RNA (RNAseq) sequencing at diagnosis and each progression event. When >5% CPCs were detected by flow cytometry, PCs were enriched independently from both compartments, and T-cells were selected from the PB as a control for WGS and WES. This substudy within CoMMpass provides the largest, most comprehensively characterized dataset of matched MM and PCL samples to date, which can be leveraged to better understand the molecular drivers of PCL. At diagnosis, 813/1143 CoMMpass patients had flow cytometry data reporting the percent PCs in PB, of which 790 had <5%, 17 had 5-20%, and 6 had >20% CPCs. Survival analyses revealed that patients with 5-20% CPCs (median = 20 months) had poor overall survival (OS) outcomes compared to patients with <5% CPCs (median = 74 months, p < 0.001), and no significant difference in outcome was observed between patients with 5-20% and >20% (median = 38 months) CPCs. Patients with 1-5% CPCs (median = 50 months, HR = 2.45, 95% CI = 1.64 - 3.69, p < 0.001) also exhibited poor OS outcomes compared to patients with <1% CPCs (median = 74 months), suggesting that patients with >1% CPCs are a higher risk population, even if they do not meet the PCL threshold. Using a cutoff of >5% CPCs, 23/813 (2.8%) patients presented with primary PCL (pPCL) at diagnosis. Of these patients, 7 (30%) were hyperdiploid (HRD), of whom 1 had a CCND1 and 1 had a MYC translocation; while 16 (70%) were nonhyperdiploid (NHRD), all of whom had a canonical immunoglobulin translocation (6 CCND1, 5 WHSC1, 3 MAF, 1 MAFA, and 1 MAFB). Of 124 patients with serial sample collections, 5 (4%) patients without pPCL had >5% CPCs at progression, and thus relapsed with secondary PCL (sPCL). Of the 5 sPCL patients, 2 (40%) were NHRD with a CCND1 or MAF translocation; while 3 (60%) were HRD, 1 with a WHSC1 translocation. Median time to diagnosis of sPCL was 22 months (range = 2 - 31 months), and patients with sPCL (median = 22 months) and pPCL (median = 30 months) exhibited poor OS outcomes as compared to MM patients (74 months, p < 0.001). Sequencing data was available for 15 pPCL and 5 sPCL samples. For 12 patients with WES, WGS, and RNAseq performed on their PCL tumor sample, an integrated analysis identified recurrent, complete loss-of-function (LOF) events in only CDKN2C/FAF1, SETD2, and TRAF3. Five pPCL patients had complete LOF of a gene involved in G1/S cell cycle control, including CDKN2C, CDKN2A, CDKN1C, and ATM. These LOF events were not observed in NHRD t(11;14) PCL patients, suggesting that CCND1 overexpression and LOF of genes involved in G1/S cell cycle control may represent independent drivers of PCL. Comparing WES and WGS data between matched MM and PCL tumor samples revealed a high degree of similarity in mutation and copy number profile. However, differential expression analysis performed for 13 patients with RNAseq data comparing their MM and PCL tumors revealed 27 up- and 39 downregulated genes (padj < 0.01, FDR = 0.1) in PCL versus MM. Pathway analysis revealed an enrichment (p < 0.001) for genes involved in adhesion and diapedesis, including upregulation of ITGB2, PF4, and PPBP, and downregulation of CCL8, CXCL12, MMP19, and VCAM1. The most significantly downregulated gene in PCL (log2FC = -6.98) was VCAM1, which plays a role in cell adhesion, and where loss of expression (TPM < 0.01) was observed across all PCL samples. Upregulation of four S100 genes including S100A8, S100A9, S100A12, and S100P, which have been implicated in tumor growth, metastasis, and immune evasion, was also observed in PCL. Interestingly, a S100A9 inhibitor has been developed and may represent a novel treatment option for PCL patients. In summary, PCL was found to be associated with molecular events dysregulating G1/S cell cycle control coupled with subtle changes in transcription that likely occur in a subclonal population of the MM tumor. Disclosures Lonial: Genentech: Consultancy; GSK: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Amgen: Consultancy.

Early Salvage Treatment with Second-Generation Novel Agents at Biochemical Relapse Prolongs Overall Survival: A Real-World Single Center Experience

In Multiple Myeloma (MM) relapse can be defined according to disease aggressiveness and the presence of clinical symptoms. Aggressive relapse can occur even at biochemical level, characterized by a rapid and relevant increase of monoclonal component or LDH, or at clinical level, defined by the presence of extramedullary disease, acute renal injury or progression to secondary plasma cell leukemia. To identify the clinical outcome upon treatment with second generation novel agents (pomalidomide, carfilzomib) and monoclonal antibodies (elotuzumab, daratumumab), we collected evidence of the best timing in providing early salvage treatment to RRMM. We reviewed files of 128 R/R MM (58% males, median age 64 years, range 43-83), treated at biochemical (N=54, 42%) or clinical relapse (N=74, 58%) between January 2017 and December 2019 in our single Institution. Median number of previous lines was 2 (1-9), including autologous stem cell transplantation (ASCT) in half of cases. FISH was repeated before to start the second-generation drugs, and it was available in 53 cases: 11 carried on high-risk (del 17p, t4;14 or t14;16) and 42 standard-risk cytogenetics, without any additional marker compared to the matched sample at diagnosis. Our series included patients who received IMiD-s based treatments, alone (pomalidomide, N= 76, 59%) or in combination with proteasome inhibitors (carfilzomib, lenalidomide and dexamethasone, KRd, N= 43, 33%) or monoclonal antibodies (daratumumab-lenalidomide, N= 3 elotuzumab-lenalidomide, N 12); 16 patients (%) received Daratumumab in monotherapy, and N=16 associated to bortezomib. After a median follow-up of 19.2 months, 66 (52%) patients were alive and 33 (25%) received a further line of therapy due to progression. In multivariable analysis only the type of relapse (biochemical versus clinical) and refractory status were independent predictors of overall survival (p<0.0001). Longer overall survival (OS) was associated to treatment at biochemical relapse (27.8 vs 15.2 months, p=0.0005), in relapsed patients instead of relapsed and refractory (34.1 vs 19.3 months, p=0.0004). Patients who received less than 3 lines of therapy or carrying standard-risk cytogenetics had longer OS (respectively, 33.6 vs 19.1 months, p=0.002 and 20.4 vs 11.2 months, p=0.04) without any significant difference due to previous ASCT or the type of second-generation treatment chosen. In 20/33 individuals who further progressed under novel agents treatment we found second biochemical relapse was anticipated by doubling sFLC ratio one month before. In 5 patients who developed extramedullary lesions (EMD) an increase of sFLC always preceded the diagnosis ofEMD relapse irrespective of M-spike measurement. Taken together, our findings suggest that using second generation novel agents can improve outcome even in heavily pretreated patients. Earlier treatment at biochemical asymptomatic relapse is associated with longer OS. Longitudinal monitoring of sFLC assay ratio can anticipateearly detection of aggressive and/or EMD relapse in the RRMM setting in real life. Disclosures Del Fabro: Janssen: Consultancy. Di Raimondo:Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Conticello:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Plasma Cell Leukemia – the Forgotten Disease

Plasma cell leukemia (PCL) is a rare dis-ease and possibly the most aggressive form of monoclonal gammopathy. It is classified into two forms -  primary PCL that occurs without a previously identifiable multiple myeloma stage, and secondary PCL that develops from previously dia-gnosed multiple myeloma. These two forms have different cytogenetic and molecular profiles, but both forms have an aggressive clinical course. Combinations of different therapeutic approaches includ-ing autologous stem cell transplantation and currently proteasome inhibitors and immunomodulatory drugs are used to treat PCL. Current dia-gnostic criteria, developed in the 1970s, may underestimate PCL prevalence; thus, prospective re-evaluation is be-ing considered.The aim of this study is to review all available information about PCL with an emphasis on dia-gnostics, treatment, and circulat-ing plasma cells features.Although PCL is rare, it is quite a severe dis-ease. Current treatments us-ing the latest therapeutics have prolonged patient survival. However, due to the low incidence of PCL, information about the dis-ease is very limited and comes mostly from small retrospective studies. Further studies of PCL are needed, because new information could increase in patient survival and our understand-ing of its pathogenesis. Key words plasma cell leukemia -  multiple myeloma -  plasma cells -  cytogenetics -  treatment This work was supported by grant NV18-03-00203. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submited: 2. 11. 2018 Accepted: 18. 11. 2018.

Epidemiology of Plasma Cell Leukemia in the Czech Republic.

Plasma cell leukemia (PCL) is arare but most aggressive form of monoclonal gammopathies. PCL is characterized by the presence of clonal plasma cells in peripheral blood. There are two forms of PCL - primary which presents denovo in patients with no evidence of previous multiple myeloma and secondary which is aleukemic transformation of relapsed or refractory dis-ease in patients with previously recognized multiple myeloma. This is the first study to provide information on PCL epidemiology in the Czech population us-ing The Czech National Cancer Registry (CNCR) as the basic source of data for the population-based evaluation of PCL epidemiology. Accord-ing to CNCR data, there were on average six newly dia-gnosed cases of PCL and four deaths caused by PCL each year in the Czech Republic in the period 2000- 2015. PCL incidence in the Czech Republic was reported at 0.57per million in 2000- 2015. We suppose that most reported cases of PCL are primary PCL because secondary PCL is arelapse of apreviously reported myeloma and, in most cases, is not coded as an independent dia-gnosis in the CNCR. Data from registries such as the CNCR can provide useful information on epidemiology of various dis-eases. These data, however, have several limitations, such as dia-gnostic criteria and proper cod-ing of not only the dis-ease itself, but also its various forms. These limitations have to be taken into account dur-ing the process of results interpretation. Key words plasma cell leukemia-  epidemiology-  Czech National Cancer Registry (CNCR)-  Czech Republic.

Retrospective Analysis of Modified Hyper-CVAD Therapy Combined with Proteasome Inhibition for Patients with Multiple Myeloma and Renal Insufficiency or Renal Failure

Background: While novel agents have allowed for successful outpatient treatment of patients with multiple myeloma (MM), multi-agent infusional chemotherapy regimens continue to have a role, particularly in high burden disease states. However, the use of platinum-based regimens is limited in patients with renal insufficiency and renal failure. We have been using a modified hyperCVAD regimen, termed HyperCD (Table 1), with omission of vincristine, and inclusion of a proteasome inhibitor (PI, either bortezomib or carfilzomib) in these aggressive clinical presentations for rapid tumor reduction. Here we present our experience with this treatment modality, with analysis of treatment outcomes and toxicities in the renal insufficiency subset.Methods:We performed a single-center chart review of all MM patients at our institution with available electronic medical records who received at least one HyperCD cycle in the setting of concurrent renal insufficiency (defined by estimated eGFR <50mL/min by CKD-EPI at treatment start) between 01/2012 and 12/2016. Data on demographics and disease characteristics were collected. Response was determined by IMWG criteria. Progression free survival (PFS) and overall survival (OS) were calculated by Kaplan Meier method, with PFS including progression or death from any cause and censoring at last known follow-up for live patients.Results:Baseline characteristics: Sixty-seven patients were included in this analysis (Table 2), including 46 non-dialysis dependent and 21 dialysis dependent patients. Median age was 62 years (range 29 - 85). 19% had known prior high-risk cytogenetics defined by t(4;14), t(14;16) and/or 17p(del). Median number of prior lines of therapy was 2 (range 0-14). 34% had prior autologous transplantation. Prior therapies included alkylator therapy in 67%, immunomodulator in 64%, anti-CD38 antibody therapy in 13%, and PI in 87%. Reasons for HyperCD administration included rapidly progressive disease (63%), hypercalcemia (30%), extensive bony (16%) or soft tissue disease (9%), primary (4%) or secondary plasma cell leukemia (7%), and stem cell mobilization (22%). Disease status at time of treatment included new diagnosis (13%), insufficient prior response (18%), and relapsed/refractory or relapsed disease (69%). The median number of cycles administered per patient was 1 (range 1-4), with 55% receiving 1 cycle and 45% receiving 2 or more cycles. The median creatinine at therapy start was 2.93 (range 1.15-8.98).Responses: Of 23 patients on dialysis, 8 (35%) were able to discontinue either during or sometime after therapy. Median percent improvement in creatinine after therapy among non-dialysis patients was 24% (p=0.0001 by wilcoxon signed rank). The overall response rate (ORR) was 69% (46/67), with 1% complete responses (CR), 28% very good partial responses (VGPR), and 39% partial responses (PR). The median time to PR or better was 1.1 months, with a median PFS of 5.1 months, and median OS of 21 months. 87% of patients were able to bridge to other therapy including autologous transplantation (22%). 81% of patients have progressed or died at last follow-up, with disease being the most common cause of death (29/34, 85%).Therapy related toxicities: Median duration of severe neutropenia (ANC</=500/µl) was 4 days (range 0-17) and severe thrombocytopenia (platelets </= 50,000/µl) 7 days (range 0-29), per cycle. 24% of patients had neutropenic fever with documented infections in 37%. Other toxicities included severe bleeding (4%), deep vein thrombosis (7%), and cardiac events (25%), including tachyarrhythmia (9%), demand ischemia (3%), heart failure (2%), pulmonary hypertension (3%), and volume overload (9%). One patient (2%) had potential treatment related mortality (TRM) approximately 3 months after therapy and 1 patient (2%) died within 30 days from progressive disease.Conclusion: HyperCD-based regimens yielded relatively high response rates in MM patients with renal insufficiency, including renal failure. Several patients discontinued dialysis, with improvement in renal function also seen in non-dialysis patients. While TRM was low, hematologic, infectious, and cardiac toxicities were common. The majority of patients were able to successfully bridge to other therapy. HyperCD-based regimens may thus be a potential alternative to platinum based therapies in myeloma patients requiring intensive infusional chemotherapy. [Display omitted] DisclosuresShah:Nekktar: Consultancy; Teneobio: Consultancy; Amgen: Consultancy; Sutro Biopharma: Research Funding; Janssen: Research Funding; Nkarta: Consultancy; Indapta Therapeutics: Equity Ownership; Takeda: Consultancy; Celgene: Research Funding; Indapta Therapeutics: Consultancy; Bluebird: Research Funding; University of California San Francisco: Employment; Kite: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy. Wong:Janssen: Research Funding; Roche: Research Funding. Martin:Sanofi: Research Funding; Amgen: Research Funding; Roche: Consultancy. Wolf:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy.

JCARH125, Anti-BCMA CAR T-cell Therapy for Relapsed/Refractory Multiple Myeloma: Initial Proof of Concept Results from a Phase 1/2 Multicenter Study (EVOLVE)

JCARH125, Anti-BCMA CAR T-cell Therapy for Relapsed/Refractory Multiple Myeloma: Initial Proof of Concept Results from a Phase 1/2 Multicenter Study (EVOLVE)

Update of diagnosis and treatment of plasma cell leukemia

Plasma cell leukemia (PCL) is a rare and aggressive malignant plasma cell tumor that is clinically susceptible to extramedullary lesions. It is classified into two types: primary PCL (pPCL) and secondary PCL (sPCL), of which 60 % are pPCL. The treatment of new drugs such as bortezomib and lenalidomide is important for improving the overall survival and disease-free survival of PCL, especially after induction of bortezomib-based chemotherapy, combined with autologous hematopoietic stem cell transplantation (auto-HSCT) can improve the survival of patients. Whether to adopt the next step of allogeneic hematopoietic stem cell transplantation (allo-HSCT) still needs further investigation. For young and suitable patients, early new drug-based regimen chemotherapy combined with auto-HSCT can be used, and if a suitable donor is available, the further allo-HSCT consolidation therapy is feasible. For elderly patients (≥65 years old), a new drug-based regimen can be used to induce chemotherapy, and further followed consolidation therapy plus maintenance therapy. Whether to take auto-HSCT after early induction chemotherapy depends on the individualized factors of the patient. The next generation anti-plasma cells drugs, monoclonal antibodies and other immunotherapies or new drugs in clinical trials are also worth exploring. Key words: Leukemia, plasma cell; Hematopoietic stem cell transplantation; Bortezomib; Lenalidomide

Abstract 3351: Aberrant RNA editing of GLI1 promotes malignant regeneration in multiple myeloma

Abstract Introduction: Despite novel therapies, most of multiple myeloma (MM) patients relapse as a result of clonal evolution in inflammatory microenvironments. Adenosine-to-inosine (A-to-I) RNA editing, driven by inflammatory cytokine-responsive adenosine deaminase acting on RNA1 (ADAR1), promotes cancer progression by enhancing survival and self-renewal of malignant progenitor cells. Amplifications of chromosome 1q21, containing IL-6R and ADAR1 loci, occur frequently in high-risk MM patients, who frequently develop secondary plasma cell leukemia (PCL) and have shorter survival. While increased IL-6 signaling has been linked to relapse and A-to-I editing contributes to therapeutic resistance in a broad array of malignancies, the role of ADAR1 in MM pathogenesis has not been elucidated. This study aimed to investigate whether pro-inflammatory cues in MM activate ADAR1 editing thereby promoting malignant regeneration. Procedures: Publicly available primary patient datasets were analyzed and validated in a separate cohort of biobanked primary samples and human myeloma cell lines. Lentiviral vector-mediated activation or knockdown of ADAR1, or treatment with extrinsic pro-inflammatory stimuli, was utilized to probe the functional impact of RNA editing activity in MM models. Site-specific qPCR was used to quantify RNA editing in specific cancer stem cell-associated loci. Functional effects of ADAR1 activity were assessed in in vitro survival and self-renewal assays, and in novel in vivo PCL xenografts. Results: Patients harboring 1q21 amplification showed significant and stage-dependent increases in ADAR1 expression. In a set of separate primary PCL samples, aberrant RNA editing in the coding region of the Hedgehog (Hh) pathway transcription factor GLI1 was observed in high ADAR1-expressing samples. Notably, increased GLI1 editing, previously reported to have increased capacity to activate its transcriptional targets, was detected in serially transplantable, patient-derived xenograft models. Furthermore, abolition of ADAR1 editase activity impaired GLI1 editing. Lastly, in vitro pro-inflammatory IL-6 stimulation, or continuous exposure to the immunomodulatory drug lenalidomide led to increased ADAR1 mRNA and protein levels, with a concomitant induction of RNA editing activity. Conclusions: In MM, 1q21 amplification has been linked to progression. We provide new evidence linking expression and activity of ADAR1, located on 1q21, and disease stage. Because ADAR1 induces transcript recoding, A-to-I editing could contribute to the marked transcriptomic diversity typical of advanced MM. While the Hh pathway has been linked to cancer stem cell generation in human MM, here we identified a primate-specific mechanism of Hh pathway activation in MM through RNA editing-dependent stabilization of GLI1. Together, both genetic and microenvironmental factors modulate epitranscriptomic deregulation of cancer stem cell pathways in MM. Citation Format: Elisa Lazzari, Nathaniel Delos Santos, Christina Wu, Heather Leu, Gabriel Pineda, Shawn Ali, Caitlin Costello, Mark Minden, Raffaella Chiaramonte, Leslie Crews, Catriona Jamieson. Aberrant RNA editing of GLI1 promotes malignant regeneration in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3351. doi:10.1158/1538-7445.AM2017-3351

Proteome alterations associated with transformation of multiple myeloma to secondary plasma cell leukemia.

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

Plasma Cell Leukemia in China: Retrospective Analysis of Clinical Characteristics and Prognosis

Background: Plasma cell leukemia (PCL) is an aggressive malignancy characterized by the presence of ≥ 20% plasma cells in the peripheral blood or an absolute plasma cell count >2× 109/L. PCL exists in two forms: primary PCL (PPCL) presents de novo, whereas secondary PCL (SPCL) defined as a leukemic transformation from a previously diagnosed MM.Materials and methods: We conducted a retrospective analysis in 46 cases with PCL patients enrolled in Blood Diseases Hospital, Chinese Academy of Medical Sciences from June 1997 to June 2016. Survival analysis and treatment response according to the response criteria of IMWG were analyzed to assess the efficacy of Bortezomib or Thalidomide based therapy combined with standard chemotherapy.Results: Median age of 46 cases was 54.5 years (29-72 years), 28 males and 18 females; primary PCL 20 cases, secondary PCL 26 cases. Among those, 20 cases with kappa type, while 22 λ cases, 4 cases no secretion. Renal dysfunction occurs 51.4% of patients, 69.6% with osteolytic changes. D-S stage: I 1 case, 2 cases of stage II, stage III 43 cases. Complex karyotypes accounted for 45.2%, high frequency of cytogenetic abnormalities occur in IgH / CCND1 rearrangement with 8 cases, 1q21 amplification in 8 cases, RB-1 abnormalities in 6 cases, 4 cases of 17p deletion and 1 IgH / MAF rearrangement . 36 patients were evaluated in treatment responses, the overall reaction (≥MR) was 97.2%; 7 cases acquired complete remission (CR), 14 near complete remission (nCR), 6 very good partial response (VGPR), 8 cases of partial remission (PR), 1 case loss response. 16 cases of Bortezomib based therapy combined with chemotherapy; while 18 patients were treated with thalidomide combined with chemotherapy, 2 cases were conducted with allogeneic stem cell transplantation, 2 patients with chemotherapy underwent autologous stem cell transplantation after standard chemotherapy. Mean Overall survival (OS) was 19 months; primary and secondary PCL median OS was 15 months and 22 months separately (P = 0.098); Thalidomide based regimens and bortezomib-based regimen acquired a median OS 15 months and 30 months (P = 0.083). Median time to progression (TTP) of thalidomide and bortezomib based therapy was 6 months and 25 months (P = 0.03). The overall median TTP was 9 months.Conclusions: Higher incidence in cytogenetic aberrations was observed in plasma cell leukemia. Combined chemotherapy with bortezomib can improve progression-free survival of patients, but cannot improve overall survival. DisclosuresNo relevant conflicts of interest to declare.

Pilot Study of Anti-CD19 Chimeric Antigen Receptor T Cells (CTL019) in Conjunction with Salvage Autologous Stem Cell Transplantation for Advanced Multiple Myeloma

Background: Though CD19 is expressed only rarely on multiple myeloma (MM) plasma cells (PC), rare CD19+ B cells can be identified in MM patients that are clonally related to the MM PC. These clonotypic B cells may exhibit properties of cancer stem cells (enhanced MM-propagating properties and drug resistance compared to MM PC) and thus be a potential therapeutic target in conjunction with therapies that target MM PC. CTL019 consists of autologous T cells transduced via lentiviral vector with an anti-CD19 scFv coupled to CD3-zeta and 4-1BB signaling domains and expanded ex vivo with anti-CD3/CD28-conjugated beads. To target both clonotypic B cells and MM PC, we conducted a pilot clinical trial of CTL019 administered after high-dose melphalan and autologous stem cell transplantation (ASCT) in relapsed/refractory MM patients who had previously undergone first-line ASCT with short progression-free survival (PFS).Methods: Subjects were required to be medically fit for ASCT and have progressed within 1 year of a prior ASCT performed as part of first-line therapy. Study therapy consisted of ASCT with melphalan 140-200 mg/m2 followed by 1-5x107 CTL019 cells 12-14 days later. The primary endpoint was safety and feasibility of CTL019 manufacturing and administration in this clinical setting. Secondary endpoints included assessments of CTL019 in vivo persistence and activity against normal B cells, plasma cell immunophenotype as a response biomarker, and PFS after ASCT + CTL019 in comparison to PFS after initial ASCT.Results: Twelve subjects enrolled, and 10 received study therapy; autologous T cells failed to expand ex vivo in one enrolled subject, and one enrolled subject elected to pursue off-study therapy. Median age was 61 (range 48-68). Median prior lines of therapy was 6 (range 2-10). Poor-prognosis features were present in 8/10 subjects (6/10 with poor-prognosis cytogenetics, 2/10 with BRAF V600E mutations, 1/10 with secondary plasma cell leukemia). Median PFS after first-line ASCT was 258 days (range 100-342). In pre-ASCT bone marrow (BM), the dominant MM PC population was CD19-negative by flow cytometry in 9/9 evaluable subjects, though 7/9 exhibited rare CD19+ subsets comprising 0.05-1.5% of MM PC. Melphalan dose was 140 (N=7) or 200 (N=3) mg/m2. All subjects infused received the maximum target dose of 5x107 CTL019 cells. Adverse events (AE) consisted mostly of expected ASCT toxicities. Grade ³3 AE that were at least possibly related to CTL019 included grade 3 autologous GVHD (N=1, resolved with corticosteroids) and oral mucositis (N=1). Grade 1 cytokine release syndrome occurred in 1 subject. There was no ASCT-related mortality. After infusion, CTL019 cells were detectable in peripheral blood (PB) of all subjects and persisted for median of 44 days (range 14-156). Presence of PB CTL019 cells was associated with absence of PB B cells. Notably, CTL019 cells were detected in BM in 9/10 subjects at day 42 and/or 100 post-ASCT. Median PFS after ASCT + CTL019 was 185 days (range 42-479); all subjects have progressed. The peak BM CTL019 frequency correlated significantly with favorable PFS (SpearmanÕs rho=0.77, P=0.009). There was no association between PFS and peak frequency of CTL019 or duration of CTL019 persistence in PB. In 3/10 subjects, PFS after ASCT + CTL019 met or exceeded PFS after first-line ASCT (Figure). For comparison, in a historical cohort of 18 patients who received first-line and salvage ASCT at our institution since 2008, no patients exhibited longer PFS after salvage ASCT.Conclusion: CTL019 manufacturing and administration post-ASCT is safe and feasible in patients with advanced MM. Correlation of PFS with CTL019 frequency in BM and prolonged PFS in 3 subjects is suggestive of clinical efficacy. A phase-two study of CTL019 using a 10-fold higher dose after first-line ASCT in high-risk MM patients is ongoing. [Display omitted] DisclosuresGarfall:Medimmune: Consultancy; Bioinvent: Research Funding; Novartis: Consultancy, Research Funding. Stadtmauer:Novartis: Consultancy; Takada: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Teva: Consultancy; Celgene: Consultancy. Maus:Novartis: Patents & Royalties: related to CTL019, Research Funding. Hwang:Novartis: Research Funding. Vogl:Takeda: Consultancy, Research Funding; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Constellation: Research Funding; Celgene: Consultancy; Acetylon: Research Funding; Karyopharm: Consultancy. Cohen:Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Weiss:Novartis: Consultancy. Porter:Genentech: Employment; Novartis: Patents & Royalties, Research Funding. Frey:Novartis: Research Funding; Amgen: Consultancy. Milone:Novartis: Patents & Royalties, Research Funding. Mangan:Novartis: Speakers Bureau. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Patents & Royalties: Novartis, Research Funding. Ambrose:Novartis: Research Funding. Chen:Novartis: Research Funding. Kulikovskaya:Novartis: Research Funding. Levine:Novartis: Patents & Royalties, Research Funding; GE Healthcare Bio-Sciences: Consultancy. June:Johnson & Johnson: Honoraria; Tmunity Therapeutics: Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Immune Design: Consultancy, Equity Ownership; Celldex: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Pfizer: Honoraria.

Response-Adapted Therapy for Newly Diagnosed Myeloma

Background: Before SWOG S0777 (Durie BGM at al. ASH 2015, abstract #25) it was not clear whether standard upfront regimens VRd (bortezomib, lenalidomide, dexamethasone) or Rd (lenalidomide, dexamethasone) yield different survival outcomes for newly diagnosed myeloma patients (pts.) but it was known that the higher response rate of VRd comes at a higher risk for severe peripheral neuropathy. Since no test predicts who requires the more toxic regimen to avoid adverse myeloma effects we designed a carepath that tailors therapy according to early response endpoints.Methods: Newly diagnosed symptomatic MM patients (pts) with measurable disease who were not eligible for or elected against a clinical trial were advised to begin a 2-drug regimen of lenalidomide (R) and weekly dexamethasone (d) or, if cast nephropathy suspected or R copay too high, bortezomib (V) and dexamethasone (D). Depending on response assessment per IMWG 2011 criteria after each cycle, treatment intensity was to be increased with sequential addition of agents (R or V, cyclophosphamide, and then liposomal doxorubicin) when there was not at least minor response (MR) after the first, or at least partial response (PR) after the second cycle of an administered combination. Once PR was reached, pts. were evaluated for high dose melphalan (HDM) and ASCT or consolidation with their induction regimen followed in either case by lenalidomide or bortezomib maintenance. After IRB approval, pts treated on carepath were identified through our registry and electronic medical records were reviewed.Results: From Oct 2012 to Dec 2015 the carepath was used in 91 pts. Their median age at treatment start was 64 years (34-84), 40 (44%) were ≥ 65, 11 (12%) ≥ 75 years old; at least one cytogenetic risk study (MyPRS®, FISH panel, karyotype analysis) was obtained in 81 (89%) and of them 23 (28.4%) had high risk features (MyPRS® score > 45.2, del17p, 1q amp, t4;14, t;14;16 and non-hyperdiploid karyotype abnormalities), 33 (36%) had ISS stage III and 21 (23%) had serum creatinine ≥ 2mg/dL, 6 (7%) were on dialysis. At median follow up of 20.5 months (1.7-44.6), at least PR was achieved in 84 pts (92%), at least very good partial remission (VGPR) in 63 (69%), with negative immunofixation in blood and urine in 24 (26%) and complete remission (CR) documented by bone marrow exam in 6 (7%). Only one pt (1%) had progressive disease as best response, stable disease and MR were seen in 3 pts. (3%) each. Induction required 2, 3, 4 and 5 drugs in 49 (54%), 33 (36%), 8 (9%), 1 (1%) pts, respectively, and was followed by high dose melphalan and autologous stem cell transplant in 19 (21%). Sixty-three pts. (69%) remain on carepath treatment without progression, while 28 (31%) have experienced progression with skeletal events in 4 (4%) and ARF in 2 pts. (2%). Nine pts. (10%) have died, 4 while in remission of whom 3 suffered a bleed while anticoagulated for DVT or pre-existing A-fib and died 1 after transition to hospice; the remaining 5 died after progression, of infection (3), secondary plasma cell leukemia (1), or after transition to hospice (2). No patient developed shingles or second primary malignancies so far; mild peripheral neuropathy (PNP) occurred in 27 pts (30%), severe or painful PNP in 4 (4%) and 8 pts. (9%) suffered venous thromboembolism (9%) on DVT prophylaxis with aspirin.Conclusions: Carepath therapy required only two drugs during induction in over 50% of patients to achieve an overall response rate of 92% with ≥ VGPR in 69% in a real-world setting without exclusion of patients on dialysis. Reduction in costs and side effects compared to upfront use of VRd for everyone were accompanied by promising early Kaplan-Meier estimates for progression-free and overall survival (Fig. 1) supporting the carepath principle and future randomized comparison of response-adapted therapy to fixed regimens like the new SWOG S0777 defined standard triplet VRd. [Display omitted] DisclosuresReu:Novartis: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Signal Genetics: Consultancy. Valent:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Faiman:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Takeda: Consultancy. Hamilton:Takeda: Speakers Bureau. Smith:Celgene: Honoraria; Spectrum: Honoraria; Genentech: Honoraria; Abbvie: Research Funding.

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 Leukaemia. Experience from Tertiary Referral Centres in Abu Dhabi

Plasma cell neoplasms range from an indolent disease (MGUS) to highly aggressive and relatively rare Plasma Cell Leukaemia (PCL). The diagnostic criteria for PCL is well established and includes plasmacytosis of greater than 20% of total white cell count or an absolute plasma cell count of greater than 2 X 109/L in peripheral blood. It is classified as either primary (pPCL) if there is no antecedent history of Multiple Myeloma (MM) or secondary (sPCL) arising as a leukemic event of MM. The median survival of PCL remains poor despite the use of novel agents and stem cell transplant. Here we report our experience with PCL.Method:Retrospective review of the medical records of patients with plasma cell dyscrasia identified through the tumour registry between January 2008 and March 2016. Eight patients were identified with diagnosis of PCL.Results:The median age was 53.5 years (range 34-77 years), male to female ratio was 5:3. There were four cases of sPCL while the other four patients had pPCL. The median time for transformation in sPCL was 199 weeks (range 163 to 244 weeks).All 4 patients with sPCL had received treatment with novel agents including bortezomib and IMIDS (lenalidomide/thalidomide) as part of their myeloma therapy. At the time of transformation two patients were unfit for any therapy while the other two patients were re-induced with bortezomib, lenalidomide and dexamethasone (RVd) with no response. None of the four patients had undergone autologous stem cell transplantation (due to unavailability of hematopoietic stem cell transplant facilities in UAE as well as socioeconomic reasons). The median survival after diagnosis of sPCL was 5.4 weeks (range 4-11 weeks).Patients with pPCL were treated with RVd (n=3) and VMP N=1. One patient also had an autologous stem cell transplant. Patients with primary PCL had a better median survival of 37 weeks (range 14 - 133 weeks) with one patient alive and under therapy 14 weeks after diagnosis.Conclusion:Plasma cell leukaemia remains a disease with extreme poor prognosis and an overall mortality of 88 per cent in our experience. Interestingly two patients with pPCL were noted to have evidence of plasma cell disorder (elevated total protein) a median of 8 months before the diagnosis of pPCL. Whether these two cases truly represent pPCL or 2ndry event because of under diagnosis of MM remains speculative at best. One of the above two patients also had a diagnosis of chronic myeloid leukaemia on Imatinib and was in a major molecular remission. Patients with primary plasma cell leukaemia tend to do relatively better as compared to secondary plasma cell leukaemia where the transformation is catastrophic with a very short median survival. The difference in survival between pPCL and sPCL is most likely because the sPCL has a more resistant disease due to previous treatment and clonal evolution of their disease.Second generation novel agents including carfizlomib and the monoclonal antibodies daratumomab and elotuzumab should be evaluated in the induction and maintenance strategy to improve the outcome of PCL. DisclosuresAlam:BMS: Consultancy, Honoraria; Biologix: Honoraria.

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.

Clinical profile of plasma cell leukemia at Tertiary Care Hospital in Kashmir, India

Introduction: Plasma cell dyscrasias represent 1.4–2% of all malignancies and among hematologic malignancies; it constitutes 10% of the tumors. Plasma cell dyscrasias are composed of multiple myeloma (MM), and primary and secondary plasma cell leukemia. Materials and Methods: Primary plasma cell leukemia (pPCL) is a rare and aggressive disease, representing 1–4% of plasma cell dyscrasias. Results: The prognosis of this is very poor with median survival of 8–11 months in different reported series. Discussion: We are reporting a study from our hospital over a period of 8 years and 9 months, in which pPCL was found in 1.8% of MM patients, with slight male predominance and earlier age than MM, and all had high disease burden with high lactate dehydrogenase (LDH), β2-microglobulin, and plasmacytosis. Conclusion: This disease had very aggressive behavior, especially with light chain lambda disease, and all patients succumbed within 8 months of treatment.

Plasma cell leukemia: Single institution experience

The first case of plasma cell leukemia (PCL) was recognized by Gluzinski and Reichentein. It is the most aggressive among the monoclonal gammopathies. It is diagnosed by the presence of more than 20% plasma cells in the peripheral blood or an absolute plasma cell count of> 2000/mm3. Because of the relatively low incidence, most data come from case reports and retrospective studies. No prospective series have been published, and only seven reports including more than twenty patients have been identified. We report a retrospective series of 18 patients identified as PCL. To study the clinical features and outcome of patients with PCL. A retrospective study was conducted from the year 2006 to 2015 wherein all the patients diagnosed with PCL were identified. Complete clinical and treatment details and outcome were obtained from the records. There were total 18 cases of PCL (3.7% of cases with multiple myeloma) diagnosed between the year 2006 and 2015. 16 cases (84%) were primary PCL, and two cases were secondary PCL. Twelve patients were males and six were females. The median age was 56.5 years. All patients had aggressive clinical course and median overall survival even with immunomodulatory agents was only 3 months. PCL is a very aggressive disease, and no prospective trials have been conducted. Patients with PCL require induction with immunomodulators, proteasome inhibitors, and further trials are needed to evaluate the role of autologous stem cell transplant in this disease.

Distinct Clinico-Pathological Profile of Plasma Cell Leukemia Patients from North India

Introduction: Plasma cell leukemia (PCL) is a rare and aggressive plasma cell neoplasm where clonal plasma cells comprise ≥ 20% of peripheral blood (PB) leukocytes and/or absolute clonal PB plasma cell count is ≥ 2×109/L. Primary plasma cell leukemia (PPCL) originates de novo, whereas, secondary plasma cell leukemia (SPCL) evolves from pre-existing multiple myeloma (MM). Literature does reveal a few large case series on PCL, however, data on this rare neoplasm is very sparse from Indian sub-continent. We present clinico-pathological profile 14 cases of PCL from single tertiary care centre of north-India.Materials and methods: Archival files were screened for period of 8 years (Jan 2007 to Dec 2014) and clinico-pathological profile, including overall survival, of patients of PCL was systematically analysed, retrospectively.Results: Ten PPCL and four SPCL patients were traced in duration of 8 years, all belonging to north-Indian states of Punjab and Haryana. Eight PPCL and three SPCL patients had complete clinical data. Our patients had less frequent renal failure (12.5%), more frequent hepatomegaly (75%) and non-secretory type (33%) disease. Flow cytometric immunophenotyping revealed expression of CD138 (67%), CD56 (33%) and CD20 (0%), which was different from reported western data. With novel therapeutic agents, these patients fared a higher median survival of 15 months.Conclusion: Our patients of PCL from neighbouring states of north-India have a distinct clinico-pathological profile, with better survival as compared to existing literature. The significance of our findings must be tested in a larger patient cohort and must be supported with molecular and cytogenetic investigations to unmask any significant pathogenesis. DisclosuresNo relevant conflicts of interest to declare.