Primary Plasma Cell Research Articles

Real Life, Retrospective Analysis of Bortezomib Re-Use As Second Treatment for Relapsed Multiple Myeloma Patients Previously Exposed to Bortezomib-Based Therapies As First Line: The Rebound Study

Background: Several trials and analysis have explored the efficacy of bortezomib re-use in relapsed patients with multiple myeloma (MM), notably in those who have experienced good response and late relapse after the end of frontline treatments including the same drug. However, very few specific evidences on bortezomib re-challenge at first relapse are available.Patients and methods: This observational, retrospective study enrolled 135 MM patients treated from January 2002 to May 2015 in 12 Italian centres with bortezomib-based regimens as first line therapy (both in daily practice or clinical trials) and who had received again a salvage treatment containing bortezomib at first relapse, according to current clinical practice and/or guidelines recommendations.Results: Median age was 61 years (range 28-95) and 60% of patients were males. At diagnosis, ISS was 30% stage I, 30% stage II and 40% stage III; r-ISS (available in 45 cases) was 25% stage I, 44% stage II and 31% stage III. Two patients presented as primary plasma cell leukemia (PCL). First line induction treatments included VD (27%), VTD (25%), VMP (23%), PAD (10%), and further combinations of bortezomib with cyclophosphamide (11%) or other drugs (4%). Eighty-two percent of patients received a twice-week schedule and 18% once-a-week administration of bortezomib, which was initially given i.v. in 71% and s.c. in 29% of patients, respectively. Seventy-five patients (56%) underwent single (72%) or double (28%) autologous stem cell transplantation (AuSCT) as part of their frontline therapy. Consolidation or maintenance with borteomib were performed in 17 and 4 patients, respectively. As per inclusion criteria, all patients achieved PR or better response (according to IMWG criteria), including at least VGPR in 36%, CR in 20% and sCR in 1% of cases. Median duration of PFS1 was 33 months (95% CI 28-36), while median treatment free-interval (TFI) was 23 months (95% CI 22-28). Median PFS1 was 35 months (95% CI 31-43) and 27 months (95% CI 20-33) for patients undergoing or not AuSCT, respectively (p n.s.).At first relapse (clinical 65%, only biochemical 35%), anemia, neutropenia and thrombocytopenia were present in 42%, 5% and 9% of patients, respectively. Median bone marrow plasma cell infiltration was 40% (range 2-99). Bone lesions were present in 74%, hypercalcemia in 7%, high LDH values in 15% of patients. Serum beta2-microglobulin levels were increased in 48%, while albumin was decreased in 17%. Renal failure was observed in 14%, with a median value of serum creatinine of 2.2 mg/dl (range 1.4-7). PCL occurred in 3 patients. Second line regimens included VD (44%), VCD (11%), PAD (9%), VTD (7%), BVD (7%), VMP (7%), VRD (4%), VRCD (2%), or other combinations (9%). Six patients had maintenance therapy with bortezomib. Twenty-one patients (16%) received AuSCT as part of their salvage therapy, while 4 patients (3%) underwent allogeneic transplantation (AlloSCT) and 5 (4%) a tandem sequence of AuSCT followed by AlloSCT. Seventy-four percent of patients received bortezomib once-a-week, 26% twice-weekly, 35% i.v. and 65% s.c. A total of 782 cycles (median 6, range 1-13) were given. Grade 3-4 hematological and non-hematological toxicities occurred in 27% and 10% of patients, respectively. No patient reported grade 3-4 neuropathy. Bortezomib dose reductions were needed in 12%. SPM occurred in 1 patient. Overall response rate was 70%, with 24% at least VGPR and 7% CR (sCR/nCR 1.5%). Improvement of renal failure (13 cases) was complete in 4 and partial in 6 patients. Bone disease improved in 31% of patients with osteolytic lesions. Median duration of second PFS was 19 months (95% CI 13-23), while that of second TFI was 14 months (95% CI 8-17). Median PFS2 was 56 months (95% CI 50-70); it was 60 months (95% CI 54-78) for patients who underwent AuSCT and 50 months (95% CI 45-68) for those who did not (p n.s.). Median OS was 94 months (95% CI 80-121) for the entire cohort, 94 months (95% CI 75-107) for patients undergoing AuSCT, and 86 months (95% CI 76-92) for those who did not receive AuSCT. After a median follow up of 56 months, 85 patients (63%) are alive, with 41 of them in response after second line therapies containing bortezomib.Conclusions: This real-life survey indicates that re-treatments including bortezomib as first salvage therapy should be considered for selected MM patients achieving prolonged response after initial exposure to first line, bortezomib-based regimens. DisclosuresMusto:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cascavilla:Janssen-Cilag: Honoraria. Falcone:Janssen-Cilag: Honoraria. Petrucci:Janssen-Cilag: Honoraria. Di Raimondo:Janssen-Cilag: Honoraria. Ria:Binding Site: Speakers Bureau; BMS: Speakers Bureau; BMS: Speakers Bureau; Italfarmaco: Consultancy, Speakers Bureau; Janssen-Cilag: Other: Advisory Board, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau. Mastrullo:Janssen-Cilag: Honoraria. D'Arena:Janssen-Cilag: Honoraria. Bringhen:Janssen-Cilag: Honoraria; Celgene: Honoraria; BMS: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Di Renzo:Janssen-Cilag: Honoraria. Caravita:Janssen-Cilag: Honoraria. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Corso:Janssen-Cilag: Honoraria.

Comparison of Haematopoietic Stem Cell Transplantation Approaches in Primary Plasma Cell Leukaemia

IntroductionPrimary plasma cellleukemiais a rare and aggressive disorder. While autologous stem cell transplantation has been shown to improve outcome, response durations are short and further strategies are needed. Data is needed to help guide clinicians on the best approach to manage this disease. Therefore in an era of novel agents and improved autologous and allogeneic transplantation strategies this study compared different transplantation approaches in the treatment of PCL.Material and MethodsA retrospective analysis was undertaken of theEuropean Group for Bone Marrow Transplantation (EBMT) experience of patients with primary PCL undergoing hematopoietic stem cell transplantation between 1998 and 2012. Only patients who had achieved complete response, partial response or stable disease prior to transplantation were included. Patients with progressive or relapsed disease were excluded.Data was collected using MED A and MED B forms. The primary end point was overall survival and data was analysed according to the information on the planned transplant strategy reported at the time of first transplant (intent-to-treat principle).ResultsA total of 460 patients were identified and categorised into 4 transplant groups.1. One patient did not proceed to Allo2. Four patients not classifiedThe follow up period ranged from 1 to 208 months with a median follow up of 48.9 months.Patients undergoing allo upfront were found to have the worst overall survival. Compared to single auto this was statistically significant with a Hazard Ratio (HR) 1.85 (p=0.007).Compared to auto-allo the allo up front group had an even higher risk HR 3.18 (p=0.018). The double auto versus single auto had a HR 1.39 which was not statistically significant (p=0.28).The auto-allo compared to single auto has a time varying effect with a higher mortality at the beginning and better risk afterwards. The effect on average is not significant HR 0.58 (p=0.24).When we consider time varying effects three periods were examined, 0-12, 12-36 and 36-60 months. Allo upfront is still confirmed to be inferior to single auto and also to auto-allo in the first year. Auto-allo has a trend to superiority versus single or double auto in the mid-term. However due to lack of follow up data in the auto-allo group it is difficult to assess possible benefits of auto-allo in the long term as there are few patients still at risk. Our initial analysis does suggest an advantage.Preliminary analysis suggests that the auto-allo group enjoy the best progression free survival. The superiority of auto-allo versus allo upfront may be attributed to the higher rates of non-relapse related mortality observed in allo upfront.ConclusionOur preliminary work has demonstrated that allo upfront is associated with the worst overall survival. Further data is needed to reliably assess the outcome of auto-allo group which appears to be superior. Therefore we plan to request additional information from involved centres to strengthen the power of our results. [Display omitted] DisclosuresFoà:Ariad: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Genetech: Consultancy; Roche: Consultancy, Speakers Bureau. Garderet:Takeda: Consultancy; Amgen: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy.

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.

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.

Long Term Follow-up of Hematopoietic Stem Cell Transplantation (HSCT) for Primary Plasma Cell Leukemia (pPCL): Final Results of a Prospective Study of IFM Group

Introduction:pPCLis a rare form of multiple myeloma (MM) with very poor outcome. Current strategies including novel agents and transplantation (auto or allo-HSCT) may improve survival but the prognosis remains poor. The IFM recently published results from a prospective study incorporating tandem auto/allo-HSCT or auto/auto and maintenance after alternate induction (doxorubicin-bortezomib-cyclophosphamide and dexamethasone: PAD/VCD) in 40 pPCL patients. We report here outcomes of patients who effectively underwent second transplant (auto or allo) with long-term follow-up.Methods:24 over 40 patients actually received second transplant:allo-HSCT (as per protocol) forpatients< 60 years-old with a donor, second auto-HSCT for others. At time of second transplant, response rates were: sCR (n=1), CR (n=8), VGPR (n=10), PR (n=5) (cf table).7 patients received high-dose melphalan (HDM)/auto-HSCT followed by maintenance consisting in Bortezomib-Lenalidomide-Dex (VRD) every 3 months and Lenalidomideduring other months for 1 year. 17 others patients underwent allo-HSCT: syngenic(n=1) or reduced intensity conditioning (RIC)-Allo (n=16). The conditioning regimens for allo were: fludarabin-busulfan-antithymoglobulin(n=13), fludarabin-melphalan(n=1), bortezomib-fludarabin-melphalan(n=2) and HDM for syngenic(n=1). They were grafted with peripheral blood stem cells except 1 who received bone marrow and 1 cord blood unit, from related (n=9) or HLA-matched unrelated donors (n=8): median infused CD34 cells was 6.8 106/kg [3-8.5]; all pts receivedciclosporine+/-methotrexate as GvHD prophylaxis.Results:As of June 2016, median follow-up from diagnosis was44.7months[41.0;57.6], 10 patientswerestillalive.MedianPFS for allo and auto ptswas18.5months[17.8;-] and 50.1months[25.6;-]respectively ;medianOSwas39.3months[26.6;-] and notreached,respectively.Inlandmarkanalysisfromdate of second transplant, PFSwas12.2 months [8.1 ;-] for allo pts and 40.0months[17.7;-] for auto pts (p=0.085); OSwas30.0months[28.6;-] and notreached,respectively(p=0.026). 2 allo ptsdiedbefored100evaluation ; 18 patients (75%)werein VGPR orbetter : sCR=2, RC=8, VGPR=8 ; 4 patients (17%)werein PR.For allo-HSCT : 6patients developed acute GvHD which responded to steroid in 5 cases and 1 was steroid-resistant and responded secondary to anti-IL2Rα antibody;5 patients experienced chronic GVHD (mild [n=4], extensive [n=1]).3 patients received 3 months after allo as immunomodulation, donor lymphocyte infusions plusLenalidomide-Cyclophosphamide-Fludarabin(n=1), Bortezomib (n=1) and Lenalidomide (n=1): one patient in PR achieved CR and the two others in VGPR maintained their response.Day 100 treatment-related mortality was 12%: 2 patients had Epstein-Barr virus reactivation, with 1 experiencing neuromeningeal relapse of pPCL and 1 concomitant disseminated toxoplasmosis.For auto-HSCT: as per protocol, 6 received a second HDM/auto, and 1 declined. Consolidation with VRD/Len was initiated in these 7 patients: 4 receiving the planned 1 year of treatment and 3 discontinuing after 4, 8, and 10 months as a result of prolonged cytopenia.Conclusion:This is the first large prospective trial for pPCL patients including tandem auto/auto-HSCT or tandem auto/RIC-allo after induction including proteasome inhibitor. This approach is feasible, and induces high response rate but relapses remain frequent especially after RIC-allo. Tandem auto/auto plus maintenance may be superior to tandem auto/alloregarding PFS and OS. In a future trial, we will investigate tandem auto/auto after induction incorporating novel proteasome inhibitor, anti-CD38 monoclonal antibody and Lenalidomide, and followed by consolidation and prolonged maintenance. [Display omitted] [Display omitted] DisclosuresRoussel:amgen: Consultancy; Janssen: Consultancy; celgene: Consultancy. Karlin:janssen-cilag: Consultancy, Honoraria; amgen: Consultancy, Honoraria; celgene: Consultancy, Honoraria; Bristol: Consultancy; takeda: Consultancy. Hulin:Janssen: Honoraria; Bristol: Honoraria; Amgen: Honoraria; takeda: Honoraria; celgene: Honoraria. Macro:sanofi: Consultancy; Novartis: Honoraria; Bristol: Consultancy; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgen: Consultancy, Honoraria. Belhadj:janssen: Consultancy; novartis: Consultancy. Chaleteix:Amgen: Honoraria; Janssen: Honoraria. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Garderet:Takeda: Consultancy; Amgen: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy. Choquet:Janssen: Consultancy; Celgene: Consultancy. Fornecker:Roche: Consultancy; Takeda: Consultancy; Gilead: Consultancy; Mundipharma: Speakers Bureau. Facon:Novartis: Consultancy; Amgen: Consultancy, Speakers Bureau; Millenium/Takeda: Consultancy; Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Bristol: Consultancy; Karyopharm: Consultancy. Moreau:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria.

Epidemiologic features of myeloma in Szabolcs-Szatmár-Bereg county, Hungary. Analysis of data of a 33-year period

In their previous work, the authors reported findings from 30 years on the incidence of hematological malignancies in Szabolcs-Szatmár-Bereg county, Hungary. Until now there are no other studies on this topic available in Hungary. Detailed analysis of epidemiologic features of patients with myeloma. During a 33-year period (between January 1, 1983 and December 31, 2015) 4521 adult patients with hematologic malignancies were recorded in the leukaemia/lymphoma registry of Szabolcs-Szatmár-Bereg county. Among them 440 patients with myeloma (9.73%) were registered (397 multiple myeloma, 38 solitary, bone/soft tissue plasmocytoma, 5 primary plasma cell leukaemia). The incidence of myeloma in Szabolcs-Szatmár-Bereg county showed an increasing tendency, with an overall incidence rate of 2.33/100 000 inhabitants/year. The male:female ratio was 45.9%:54.1%, the average age of patients was 65.1 (28-90) years, and 59.4% of the patients with multiple myeloma had IgG-type monoclonal immunoglobulin. There was no town or village in this county where the occurrence of patients with myeloma in one thousand inhabitants was significantly higher, than the average (0.78). The epidemiologic features of myeloma in Szabolcs-Szatmár-Bereg county - except a moderate female dominance - is essentially similar to data published in the literature. Orv. Hetil., 2016, 157(34), 1357-1360.

Dolor de la región lumbar como presentación de leucemia de células plasmáticas primaria avanzada con marcadores de mal pronóstico

&lt;p&gt;La leucemia de células plasmáticas es una entidad rara que representa el 1-2% del total de las neoplasia hematológicas; es una enfermedad agresiva con mala respuesta al tratamiento y un promedio de sobrevida de siete meses. Se presenta el caso de una paciente diagnosticada con leucemia de células plasmáticas primaria con marcadores de mal pronóstico y tratamiento, quien tuvo como manifestación clínica inicial dolor lumbar, el cual evoluciono desfavorablemente y con desenlace fatal.Abstract Plasma cell leukemia is a rare disease that accounts for 1-2% of all hematologic neoplasia. It is an aggressive disease with poor response to treatment and an average survival period of seven months. The case of a patient diagnosed with advanced primary plasma cell leukemia with markers of poor prognosis and treatment whose first symptom was back pain, which did not evolve in a positive way and ended in the death of the patient.&lt;/p&gt;

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

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

Bortezomib, Doxorubicin, Cyclophosphamide, Dexamethasone Induction Followed by Stem Cell Transplantation for Primary Plasma Cell Leukemia: A Prospective Phase II Study of the Intergroupe Francophone du Myélome

Primary plasma cell leukemia (pPCL) is a rare and aggressive malignancy with a poor prognosis. With conventional chemotherapy, patients typically die within 1 year. In all but one of the retrospective studies reported to date, bortezomib and lenalidomide seem to improve survival. We conducted a prospective phase II trial in patients with pPCL to assess the efficacy of an alternate regimen that combines standard chemotherapy, a proteasome inhibitor, and high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) followed by either allogeneic transplantation or bortezomib/lenalidomide maintenance. Patients 70 years old and younger with newly diagnosed pPCL received four alternating cycles of bortezomib, dexamethasone plus doxorubicin or cyclophosphamide. Peripheral blood stem cells were collected from responding patients with < 1% of circulating plasma cells before HDM/ASCT. As consolidation, young patients received a reduced-intensity conditioning allograft, whereas the remaining patients underwent a second HDM/ASCT followed by 1 year of bortezomib, lenalidomide, dexamethasone. The primary end point was progression-free survival (PFS). Forty patients (median age, 57 years; range, 27 to 71 years) were enrolled. The median follow-up was 28.7 months. In the intention-to-treat analysis, the median PFS and overall survival were 15.1 (95% CI, 8.4; -) and 36.3 (95% CI, 25.6; -) months, respectively. The overall response rate to induction was 69%. One patient underwent a syngeneic allograft and 25 HDM/ASCT (16 of whom subsequently received a reduced-intensity conditioning allograft and seven a second ASCT followed by maintenance). In this prospective trial in patients with pPCL, we show that bortezomib, dexamethasone plus doxorubicin or cyclophosphamide induction followed by transplantation induces high response rates and appears to significantly improve PFS.

Primary Plasma Cell Leukemia: Identity Card 2016.

Primary plasma cell leukemia (PPCL) is an aggressive and rare variant of multiple myeloma (MM), characterized by peculiar adverse clinical and biological features. Though the poor outcome of PPCL has been slightly improved by novel treatments during the last 10 years, due to the limited number of available studies in this uncommon disease, optimal therapy remains a classic unmet clinical need. Anyway, in the real-life practice, induction with a bortezomib-based three-drug combination, including dexamethasone and, possibly, lenalidomide, or, alternatively, thalidomide, cyclophosphamide, or doxorubicin, is a reasonable first-line option. This approach may be particularly advisable for patients with adverse cytogenetics, hyperleucocytosis, and rapidly progressive disease, in whom a fast response is required, or for those with suboptimal renal function, where, however, lenalidomide should be used with caution until renal activity is restored. In younger subjects, leukemia/lymphoma-like more intensive regimens, including hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone or continue-infusion cisplatin, doxorubicin, cyclophosphamide, and etoposide, may be also combined with bortezomib +/- thalidomide. Treatment must be started immediately after a diagnosis of PPCL is made to avoid the risk of irreversible disease complications and, in such a context, the prevention of tumor lysis syndrome is mandatory. In patients eligible for autologous stem cell transplantation (AuSCT), other alkylating agents, in particular melphalan, should be initially avoided in order to allow adequate collections of CD34+ peripheral blood stem cells (PBSC). A combination of lenalidomide and dexamethasone may be a valuable alternative option to manage older or unfit patients or those with slower disease evolution or with signs of neuropathy, contraindicating the use of bortezomib. Patients not suitable for transplant procedures should continue the treatment, if a response occurs and if tolerated, considering the possibility of a prolonged maintenance therapy. AuSCT should be pursued in all eligible patients less than 65 years old who achieve a significant response after a short course of induction treatment. PBSC collection should reach a threshold of at least 5 × 10(6) CD34+ PBSC/kg using cyclophosphamide plus G-CSF and adding the mobilizing agent plerixafor, if necessary. High-dose melphalan (HDM) (200 or 140 mg/m(2), according to age and renal function) remains the preferable conditioning regimen. A second AuSCT should be always considered, even in patients achieving complete response (CR) after the first AuSCT, as the short progression-free survival (PFS) generally seen in PPCL suggests the persistence of a relevant burden of residual disease; this provides a strong rationale for the use of post-transplantation therapies in PPCL to improve depth of response, to maintain remission, and, possibly, to increase survival, though consolidation and/or maintenance strategies with novel agents, whose efficacy has been well demonstrated in MM, have not been still extensively evaluated in PPCL. The search of a suitable donor should start as soon as possible and an allogeneic stem cell transplant (AlloSCT) with a myeloablative conditioning (MAC) regimen discussed with younger patients responsive to induction therapy and with poor prognostic parameters at diagnosis. A sequence of AuSCT followed by reduced intensity conditioning (RIC) or non-myeloablative (NMA) AlloSCT may be considered in selected cases. Salvage therapies for relapsed/refractory disease, especially using new drugs not employed at diagnosis, are sometimes effective in the short term, but a rapid relapse is still generally the rule; AlloSCT in relapsed and eligible patients with sensitive disease after salvage treatments is, therefore, recommended.

The treatment of primary plasma cell leukemia with bortezomib based combination chemotherapy concurrent autologous peripheral blood stem cell transplantation: one case report and review of the literature

目的 探索以硼替佐米为基础的联合化疗序贯自体外周血干细胞移植治疗原发性浆细胞白血病(pPCL)的效果。 方法 报道1例经硼替佐米为基础的联合化疗序贯自体外周血干细胞移植治疗pPCL，并进行相关文献复习。 结果 该例患者经硼替佐米为基础的联合化疗达到非常好的部分缓解(VGPR)，进行自体外周血干细胞移植后达到完全缓解(CR)，无进展生存达33个月。 结论 以硼替佐米为基础的联合化疗及自体造血干细胞移植可能会改善pPCL患者的预后，减少复发。

Molecular spectrum of TP53 mutations in plasma cell dyscrasias by next generation sequencing: an Italian cohort study and overview of the literature.

The prevalence of TP53 mutations greatly varies between tumor types; in multiple myeloma (MM) they were rarely detected at presentation, while increased frequency was reported with disease progression. Using next-generation sequencing, we analyzed TP53 exons 4-9 in a large representative cohort comprising patients with MM at diagnosis and more aggressive forms of plasma cell (PC) dyscrasia, identifying mutations in 4/129 (3%) MM, 6/24 (25%) primary PC leukemia, and 2/10 (20%) secondary PC leukemia cases. A similar increase in prevalence associated with disease aggressiveness (5%, 29.2% and 44%, respectively) was observed for TP53 deletion. Interestingly, in five patients mutations were not concomitant with TP53 deletion. Furthermore, longitudinal analysis revealed the acquisition of TP53 mutations in three of nineteen cases analyzed at relapse. Identified variants were mostly missense mutations concentrated in the DNA binding domain, only partly reflecting the pattern globally observed in human cancers. Our data confirm that TP53 mutations are rare in MM at presentation and rather represent a marker of progression, similarly to del(17p); however, their occurrence even in absence of deletions supports the importance of their assessment in patients with PC dyscrasia, in terms of both risk stratification and therapeutic implications.

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.

Hemorrhagic Skin Nodules and Plaques: A Diagnostic Clue to Underlying Primary Plasma Cell Leukemia.

Plasma cell leukemia (PCL) is a rare lymphoproliferative disorder characterized by a malignant proliferation of plasma cells (PC) in blood and marrow. Cutaneous involvement is very rare in PCL. We present the case of a 45-year-old lady who presented with multiple hemorrhagic nodules and plaques in the skin. Her total leucocyte count was 2,00,200/cmm with 85% abnormal plasmacytoid cells in peripheral smear. Biopsy of the skin lesions revealed diffuse infiltration by plasma cells with ‘choked’ blood vessels. A diagnosis of plasma cell leukemia with cutaneous involvement was made. On the second day of admission, the patient expired probably because of intracranial bleed due to thrombocytopenia. Post-mortem bone marrow and liver biopsy also showed diffuse infiltration by plasma cells. Monoclonality of the cells was proven by demonstrating the production of only kappa light chains.

Pulmonary Hypertension Induced by Thalidomide (and Derivatives) in Patients with Multiple Myeloma: A Systematic Review

Thalidomide is widely used in the treatment of multiple myeloma (MM). In recent years, several cases of pulmonary hypertension have been reported following treatment with thalidomide. The aim of this review was to evaluate the published literature on multiple myeloma patients with pulmonary hypertension following thalidomide treatment. A literature search was performed between 2000 and 2016. A total of 7 eligible studies were identified and deemed eligible, including 11 cases—approximately 37% (4 cases) with IgA (k), 27% (3 cases) with IgG (λ) MM, 27% (3 cases) with IgG (k) MM, and one case (9%) with primary plasma cell leukemia (PPCL). The vast majority of cases—82% (9 cases)—are associated with thalidomide, while only 18% (2 cases) are related to thalidomide derivatives (lenalidomide and pomalidomide). In conclusion, pulmonary hypertension induced by thalidomide or derivatives in multiple myeloma (MM) patients is related to a multifactorial etiology including the pathophysiology of the disease, thromboembolic events, preexisted cardiovascular conditions, comorbidities, and combination with other chemo- or bio-therapeutic agents. MM patients should be evaluated for signs and symptoms underlying cardiopulmonary disease before initiating, and during treatment with thalidomide.

Risk of Early Mortality in Patients with Newly Diagnosed Multiple Myeloma

▪BackgroundThe overall survival of patients with multiple myeloma has been improved greatly over the last two decades with the advances of treatment. Several studies reported that this improvement in survival has been ascribed to the broader use of novel drugs and autologous tandem transplantation. However, there were still a certain portion of myeloma patients died early after diagnosis. We therefore aim to investigate the risk factors of early mortality (death within 60 days after diagnosis) in patients with multiple myeloma.Patients and MethodsWe included in this study 451 consecutive patients with multiple myeloma, newly diagnosed at an Asian tertiary medical center between January 1, 2002 and April 30, 2015. A total 57 subjects who developed early mortality were identified. Risk factors for early mortality in myeloma patients were collected and analyzed.ResultsCompared with non-early mortality myeloma patients, early mortality patients had higher probability of being male, primary plasma cell leukemia, low platelet count, low serum albumin, high corrected serum calcium, high serum creatinine, high LDH, high serum β2-microglobulin, poor performance status, and high ISS stage. With multivariate analysis, we found that male (adjusted OR 2.93, 95% CI 1.17-7.31), serum albumin < 3.5g/dl (adjusted OR 2.76, 95% CI 1.17-6.52), corrected serum calcium ≥ 12mg/dl (adjusted OR 3.56, 95% CI 1.47-8.63) and LDH ≥ 250U/L (adjusted OR 3.30, 95% CI 1.62-6.74) were significant risk factors of early mortality. Pneumonia represented as the leading cause of early mortality in myeloma patients (n = 18, 31.5%), followed by renal failure (n = 7, 12.2%).ConclusionEarly mortality rate is high (12.6%) in patients with multiple myeloma. Patients of male gender, low serum albumin, high corrected serum calcium and LDH are at risk of early mortality. More than one third myeloma patients (21 out of 57) who developed early mortality are died of infection. Identifying the risk group and providing prompt intervention, such as prophylaxis antibiotics, may reduce the incidence rate of early mortality and improve the life expectancy of myeloma patients. DisclosuresNo relevant conflicts of interest to declare.

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.

Risk of Early Mortality in Patients With Newly Diagnosed Multiple Myeloma.

The overall survival of patients with multiple myeloma (MM) has been improved greatly over the last 2 decades with the broader use of novel drugs and autologous tandem transplantation. However, more than one tenth of myeloma patients still die shortly after diagnosis. We therefore aim to investigate the risk factors of early mortality (death within 60 days after diagnosis) in patients with MM. We included in this study 451 consecutive patients with MM, newly diagnosed at an Asian tertiary medical center between January 1, 2002 and April 30, 2015. A total of 57 subjects who experienced early mortality were identified. Risk factors for early mortality in myeloma patients were collected and analyzed. Early mortality occurred in 57 (12.6%) of the myeloma patients. In the multivariate analysis, being male (adjusted OR 2.93, 95% CI 1.17-7.31), serum albumin < 3.5 g/dL (adjusted OR 2.71, 95% CI 1.09-6.74), primary plasma cell leukemia (adjusted OR 17.61, 95% CI 1.01-306.05), serum albumin (adjusted OR 2.70, 95% CI 1.15-6.38), corrected serum calcium ≥ 12 mg/dL (adjusted OR 2.94, 95% CI 1.21-7.14), and LDH ≥ 250 U/L (adjusted OR 3.07, 95% CI 1.50-6.27) were identified as independent risk factors of early mortality. Pneumonia with other infections contributed most to early mortality (n = 36, 65%), followed by renal failure and cardiac failure. The early mortality rate is high (12.6%) in patients with MM. Patients who are male and those with primary plasma cell leukemia, low serum albumin, high-corrected serum calcium, or LDH are at risk of early mortality. Nearly two thirds of the myeloma patients who experienced early mortality in our study (37 of 57, 65%) died of infection. Once a high-risk group is identified, much effort is required to target new approaches for prevention, early detection, and treatment of infections.

P1-2-61 - Therapeutic approach for primary plasma cell leukemia: case reports and a review of the literature

P1-2-61 - Therapeutic approach for primary plasma cell leukemia: case reports and a review of the literature

Primary Plasma Cell Leukemia in the Era of Novel Agents: A Multicenter Study of the Japanese Society of Myeloma

We investigated the treatment and outcome of Japanese patients with primary plasma cell leukemia (pPCL) in the era of novel agents and analyzed the risk factors affecting survival. Among 3,318 patients with symptomatic multiple myeloma (MM), 38 patients were diagnosed with pPCL. The median overall survival (OS) of the pPCL patients was 2.85 years, which was significantly extended compared with that in previous reports. The proportion of patients treated with novel agents was 61%. The OS of the patients treated with novel agents was significantly extended compared with that of patients treated without novel agents according to the generalized Wilcoxon test (2.85 vs. 1.16 years, p = 0.049). This statistical finding suggests that treatment with novel agents could have prevented early death in the patients with pPCL. Age was the only statistically significant prognostic factor associated with an inferior OS (hazard ratio 4.57). Five patients received maintenance therapy with novel agents, and their OS tended to be longer than that of the other patients without maintenance (4.45 vs. 2.85 years). Unlike MM, OS for pPCL has not been improved significantly over the last decade, especially in elderly patients. Therefore, it is important to establish the treatment strategy, particularly after induction treatment.