Spinal Disease Predicts CNS Involvement in Patients with Plasma Cell Leukemia

Abstract Background: Plasma cell leukemia (PCL) is a rare and aggressive hematologic malignancy with an incidence of approximately 1,200 patients per year in the United States with a median disease-specific survival of 6 months. PCL can either originate de novo (primary PCL) or as a secondary leukemic transformation of multiple myeloma (secondary PCL). A feared complication is infiltration of plasma cells into the central nervous system (CNS), meninges, or cerebrospinal fluid (CSF) which is challenging to treat and most often results in early mortality. We have observed a higher incidence of CNS disease among patients with PCL compared to multiple myeloma and were motivated to conduct a retrospective analysis to identify risk factors for the occurrence of CNS involvement among patients with primary or secondary PCL. Aim: Identify risk factors that should prompt clinicians to obtain a lumbar puncture and neuroimaging to screen for CNS involvement in patients with PCL. Methods: We conducted a retrospective analysis utilizing clinical data from patients who were found to have greater than 5% abnormal plasma cells in their peripheral blood detected by flow cytometry at the Seattle Cancer Care Alliance from 1990 to the present. IRB approval was obtained before data abstraction. Features extracted included laboratory values, radiographic data, pathologic data, treatment regimens, and response outcomes to chemotherapy regimens. The Fisher test was used identify risk factors associated with CNS disease. A P value <0.05 indicated a significantly asymmetrical distribution. The Kaplan-Meier product-limit method was used to estimate survival functions for groups in each risk factor. To determine the independent prognostic ability of each risk factor, multivariate survival analysis was performed using a Cox proportional hazards model. Results: To date, we have studied 21 patients which include 12 males and 9 females. Among this group, 18 patients were Caucasian, 2 patients were African American, and 1 patient's ethnicity was unknown. Four patients were diagnosed with primary PCL and 17 patients had secondary PCL. PCL was detected in the CSF by lumbar puncture in 5 patients (24%). The median overall survival of patients with CNS involvement from the time of PCL diagnosis was 192 days compared to 722 days in patients without CNS involvement. We reasoned that leukemic cells may translocate to the CSF more commonly in patients with spinal disease and evaluated the prevalence of spinal abnormalities. We found that all patients with CNS involvement and only 72% without CNS involvement had one or more spinal abnormalities which included degenerative disc disease, compression fractures of the spine, or lytic lesions of the spine (P < 0.05). We also found a significant correlation between CNS involvement by PCL and Caucasian race, a diagnosis of secondary PCL, and initial treatment with cyclophosphamide and dexamethasone (P < 0.05) Conclusions: In our study population, we observed a high incidence of CNS involvement (24%) among patients with PCL and identified multiple risk factors for the disease including evidence of malignant and non-malignant disease of the spine. These results suggest all patients with PCL should have spinal imaging performed at diagnosis and lumbar puncture should be considered for all patients, especially those with known spinal disease. Disclosures No relevant conflicts of interest to declare.

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A Pilot Study of Lenalidomide and Dexamethasone as First Line Therapy in Patients with Primary Plasma Cell Leukemia.

Blood ◽

10.1182/blood.v114.22.4951.4951 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4951-4951

Author(s):

Pellegrino Musto ◽

Maria Teresa Petrucci ◽

Fortunato Morabito ◽

Francesco Nobile ◽

Fiorella D'Auria ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Plasma Cells ◽

Early Response ◽

Plasma Cell Leukemia ◽

Cell Leukemia ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Primary Plasma Cell Leukemia

Abstract Abstract 4951 Background Primary Plasma Cell Leukemia (PPCL) is an aggressive, rare variant of multiple myeloma, with clinical, molecular and phenotypic peculiarities, which accounts approximately for 2% to 4% of all myeloma diagnoses. The prognosis of PPCL patients is usually poor, with less than half of patients responding to conventional chemotherapy and a median survival of 7 months. Even by using autologous or allogeneic transplant procedures, survival generally does not exceed three years. Bortezomib has recently provided some promising results in this setting, but, given all the above, new treatments for PPCL are greatly awaited. Lenalidomide is a new immunomodulating agent with great efficacy in multiple myeloma, especially when associated with dexamethasone or other drugs. There are, indeed, some sporadic case reports of PPCL patients treated with lenalidomide as salvage therapy, but no data are currently available on the use of this drug as first line therapy in this disease. Patients and Methods On March, 2009, we started an open label, prospective, multicenter, exploratory, single arm, two-stage study aiming to evaluate safety and antitumor activity of the lenalidomide/low dose dexamethasone combination (Rd), as first line therapy in patients with PPCL. The primary endpoint was early response rate according to International Uniform Criteria. The secondary endpoints were TTP, PFS, OS, percentage of eligible PPCL patients able to collect peripheral blood stem cells and to undergo autologous or allogeneic stem cells transplantation after Rd, serious and severe adverse event rate. According to this study protocol, all eligible, newly diagnosed adult patients with PPCL receive Lenalidomide at a dose of 25 mg daily for 21 days every 28 days. Oral dexamethasone is administered at a dose of 40 mg daily on days 1, 8, 15, and 22 for each 28-day cycle. After 4 cycles, patients who achieve at least PR and not eligible for autologous or allogeneic stem cell transplantation, continue with Rd until clinically appropriate (disease progression, unacceptable toxicity, patient's decision to leave the protocol). In these patients, a maintenance dose of lenalidomide alone equal to 10 mg/die days 1-21 every month is considered after at least 8 full dose Rd cycles. Patients responding after 4 Rd cycles and eligible for transplant procedures, proceed according to single Centre transplant policy. Patients not responding after 4 cycles or progressing under Rd treatment are considered off-study. Appropriate contraception methods and anti-thrombotic prophylaxis are planned. Results Four enrolled patients (1 male, 3 female, mean age 65 years, range 58-69) are currently evaluable for early response. All had unfavourable cytogenetics, including del13, t(4;14), t (14;16), or a complex karyotype. Circulating plasma cells ranged from 4.4 to 9.2 ×10e9/l. One patient had at baseline a moderate degree of renal failure (serum creatinine levels 2 mg/dl). After at least 2 Rd cycles (range 2-4), two PR and two VGPR were achieved (overall response rate 100%), with disappearance or near complete reduction of circulating plasma cells in all cases. The most relevant toxicities were grade 3 neutropenia and pneumonia, occurring in one patient and resolved by appropriate lenalidomide dose reduction, introduction of G-CSF and antibiotic therapy. One patient died in PR, due to causes unrelated to PPCL or treatment. As, according to the Simon, two-stage design adopted, more than two responses occurred within the first ten patients enrolled (stage 1), a total of 22 PPCL subjects will be accrued to complete the stage 2 of the trial. Conclusions These findings, though very preliminary, suggest that the combination of lenalidomide and dexamethasone may be a safe and promising initial therapy for PPCL patients, which can rapidly control the disease and could permit to perform following single patient-adapted therapeutic strategies. An update of this study, including molecular data, a larger number of patients and a longer follow-up, will be presented at the Meeting. Disclosures Musto: Janssen-Cilag: Honoraria; Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide is approved in Italy for advanced multiple myeloma, not for plasma cell leukemia. This is a clinical trial registered at AIFA (Italian regulatory Agency for Drugs), EudraCT No. 2008-003246 28. Petrucci:Janssen-Cilag: Honoraria; Celgene: Honoraria. Morabito:Celgene: Honoraria; Janssen-Cilag: Honoraria. Cavo:Celgene: Honoraria; Janssen-Cilag: Honoraria. Boccadoro:Celgene: Honoraria; Janssen-Cilag: Honoraria. Palumbo:Celgene: Honoraria; Janssen-Cilag: Honoraria.

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A life-threatening presentation of primary plasma cell leukemia

Journal of Clinical Images and Medical Case Reports ◽

10.52768/2766-7820/1094 ◽

2021 ◽

Vol 2 (2) ◽

Author(s):

Roma S Fourmanov ◽

◽

Annemiek Joosen ◽

Lidwine Tick ◽

Heleen S de Lil ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Plasma Cells ◽

Hemoglobin Concentration ◽

Plasma Cell Leukemia ◽

Plasma Cell Dyscrasia ◽

Bone Lesions ◽

High Dose ◽

Cell Leukemia ◽

Primary Plasma Cell Leukemia

Background: Multiple myeloma is a relatively common type of plasma cell dyscrasia, in which monoclonal plasma cells proliferate. This frequently leads to anemia, renal failure, hypercalcemia and bone lesions. Primary plasma cell leukemia is a much rarer type of plasma cell dyscrasia, with measurable plasma cells in the blood circulation and usually more acute presenting signs. Case: A 57-year-old woman presented to the emergency department with dyspnea. Because of hypoxemia due to a hemoglobin concentration of 3.1 g/dL (1,9 mmol/L), asystole occurred, and cardiopulmonary resuscitation had to be started. The severe anemia turned out to be due to a primary plasma cell leukemia. Palliative treatment was started with combination chemotherapy with VTD (bortezomib, thalidomide and dexamethasone) with a very good partial response, after which she proceeded to an autologous stem cell transplantation with high dose melphalan conditioning. Conclusion: Primary plasma cell leukemia is a plasma cell dyscrasia with both resemblances and differences from the better-known multiple myeloma. It is less common, but presenting signs often are more acute and more severe. Currently there is no curative treatment. Keywords: Plasma cell leukemia; Hematological emergency; Multiple myeloma; VTD.

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Clonal plasma cells from monoclonal gammopathy of undetermined significance, multiple myeloma and plasma cell leukemia show different expression profiles of molecules involved in the interaction with the immunological bone marrow microenvironment

Leukemia ◽

10.1038/sj.leu.2403647 ◽

2005 ◽

Vol 19 (3) ◽

pp. 449-455 ◽

Cited By ~ 62

Author(s):

M Pérez-Andrés ◽

◽

J Almeida ◽

M Martín-Ayuso ◽

M J Moro ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Plasma Cell ◽

Monoclonal Gammopathy ◽

Plasma Cells ◽

Expression Profiles ◽

Bone Marrow Microenvironment ◽

Plasma Cell Leukemia ◽

Cell Leukemia ◽

Undetermined Significance

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Primary plasma cell leukemia: consensus definition by the International Myeloma Working Group according to peripheral blood plasma cell percentage

Blood Cancer Journal ◽

10.1038/s41408-021-00587-0 ◽

2021 ◽

Vol 11 (12) ◽

Author(s):

Carlos Fernández de Larrea ◽

Robert Kyle ◽

Laura Rosiñol ◽

Bruno Paiva ◽

Monika Engelhardt ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cell ◽

Peripheral Blood ◽

Plasma Cells ◽

Plasma Cell Leukemia ◽

Prognostic Impact ◽

Cell Leukemia ◽

Consensus Definition ◽

Cell Percentage ◽

Primary Plasma Cell Leukemia

AbstractPrimary plasma cell leukemia (PCL) has a consistently ominous prognosis, even after progress in the last decades. PCL deserves a prompt identification to start the most effective treatment for this ultra-high-risk disease. The aim of this position paper is to revisit the diagnosis of PCL according to the presence of circulating plasma cells in patients otherwise meeting diagnostic criteria of multiple myeloma. We could identify two retrospective series where the question about what number of circulating plasma cells in peripheral blood should be used for defining PCL. The presence of ≥5% circulating plasma cells in patients with MM had a similar adverse prognostic impact as the previously defined PCL. Therefore, PCL should be defined by the presence of 5% or more circulating plasma cells in peripheral blood smears in patients otherwise diagnosed with symptomatic multiple myeloma.

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

Blood ◽

10.1182/blood-2019-130697 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1782-1782

Author(s):

Sheri Skerget ◽

Austin Christofferson ◽

Sara Nasser ◽

Christophe Legendre ◽

The MMRF CoMMpass Network ◽

...

Keyword(s):

Cell Cycle ◽

Multiple Myeloma ◽

Bone Marrow ◽

Flow Cytometry ◽

Plasma Cell ◽

Peripheral Blood ◽

Research Funding ◽

Plasma Cells ◽

Cell Cycle Control ◽

Cell Leukemia

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.

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Cell Cycle Gene Sets Coordination In Multiple Myeloma and Plasma Cell Leukemia

Blood ◽

10.1182/blood.v122.21.1901.1901 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1901-1901

Author(s):

Fedor Kryukov ◽

Ivana Ihnatova ◽

Pavel Nemec ◽

Alexander Schmitz ◽

Julie S Brødker ◽

...

Keyword(s):

Cell Cycle ◽

Multiple Myeloma ◽

Plasma Cell ◽

Plasma Cells ◽

Plasma Cell Leukemia ◽

Cell Cycle Gene ◽

Cell Leukemia ◽

Myeloma Cells ◽

Healthy Donors ◽

Gene Coordination

Abstract Background In multiple myeloma (MM), unlike normal plasma cells (PC), myeloma cells retain the self-renewing potential. Majority of medullary myeloma cells regardless over-expression of cyclins D stay in the G1 phase due to pro-apoptotic and cell cycle regulatory capacity of p53 depended axis. Nevertheless, after leukemic transformation in secondary plasma cell leukemia (PCL) or de novo in case of primary PCL, bone marrow myeloma cells become highly proliferative and even presenting as circulating plasma cells in the peripheral blood. We anticipate that complex “re-setting” of cell cycle gene coordination during leukemic transformation creates required background to restore proliferation activity and breakthrough mitotic restriction points. Aims The objective of our study was to define and describe complex “re-setting” of cell cycle gene coordination in MM and PCL. Materials and Methods In total, 7 healthy donors, 6 multiple myeloma and 7 plasma cell leukemia samples enrolled in this study. The mRNA from CD138+ cells was isolated using uMACS mRNA Isolation Kit Small scale (Miltenyi Biotech) and directly amplified and labeled using WT-Ovation™ Pico RNA Amplification System Version 1.0 plus WT-Ovation™ Exon Module Version 1.0 (NuGEN). Generated SPIA-cDNA was fragmented & labeled using Encore™ Biotin Module (NuGEN). cDNA was hybridized to Affymetrix GeneChip Human Exon 1.0 ST Arrays (Affymetrix, Santa Clara, USA). All samples were labeled and scanned in a randomized order to avoid batch effects. Gen sets, connected with cell cycle regulation (GO:0045786; GO:0045787) with all direct descendants (child terms) and regulation of apoptotic process (GO:0043065; GO:0043066), were taken for the Gene Set Enrichment Analysis (GSEA) and Gene Set Differential Coordination Analysis (GSDCA). Results Comparing of PCL, MM and healthy donors revealed coordinating changes between regulation of mitosis (GO:0045839; GO:0045840), apoptosis (GO:0043065; GO:0043066) and cell cycle arrest (GO:0007050). These changes were relevant for both positive and negative regulation sets. Gene expression profiling of MM samples revealed affected early phases of cell cycle (G1 phase and G1/S transition). In PCL samples co-expression changes was associated with late phases of cell cycle (G2/M transition, S and M phase) together with severe alteration in early phases. The mechanisms controlling differential cell cycle coordination were based on bioinformatic analysis suggested to include alternative transcription start sites, exon skipping and shortening of 3'UTR. The probe sets covering the 3'UTR of CCND2 were for example significantly down regulated in plasma cells of MM and PCL as compared to healthy donors supporting the existence of a phenomenon observed in breast cancer where shortening of 3'UTR mRNA CCND2 confers higher mRNA stability leading to higher protein expression and more cells to enter the S phase. Conclusion Considering revealed coordination changes allow us to offer following statements. Expression of cell cycle positive regulators is in dynamic equilibrium with cell cycle negative regulators. We suppose that this equilibrium serves as a compensatory mechanism to oncogenic events. Despite compensation mechanisms activation, whole regulatory complex seems to be imbalanced by growing “oncogenic stress” during MM to PCL progression. This study was supported by grants NT11154, NT12130, NT13190 and the EU 6th FP to MSCNET (LSHC-CT-2006-037602), the Danish Cancer Society, the Danish Research Agency (#2101-07-0007) and the KE Jensen Foundation (2006-2008). Disclosures: No relevant conflicts of interest to declare.

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Implication of the Anti-Apoptotic Protein Bcl-B (BCL2L10) in the Pathogenesis of Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.2958.2958 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2958-2958

Author(s):

Valentine Richez ◽

Frederic Luciano ◽

Amine Hamouda ◽

Alexandre Puissant ◽

Guillaume Robert ◽

...

Keyword(s):

Internal Medicine ◽

Multiple Myeloma ◽

Cell Population ◽

Plasma Cell ◽

Plasma Cells ◽

Plasma Cell Leukemia ◽

Healthy Individuals ◽

Cell Leukemia ◽

First Line ◽

Apoptotic Protein

Abstract Multiple myeloma (MM) is a haematological cancer characterized by a malignant plasma cell infiltration restricted to the bone marrow (BM). Bcl-B protein is the last anti-apoptotic member of the Bcl-2 family to be discovered and is mainly expressed in B lymphocytes and human plasma cells. However, its pathophysiologic role is still unknown. Our team has generated a transgenic mouse model (Eμ-Bcl-B) where Bcl-B protein expression is restricted to the B cell compartment; Eμ-Bcl-B mice develop with age a lymphoproliferative syndrome recapitulating all of the human MM characteristics. Following these promising results, we focused our attention on the potential role of Bcl-B protein in the pathogenesis of MM to designate this anti-apoptotic protein as a prognostic marker and eventually as a new therapeutic target. BM samples were collected with the support of the internal medicine and clinical hematology departments of Nice CHU to study the expression of Bcl-B protein in the plasma cell population. BM extracts were separated into 2 parts: 1) 3 millions cells were used to measure Bcl-B expression level by flow cytometry. For this purpose, we performed successively an intracellular (Bcl-B) and an extracellular (CD138+ plasma cells) staining. For each patient, results were expressed as the percentage of plasma cells (CD138+) expressing intracellular Bcl-B marker. 2) The remaining cells were subjected to CD138 positive magnetic sorting to isolate plasma cells. The quantification of Bcl-B protein in the plasma cells was performed in this case by semi-quantitative Western blot experiment. Between March 2011 and July 2015, 68 BM extracts were analyzed. Among these patients, the median age was 70 years with a sex ratio 1:1. We studied the expression of Bcl-B in 3 healthy individuals, 21 MGUS (Monoclonal Gammopathy of Undetermined Significance) patients, 15 MM patients at diagnosis and 1 patient suffering plasma cell leukemia. In addition we analyzed 7 samples from MM patients treated with first-line therapies and 21 samples from relapsed MM patients. Using flow cytometry, we determined that the average expression of the Bcl-B protein was 3.66% within the plasma cell population of healthy individuals, 4.56% in MGUS patients, 53.56% in newly diagnosed MM patients and 99% in untreated plasma cell leukemia. In addition, the average expression of Bcl-B protein in the plasma cell population was 9.14% in MM patients treated with first-line therapies and 50.33% in relapsed MM patients. Western Blot experiments performed with CD138+ sorted plasma cells revealed an overexpression of Bcl-B protein in newly diagnosis and relapsed MM patients and in patients suffering plasma cell leukemia. MGUS and MM patients treated with first-line therapies revealed a low expression of Bcl-B. In conclusion, thanks to the BM patients samples collected with the support of the internal medicine and clinical hematology departments of the Nice CHU, we showed overexpression of the anti-apoptotic Bcl-B protein in MM patients at diagnosis or after relapse compared to patients with MGUS. Importantly, the Bcl-B protein was undetectable in MM patients that respond to first-line therapies. Altogether, these results, combined with those obtained from our transgenic mice Eμ-Bcl-B model, suggest that Bcl-B protein could be a new diagnostic marker for MM and a pertinent tool to predict the quality of response treatment. Disclosures No relevant conflicts of interest to declare.

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Phase 2 Trial of Pomalidomide, Ixazomib and Dexamethasone in Patients with Multiple Myeloma with Extramedullary Disease or Plasma Cell Leukemia

Blood ◽

10.1182/blood-2020-142641 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-35

Author(s):

Francis K. Buadi ◽

Martha Q. Lacy ◽

Gabriela Perez ◽

Liang Phuong-Dung ◽

Ankit Kansagra ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Plasma Cell ◽

Research Funding ◽

Plasma Cells ◽

Response Rate ◽

Advisory Board ◽

Plasma Cell Leukemia ◽

Cell Leukemia ◽

Grade 3

Background: Multiple myeloma is typically characterized by clonal expansion of malignant plasma cells within the bone marrow compartment. Presence of extramedullary disease (EMD) either in the form of soft tissue plasmacytoma or circulating plasma cells can be seen at diagnosis but is more common in the relapsed and refractory patients. Presence of EMD is typically associated with a poor prognosis, both in the newly diagnosed and relapsed setting, but trials designed specifically for patients with EMD are sparse. Treatment of EMD can be challenging and the responses even when seen are often short lasting, highlighting the need for developing specific treatment approaches aimed at these patients. Based on initial trials suggesting activity of pomalidomide in the setting of EMD and the increased tissue distribution with the oral proteasome inhibitor ixazomib, we designed this trial to examine if the all oral combination of ixazomib, pomalidomide and dexamethasone can be effective in the setting of EMD. Patients and Methods: Patients with previously treated multiple myeloma, with adequate hematologic and organ function were enrolled if there was evidence, at study entry, of EMD defined as one or more plasmacytomas, outside the bone marrow that were non-contiguous with a bone lesion and had a single diameter of ≥2 cm OR as plasma cell leukemia, with circulating plasma cells > 5% of peripheral blood leukocytes or at least 0.5 X 109/L or 200 cells/150000 events by flowcytometry. Patients were treated on 28-day cycles, with ixazomib 4 mg on days 1, 8, and 15 along with pomalidomide 4 mg PO daily on days 1-21 and dexamethasone 40 milligrams weekly until disease progression or unacceptable toxicity. The goals of the study were to determine confirmed response rate (≥ PR), toxicities of this combination, differential response rates and progression-free survival (PFS). Confirmed response rate, differential response rates and PFS were estimated using Duffy and Santner approach, exact binomial distributions and Kaplan Meier curves, respectively. The study was designed to accrue 30 patients. Results: This study was designed to enroll up to 30 patients but was closed after enrolling 17 patients due to slow accrual. The baseline characteristics are as indicated in Table 1. Eleven patients were enrolled with an extramedullary plasmacytoma while the remaining six patients had plasma cell leukemia. Median number of lines of prior therapy was 3 (range: 1, 7). Overall, 10 (58.8%) patients had progressive disease and 11 (64.7%) patients have died, median (range) follow-up for the live patients is 22.2 (2.1, 37.9) months. Patients were treated for a median of 2 (range 1-34) cycles. A grade 3+ AE, at least possibly attributed, was seen in 53%. Grade 3+, at least possibly related, hematologic toxicity was noted in 41%, with 29% experiencing grade 3+ neutropenia. Notable grade 3+ non-hematologic toxicities (regardless of attribution), with >10% incidence rate were anemia, hypoxia, infections and lung infection. The confirmed response rate in evaluable patients was 35% (1 CRs and 5 PRs), with a 90% CI of 6% - 37%. While 33% (4/12; 95% CI: 1-8%) of patients reported a biochemical response, 40% (2/5; 95% CI: 0-4%) of patients reported an extramedullary response. The median PFS was 4.5 (95% CI: 2-11.8) months. Conclusions: The combination of ixazomib, pomalidomide and dexamethasone resulted in disease response in a third of this group of high-risk patients with EMD; however, the responses were not very durable, with a median PFS of only 4.5 months. The trial highlights the feasibility of doing clinical trials specifically targeted towards this high-risk patient population. Future trials should explore combinations of novel agents, including monoclonal antibodies through multicenter collaborative efforts. Disclosures Kansagra: Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics: Other: Advisory Board. Witzig:Spectrum: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; AbbVie: Consultancy; MorphSys: Consultancy; Celgene: Consultancy, Research Funding. Kumar:Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genecentrix: Consultancy; Carsgen: Other, Research Funding; Cellectar: Other; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Adaptive Biotechnologies: Consultancy; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Sanofi: Research Funding; Tenebio: Other, Research Funding.

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