Impact of sFLC Ratio on Outcome in Patients with MM: Validating the Utility of sFLC in Response Definition

Background: The treatment of Multiple Myeloma (MM) has evolved significantly in the past decade with the introduction of novel agents and drug combinations, thus enhancing treatment efficacy and allowing more patients to achieve complete response (CR). This has created a need to identify surrogates for depth of treatment response. Serum free light chain (sFLC) ratio normalization has been shown to be prognostic for progression free survival as well as overall survival in patients achieving a complete response to therapy. Consequently, it has been incorporated as a defining feature for stringent CR, along with lack of clonal plasma cells by immunohistochemistry (IHC) or low sensitivity flow cytometry. The routine use of multiparametric flow cytometry with higher sensitivity to detect residual disease than IHC or the older 4-color flow cytometry, has raised the question as to whether sFLC ratio is still a valid indicator of response depth. Moreover, in nearly half of the patients with an abnormal sFLC ratio after treatment, the abnormality is secondary to suppression of one or both serum light chains. Therefore, we designed a retrospective study to address these issues. Patients and Methods: This is a retrospective study using the Multiple Myeloma Database at Mayo Clinic, Rochester. We included patients who, after any line of therapy, had negative serum and urine immunofixation and absence of clonal bone marrow plasma cells by flow cytometry (PC-PRO), which has a sensitivity of >10-4. Simultaneous sFLC data was also extracted. Patients were grouped into three categories based on their sFLC ratios: 1) normal ratio (normal), 2) abnormal ratio due to suppression of the uninvolved light chain (LC), involved LC, or both (Abn-suppressed) and 3) abnormal ratio due to elevation of the involved LC (Abn-inv elevated). The primary endpoint was the median time to next treatment (TTNT), defined as the time from sample collection to the time of initiation of the subsequent therapy or time of last follow up if a subsequent line of treatment was not initiated. Results: The cohort consisted of 510 patients. 285 (56%) were males and 225 (44%) females. Median age was 61 years (IQR: 55-67). Median Follow-up was 41 months. The last treatments administered prior to data collection included stem cell transplant (SCT) (with or without maintenance) in 290 (57%) patients, and non-SCT regimens in the others. The sFLC ratio was normal in 337 (66%) and abnormal in 173 (34%) patients. Among the patients with abnormal sFLC ratios, 81 had elevated involved LC, 25 had suppression of the involved LC, 45 had suppression of the uninvolved LC and 22 had suppression of both LCs. We first examined the TTNT for the three groups and found that the TTNT was identical for those with a normal ratio and those with an abnormal ratio due to suppression of one or both light chains (Figure 1). So, we combined these two groups (Normal-Abn suppressed) and compared their outcomes to the patients with abnormal sFLC ratio due to elevated involved LC. The Abn-inv elevated group had a shorter TTNT as shown in Figure 2 (log-rank 0.06, Wilcoxon <0.01). The Abn-inv elevated group also had decreased overall survival compared to the other group (log-rank: 0.05, Wilcoxon: 0.01) (Figure 3). Conclusion: This study provides 2 important observations. First, patients with an abnormal ratio due to suppression of one or both LCs have outcomes similar to those with a normal ratio, suggesting a need to clarify the current definition of stringent CR. Second, the study suggests an important prognostic value for an abnormal sFLC ratio due to elevated involved LC, suggesting this as an important surrogate for depth of response. Disclosures Kapoor: Janssen: Research Funding; Takeda: Honoraria, Research Funding; Cellectar: Consultancy; Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Leung:Takeda: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

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Deregulation of TNFRSF18 (GITR) Through Promoter CpG Island Methylation Induces Tumor Proliferation in Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.2424.2424 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2424-2424

Author(s):

Yang Liu ◽

Yong Zhang ◽

Phong Quang ◽

Hai T Ngo ◽

Feda Azab ◽

...

Keyword(s):

Gene Expression ◽

Bone Marrow ◽

Flow Cytometry ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Cpg Island ◽

Advisory Committees ◽

Brdu Assay

Abstract Abstract 2424 Introduction Tumor necrosis factor receptor super families (TNFRSFs) play an important role in activation of lymphocyte and cell apoptosis. However the function of TNFRSFs in multiple myeloma (MM) remains unknown. Loss of function mutation of Fas antigen (TNFRSF6) was identified in MM cells, thus suggesting the possible role of TNFRSFs in regulating MM pathogenesis. We therefore investigated the epigenetic mechanisms that may mediate inactivation of TNFRSFs and its functional role in MM. Methods Dchip software was utilized for analyzing gene expression dataset. DNA was extracted from both primary CD138+ MM plasma cells and MM cell lines using blood & tissue DNA isolation kit (Qiagen, Inc.). Expression of GITR in primary CD138+ plasma cells was detected by Imunohistochemistry (IHC) DNA methylation was analyzed by methylated DNA immunoprecipitation (Medip) assay and bisulfate sequencing. 5'azacytidine was used to demethylate genomic DNA. Gene expression was detected by qRT-PCR and confirmed at the protein level by flow cytometry and western-blot. Over-expression of GITR was obtained in MM1.S cells by using GITR recombinant plasmid and electroporation. Apoptosis was determined using Annexin/PI staining and flow cytometry analysis. Activation of apoptotic signaling was studied by western blot. Cell survival and proliferation were analyzed by MTT and BrdU assay, respectively. Recombinant GITR-lentivirus was obtained from the supernatant of culture medium after 72 hours transfection in 293 cells. GFP positive MM cells were sorted and analyzed by flow cytometry. In vivo effect of GITR on MM tumor growth was determined by injection of GITR over-expressing MM cells in null mice. Mice skull, femur and vertebrae were isolated after 4 weeks injection. Anti-human CD138+ mAb microbead was used to detect MM cells extracted from mice tissue by flow cytometry. Results Gene-expression profiling showed down-regulation of TNFRSFs, including TNFRSF11A, TNFRSF11B, TNFRSF8, TNFRSF10C, TNFRSF9, TNFRSF21, TNFRSF1B, TNFRSF1A and TNFRSF18, compared to normal plasma cells. Moreover, Our IHC results also showed that GITR expression was positive in primary CD138+ plasma cells from 9 normal bone marrow, but negative in 9 MM samples. Importantly, we found that low GITR expression significantly correlated with MM progression. Indeed, GITR gene levels were lower in smoldering and active MM patients compared to MGUS patients and normal donors. Promoter CpG island (CGI) methylation of GITR was indentified in 5 out of 7 MM primary bone marrow (BM)-derived CD138+ cells but not in normal BM-derived plasma cells. Bisulfate sequencing and Medip assay showed that methylation of GITR was significantly associated with GITR expression in 5 MM cell lines, including MM1.S, OPM1, U266, RPMI and INA6. Promoter CGI of GITR was highly methylated leading to complete silencing of GITR in MM1.S cell line. GITR expression was significantly up-regulated in MM cells upon treatment with the 5'azacytidine. MTT and BrdU assay revealed that the proliferation and survival of MM1.S cells was disrupted in the GITR over-expressing MM1.S cells, notably with inhibition of cell proliferation compared to control vector infected cells. Moreover induction of cytotoxicity in GITR over-expressing cells was confirmed by using GFP competition assay. GITR-induced apoptosis was supported by induction of caspase 8 and 3 cleavage. The inhibition of human CD138+ plasma cell growth in the bone marrow of SCID mice using a disseminated MM xenograft model was observed in the experimental group injected with GITR expressing cells compared to the control group after 4 weeks injection. Conclusion Our findings uncovered a novel epigenetic mechanism contributing to MM pathogenesis, showing the role of GITR methylation as a key regulator of MM cell survival. Disclosures: Roccaro: Roche:. Ghobrial:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Clapd (Clarithromycin, Pomalidomide, Dexamethasone) Therapy In Relapsed Or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.1955.1955 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1955-1955 ◽

Cited By ~ 6

Author(s):

Tomer M Mark ◽

Angelique Boyer ◽

Adriana C Rossi ◽

Dennis Kwon ◽

Roger N Pearse ◽

...

Keyword(s):

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Response Analysis ◽

Muscular Weakness ◽

Advisory Committees ◽

Disease Response ◽

Grade 3

Abstract Background Pomalidomide is a distinct IMiD® immunomodulatory agent with activity in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We have previously reported that the addition of clarithromycin enhances the anti-myeloma activity of pomalidomide+dexamethasone (Pom/Dex) in the treatment of RRMM (Mark et al, ASH 2012). We now report updated results with extended follow up from a phase 2 trial of large group of patients treated with ClaPd in RRMM. Methods One hundred nineteen patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPd. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPd is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1-21, and dexamethasone 40mg on days 1,8,15,22 of a 28-day cycle. All subjects had thromboprophylaxis with 81mg aspirin daily. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression. Results One hundred fourteen patients had completed at least 1 cycle of ClaPd and were eligible for disease response analysis at data cut-off. All patients were included in the safety analysis. Patients had undergone a median of 5 (range 3-15) prior lines of therapy. The proportion of patients who were refractory to lenalidomide, refractory to bortezomib, and double (lenalidomide+bortezomib) refractory were 85%, 79%, and 68% respectively. The median number of ClaPd cycles received was 7 (range 1-34). Overall response rate (ORR, ≥PR, entire cohort/double-refractory subgroup) was 61.4/56.4% [stringent complete remission (sCR): 4.4/4%, complete response (CR): 0.9/1.3%, very good partial response (VGPR): 14.9/11.5%, partial response (PR): 41.2/38.5%, minimal response (MR): 7/9%, stable disease (SD): 21.9/21.8%, progressive disease (PD): 9.6/12.8%, ³VGPR rate of 20.2/16.7%]. Clinical benefit (³ MR) was achieved in 68.4/65.4%. Median time to PR and maximum response was 1 (range 1-7) and 2 (range 1-18) cycles, respectively. After a mean follow up time of 11.9 months, 40 patients (34%) remain free from progression, with a median progression free survival of 8.1 months (95% CI: 5.1, 9.8). Median duration of response (DOR) was 9.3 months (95% CI: 7.2,16.1). Median overall survival (OS) has not been reached with 68 patients (57%) alive at last follow-up. Median PFS, DOR, OS were not significantly different in the double-refractory subgroup at 6.3 (CI 4.7, 8.7; p = 0.21), 8.6 (CI 6.5, 16.1; p = 0.87), and 16.8 months (CI 12.4, 28.7; p = 0.11) respectively. The most common (³% grade 3 and 4 toxicities were: neutropenia (49%), thrombocytopenia (39%), anemia (27%), pneumonia (10%), fatigue 8%, and muscular weakness 7%. Febrile neutropenia was uncommon at 2%. There were 6 cases of lower extremity venous thrombosis (5%, 1 grade 1, 4 grade 2, 1 grade 3) and no instances of pulmonary embolism. Mild peripheral neuropathy was present in 32% (19% grade 1, 13% grade 2), 0% grade 3 or 4). Grade 2 congestive heart failure, due to dexamethasone, emerged in 1 subject (0.8%). Four patients (3.3%) withdrew due to treatment related toxicity (1 with Grade 3 muscular weakness, 2 due to Grade 3 fatigue, 1 grade 4 neutropenic sepsis). There was no treatment related mortality. Conclusions ClaPd is a highly effective and tolerable regimen for heavily treated RRMM that has progressed after prior treatments. Response to ClaPd is rapid and sustained at > 8 months in the majority of subjects. The presence of double refractory disease did not significantly impact clinical outcomes. The ORR and PFS compare favorably and toxicity profile is similar to other published reports of Pom/Dex. Disclosures: Mark: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Zafar:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial

Blood ◽

10.1182/blood.v124.21.327.327 ◽

2014 ◽

Vol 124 (21) ◽

pp. 327-327 ◽

Cited By ~ 27

Author(s):

Susan O'Brien ◽

Jeffrey A. Jones ◽

Steven Coutre ◽

Anthony R. Mato ◽

Peter Hillmen ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Efficacy And Safety ◽

Advisory Committees ◽

Previously Treated ◽

Grade 3

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.

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IgM-Gammopathies Transformed into Aggressive Lymphoma: Incidence, Basal Clinical Features and Outcome of a Registry Based, Spanish Retrospective Series

Blood ◽

10.1182/blood-2019-123353 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4011-4011

Author(s):

Irene Dogliotti ◽

Cristina Jiménez ◽

Federica Cavallo ◽

Noemi Puig ◽

Gian Maria Zaccaria ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

B Lymphocytes ◽

Clinical Features ◽

Research Funding ◽

Initial Diagnosis ◽

Aggressive Lymphoma ◽

Advisory Committees ◽

Histological Transformation

Background Transformation into aggressive lymphoma (AL) is a rare complication of indolent lymphoproliferative disorders (LPDs) and is characterized by poor outcome. Immunoglobulin M (IgM) gammopathies are a spectrum of conditions, from monoclonal gammopathy of undetermined significance (MGUS) to Asymptomatic Waldenstroem Macroglobulinemia (AWM) and Symptomatic WM (SWM) that can eventually evolve to transformed WM (tWM). Actually, tWM represents a clinical challenge, mainly because of its poor characterization. Aims This registry study aims to better characterize tWM, focusing on prognostic factors heralding transformation to AL. Methods Two registries of IgM-MGUS, AWM and SWM [Owen, Semin Oncol 2003] based in Salamanca and in the region of Castilla and Leon (Spain) were investigated to identify cases with histological transformation. IgM-secreting patients with other LPDs (e.g. chronic lymphocytic leukemia, marginal zone lymphoma, IgM-multiple myeloma) were excluded from the analysis. All patients provided written informed consent in accordance to Helsinki's declaration. Statistical analysis was carried out using R v 3.3.3. tool; survival analyses were performed with Log-Rank method, while group comparison was performed with t-student for continuous variables and Chi-square tests for categorical variables. Results Data from 903 patients with IgM-secreting disorders diagnosed between 1976 and 2019 were analyzed; 587 cases with confirmed diagnosis of IgM-MGUS, AWM or SWM were selected. Out of 587 IgM-gammopathies, 22 cases with histological transformation to AL were identified. Cumulative incidence of tWM was: 1.4% at 5, 3.4% at 10 and 5.3% at 12 years, respectively (figure 1). Clinical features at first diagnosis of patients subsequently developing tWM where then analyzed: 3/22 tWM evolved from previous IgM-MGUS, while the remaining patients originally presented with AWM (6/22) or SWM (13/22). IPSS-WM prognostic score was LR for 5, IR for 12 and HR for 3/20 patients, respectively [Morel, Blood 2009]. Glancing on distributions between groups according to the outcome, tWM differed from not transformed (NT) cases for: lower median age at diagnosis (66 vs 72 years, p=0.018), lower platelets levels (median 188 vs 235 x 10^9/mmc, p=0.017), higher LDH ratio (0.8 vs 0.67, p=0.015), higher incidence of chromosome 6q deletion by FISH (40 vs 14%, p=0.021) and higher clonal B lymphocytes infiltration on marrow aspirate by flow cytometry (15 vs 4.5%, p= 0.022). Moreover, 13/22 patients received anti-WM treatment within 3 months from initial diagnosis, mainly chlorambucil-based; 5/22 patients received rituximab in first line and 13 in second line. From the whole series, after a median follow-up of 80 months, median transformation-free survival was 61 months from initial diagnosis (range: 0-228). Among these, Only 1/22 of tWM patient is still alive; 19/21 deaths were thus related to AL/WM, with a median survival after transformation of 12 months (0-53). In the whole series (n=587), median OS from initial diagnosis of IgM gammopathy was 76 months for the tWM group (6-225), that is shorter than the NT group (128 months, p=0.012, figure 2). Focusing only on patients treated at initial diagnosis, median survival after first treatment (SAFTI) was 62 vs 90 months for tWM vs NT (p=0.011, figure 3), and median time to next treatment was 28 vs 46 months, respectively (p=0.13). Overall, 10/22 tWM patients received ≥3 treatment lines, and median number of lines prior to transformation was 2 (0-3). Finally, in the whole series IPSS-WM score at diagnosis confirmed to impact on survival (median OS=151, 119 and 56 months for LR, IR and HR groups, respectively, p <0.001). However, this was not the case for tWM cases only, where OS was no longer different between groups. Conclusions In this retrospective study, we confirmed dismal outcome for tWM patients; incidence of transformation was comparable to expectations at 5 years, but higher at subsequent follow-up. At initial diagnosis of IgM gammopathy, younger age, low platelets level, high LDH ratio, high B lymphocytes infiltration by flow cytometry and presence of 6q deletion were significantly enriched among patients subsequently developing tWM. IPSS-WM score looked less predictive among tWM patients probably given to the limited numbers of tWM series. Novel prognostic tools are eagerly awaited for tWM patients. Figure Disclosures Cavallo: Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Puig:The Binding Site: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria. Ferrero:Gilead: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding.

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Role of Selectins in the Pathogenesis of Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.951.951 ◽

2009 ◽

Vol 114 (22) ◽

pp. 951-951 ◽

Cited By ~ 1

Author(s):

Abdel Kareem Azab ◽

Phong Quang ◽

Feda Azab ◽

Costas M Pitsillides ◽

John T Patton ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Flow Cytometry ◽

Endothelial Cells ◽

Cell Adhesion ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Advisory Committees

Abstract Abstract 951 INTRODUCTION: Multiple Myeloma (MM) is characterized by widespread disease at diagnosis with the presence of multiple lytic lesions and disseminated involvement of the bone marrow (BM), implying that the progression of MM involves a continuous re-circulation of the MM cells in the peripheral blood and re-entrance into the BM. Selectins are adhesion molecules expressed by activated endothelium of venules and leukocytes, and are involved in the primary interaction of lymphocytes with the endothelium of blood vessels. The binding of selectins serves as a biologic brake, making leukocyte quickly decelerate by rolling on endothelial cells, as the first step of extravasation. In this study, we have investigated the role of selectins and their ligands in the regulation of homing of MM Cells to the BM and the therapeutic implications of this role. METHODS AND RESULTS: We have used flow cytometry to characterize the expression of E, L and P-selectins and their ligands on MM cell lines, patient samples and on plasma cells from normal subjects. We found that all MM cell lines and patient samples showed high expression of L and P, but little of no E-selectin. While normal plasma cells showed low expression of all selectins and ligands.(give numbers) A pan-selectin inhibitor GMI-1070 (GlycoMimetics Inc., Gaithersburg, MD) inhibited the interaction of recombinant selectins with the selectin-ligands on the MM cells in a dose response manner. We have tested the role of the selectins and their ligands on the adhesion of MM cells to endothelial cells and found that MM cells adhered preferentially to endothelial cells expressing P-selectin compared to control endothelial cells and endothelial cells expressing E-selectin (p<0.05). Moreover, we found that blockade of P-selectin on endothelial cells reduced their interaction with MM cells (p<0.01), while blockade of E and L-selectin did not show any effect. Treating endothelial cells with GMI-1070 mimicked the effect of blocking P-selectin. Moreover, we found that treating endothelial cells with the chemokine stroma cell-derived factor-1-alpha (SDF1) increased their expression of P but not E or L-selectin detected by flow cytometry. Neither the blockade of each of the selectins and their ligands nor the GMI-1070 inhibited the trans-well chemotaxis of MM cells towards SDF1-alpha. However, blockade of P-selectin (p<0.001) on endothelial cells by GMI-1070 inhibited the trans-endothelial chemotaxis of MM cells towards SDF1-alpha. Both adhesion to endothelial cells and activation with recombinant P-selectin induced phosphorylation of cell adhesion related molecules including FAK, SRC, Cadherins, Cofilin, AKT and GSK3. GMI-1070 decreased the activation of cell adhesion molecules induced by both recombinant P-selectin and endothelial cells. Using in vivo flow cytometry we found that both anti P-selectin antibody and GMI-1070 prevented the extravasation of MM cells out of blood vessels into the bone marrow in mice. Moreover, we found that, in a co-culture system, endothelial cells protected MM cells from bortezomib induced apoptosis, an effect which was reversed by using GMI-1070, showing synergistic effect with bortezomib. CONCLUSION: In summary, we showed that P-selectin ligand is highly expressed in MM cells compared to normal plasma cells, and that it plays a major role in homing of MM cells to the BM, an effect which was inhibited by the pan-selectin inhibitor GMI-1070. This provides a basis for testing the effect of selectin inhibition on tumor initiation and tumor response to therapeutic agents such as bortezomib. Moreover, it provides a basis for future clinical trials for prevention of MM metastasis and increasing efficacy of existing therapies by using selectin inhibitors for the treatment of myeloma. Disclosures: Patton: GlycoMimetics, Inc: Employment. Smith:GlycoMimetics, Inc: Employment. Sarkar:GlycoMimetics, Inc: Employment. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Magnani:GlycoMimetics, Inc.: Employment. Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

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Rituximab Combined With Three Cycles Of High Dose Dexamethasone Provides a Long Term Response Rate Similar To That Of Splenectomy In Patients With Immune Thrombocytopenia (ITP) Of Duration Less Than 2 Years

Blood ◽

10.1182/blood.v122.21.2310.2310 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2310-2310 ◽

Cited By ~ 11

Author(s):

Christina S Lee ◽

Allison Imahiyerobo ◽

Micha Thompson ◽

Marina Izak Karaev ◽

Waleed Ghanima ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Response Rate ◽

Newly Diagnosed ◽

Advisory Committees ◽

Platelet Counts ◽

Best Response

Abstract Background Adults with newly-diagnosed and persistent ITP usually respond to steroid based treatments such as prednisone but relapse with tapering. One 4-day cycle of Dexamethasone (dex) at 40 mg/day in newly diagnosed ITP resulted in a lasting effect in 50% of patients (pts) in 1 study. An Italian study showed that 3 cycles of dex are better than 1 cycle. Approximately 50% of pts with chronic ITP experience a complete or partial response (CR & PR) to rituximab, yet only 20% of pts have a lasting, unmaintained response after 3 years. Mechanistically, rituximab (which depletes B cells but not plasma cells) and dexamethasone (which may be the most potent anti-plasma cell agent) are a logical combination in treatment of antibody-mediated diseases such as ITP. In 2 studies of newly-diagnosed pts, dex 40mg/day x 4 followed by rituximab was more effective than dex alone (one study added more dex half way through). In our pilot study, pts at Weill Cornell Medical College (WCMC) with all stages of ITP were treated with a combination of rituximab (R) and usually 3 cycles of dex. The outcome of this combination was retrospectively analyzed. Methods Combination of standard-dose rituximab (weekly x 4) and usually 3 4-day cycles of 28mg/m2 (max. 40mg) dex at 2-week intervals (R+3Dex) was explored in 67 pediatric and adult pts with ITP at WCMC. Patients were monitored with CBCs obtained weekly and then at less frequent intervals if a response was achieved. Best response (after 8 weeks to avoid transient effects of dex) was determined. Patients were categorized as CR (platelet count≥100x109/L) or PR (50-100x109/L). Relapse was defined as either two consecutive platelet counts <50x109/L and/or need for additional therapy. The duration of response was calculated from date of first rituximab administration to relapse or latest follow-up as of July 31st 2013. Results Overall, 50 of 67 pts treated with R+3Dex achieved a best response of either a CR (n=43) or a PR (n=7) at 8 weeks or later from start of therapy for an overall response rate of 75%. Seventy-three percent of pts received R+3Dex; variations were primarily in the timing and amount of dex given. Fifteen responders, 9 CRs and 6 PRs, relapsed at a median of 9 months. Seventy percent of the responders (or 52% of all pts treated) maintain a continuous response with platelet counts ≥ 50 x 109/L as of their last visit at a median f/u of 20 months. Kaplan Meier Analysis estimates 44% of all pts treated (Figure) and 59% of responders (Figure) maintained a best response without relapse at 67 months after initiating treatment. If only those with ITP ≤ 24 months are included, the estimated long term response rate is 59% (p=0.0017) versus only 19% for those with a duration of ITP > 24 months (Figure). Of 36 responding children and adults who had ITP ≤ 24 months, 29 continued to respond as of last follow up. Adults initially responded better than children (p=0.0019) but the long-term responses were not different (Figure). Pts achieving a CR had longer response than those achieving a PR. Adverse events related to R+Dex were usually mild-moderate, although 3 pts had serum sickness and 2 had transient colitis. IgG levels fell to below the lower limit of normal for age in 14 of 67 pts, 10 of whom had their IgG levels return to normal. In 6 of 14, IgG levels were < 400 mg/dl, some of whom received IVIG. Fifteen patients had serial BK/JC levels without ever detecting virus. Conclusions R+3Dex provides clearly superior results to rituximab alone. Notably, there was a 75% response rate overall (50/67 pts) compared to 50% with R alone. The 5 year response rate was almost 50% of all patients and 3/5 of responders. In patients who had had ITP for ≤ 2 years, the response is comparable to what has been reported with splenectomy. Specifically the results in the ≤ 2 year group suggest that R+3Dex is an effective way to induce indefinitely normal platelet counts in pts with a “short” duration of ITP. R+3Dex was tolerable although patients had difficulty with 3 cycles of dex. The 21% rate of hypogammaglobulinemia, higher than that seen with R alone, is also evidence of the mechanism of R+3Dex affecting both B cells and plasma cells. The lasting, long-lived, unmaintained responses observed in this study suggest that this combination therapeutic strategy should be further tested in a controlled trial in patients with newly diagnosed, persistent, and early chronic ITP, whether or not they have been previously treated with other agents. Disclosures: Bussel: Sysmex: Research Funding; Cangene: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; Genzyme: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Comparison of Standard Assays (Serum Immunofixation and Protein Electrophoresis) with Hevylite Assay in Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.5626.5626 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5626-5626

Author(s):

Hani Hassoun ◽

Rosalynn Ruiz ◽

Murata Kazunori ◽

Kathleen Azzi ◽

Sean Devlin ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Light Chain ◽

Research Funding ◽

Protein Electrophoresis ◽

Advisory Committees ◽

Assay Sensitivity ◽

Normal Ratio ◽

M Spike ◽

Abnormal Ratio

Abstract Background : TheHevylite assay (HLC Assay) is a novel assay using antibodies that recognize unique conformational epitopes presented by the association of the heavy and light chain constant regions of intact immunoglobulins (Ig) allowing quantitative measurement of each Ig class concentration and generating ratios for each pair (e.g. IgGK/IgGL). Recent studies indicate that HLC Assay can enhance the ability to detect and quantify monoclonal Ig, potentially providing greater sensitivity for detection of minimal residual disease or early relapse after treatment and providing a prognostic indicator of progression free survival (Ludwig, H. et al. Leukemia (2013) 27, 213-219; Kraj, M. et al. Adv Clin Exp Med 2014, 23, 1, 127-133). While HLC Assay could simplify and enhance the assessment of monoclonal protein response in multiple myeloma (MM), its utility as compared to standard assays (SA) (Serum Protein Electrophoresis (SPEP) and Immunofixation (IF)) is not well established. The goal of this retrospective study was to compare the performance of these tests in patients with MM seen at Memorial Sloan Kettering Cancer Center. Methods : We have previously reported on the patterns of relapse and/or progression (R/POD) in 179 patients with MM transplanted between 2001 and 2009 at MSKCC and determined the precise date of R/POD based on IMWG standard clinical criteria using serum and urine PEP and IF, as well as Free Light Chain Assay (FLCA) (Zamarin, Bone Marrow Transplant, 2013). Serum samples from 63 of these patients, collected at the time of R/POD and/or at time points preceding R/POD were analyzed by HLC Assay and compared to results obtained by SA. Results : Among the 63 patients, 22 had IgA and 41 had IgG isotype. Overall, 207 samples were available for all 63 patients, including 72 IgA and 135 IgG samples. Figure 1 shows the concordance of Hevylite ratio (on the Y-axis) with the results obtained by SA (on the X-axis), for IgA and IgG samples, respectively. These graphs reveal an excellent association between HLC Assay and SA results in the IgA samples: all IgA samples revealing an M spike by SPEP had an abnormal HLC ratio even for low M spike levels (between 0 and 0.5 g/dL). Among IgA samples with a monoclonal band detectable by IF, 43 out of 48 samples also had an abnormal ratio by HLC Assay; and among samples with no detectable band by IF, 18 out of 24 had a normal ratio by HLC Assay (sensitivity 90%, specificity 75%, p< 0.001) (Table 1, Panel 1). Interestingly, when looking at samples taken prior to relapse in IgA patients having achieved CR, HLC Assay was abnormal in 4 out of 7 patients while SA was still reported as normal. In contrast, the lack of association between the SA and HLC Assay is striking for the IgG samples, with poor sensitivity for the HLC Assay to detect monoclonal gammopathies with M spikes below 1 g/dL on SPEP. Among IgG samples with a monoclonal band detectable by IF, only 48 out of 89 samples also had an abnormal ratio by HLC Assay; while among samples with no detectable band by IF, 40 out of 46 had a normal ratio by HLC Assay (sensitivity 53% and specificity of 86% , p < 0.001) (Table 1, Panel 2). Conclusions: Although retrospective, this analysis suggests the following: 1) HLC Assay may be more sensitive than IF or SPEP in patients with IgA disease, as it can detect an abnormal HLC ratio at a time prior to relapse by SA, when IF and SPEP are still normal; 2) HLC Assay appears to be less useful in IgG patients, as its sensitivity in these patients appears much lower than IF; 3) There is a need for further detailed analysis on larger prospective cohorts to test the utility of HLC Assay compared to SA in the management of multiple myeloma patients, especially those with IgA disease. Figure 1 Association between HLC Assay and SA (SPEP/IF) results in patients with IgA disease. Figure 1. Association between HLC Assay and SA (SPEP/IF) results in patients with IgA disease. Figure 2 Association between HLC Assay and SA (SPEP/IF) results in patients with IgG disease. Figure 2. Association between HLC Assay and SA (SPEP/IF) results in patients with IgG disease. Disclosures Hassoun: Celgene: Research Funding; Binding Site: Research Funding; Novartis: Consultancy; Takeda: Consultancy, Research Funding. Kazunori:Binding Site: Research Funding. Landau:Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Korde:Medscape: Honoraria. Landgren:Takeda: Honoraria; Amgen: Honoraria, Research Funding; BMS: Honoraria; Medscape Myeloma Program: Honoraria; Merck: Honoraria; Celgene: Honoraria, Research Funding.

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Similar Efficacy and Safety of CT-P10 and Reference Rituximab in Patients with Advanced Stage Follicular Lymphoma: Updated Phase III Study Results

Blood ◽

10.1182/blood-2018-99-112716 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1616-1616

Author(s):

Won-Seog Kim ◽

Christian Buske ◽

Larry W Kwak ◽

Michinori Ogura ◽

Bertrand Coiffier ◽

...

Keyword(s):

Board Of Directors ◽

Safety Profile ◽

Research Funding ◽

Complete Response ◽

P Value ◽

Maintenance Period ◽

Advisory Committees ◽

Significant Difference ◽

Duration Of Response

Abstract Background: CT-P10 is an approved biosimilar to the innovator rituximab (RTX) from many countries including European Union based in part on the pharmacokinetics (PK) equivalence and comparable efficacy in patients with previously untreated advanced follicular lymphoma (FL) when treated with rituximab plus cyclophosphamide, vincristine and prednisone (R-CVP) as an induction therapy (Coiffier B et al. ASH 2016; Kim WS et al. ASCO 2017). Objective: We report here the updated efficacy outcomes including progression free survival (PFS), duration of response, overall survival (OS), as well as updated safety profile of CT-P10 compared to RTX in advanced FL patients with median follow-up duration of 23 months including the Maintenance Period with rituximab monotherapy. Methods: These results were derived from an ongoing randomized and double-blind study in patients with previously untreated advanced FL (NCT02162771). A total of 140 patients were randomized in a 1:1 ratio and 124 patients completed 8 cycles of R-CVP induction therapy. One-hundred twenty two patients (62 patients in CT-P10 group and 60 patients in RTX group), who showed response during the Induction Period, entered the Maintenance Period where a total of 12 cycles of rituximab monotherapy was to be administered every 2 months. The study was planned to continue until death or up to 3 years from the randomized date of the last patient. Kaplan Meier (KM) method was used to estimate PFS, duration of response, and OS. Results: Both groups had similar baseline characteristics; overall median age of 58 years, 55% female, 57% with FLIPI score ≥3, 100% with Stage III/IV, 18% with bulky disease (≥7cm) and 26% with B-Symptom. As of the cut-off date for investigator-assessed PFS, duration of response and OS, median follow-up was 23 months (range, 0.5-34) in the CT-P10 group and 22 months (range, 0.2-33) in the RTX group. The proportion of patients who had experienced relapse, disease progression or death from any cause was 22.9% (16/70) and 24.3% (17/70) for the CT-P10 and RTX groups, respectively. There was no significant difference between CT-P10 and RTX groups in PFS (log rank, p-value: 0.806) with 2-year PFS of 75.2% and 73.5%, respectively (Figure 1). In terms of sustained response, the proportions of patient who showed relapse or disease progression after achieving overall response (Complete Response, unconfirmed Complete Response, or Partial Response) were 19.4% (13/67) in CT-P10 group and 21.3% (13/61) in RTX group, and the KM curves showed no statistically significant difference between CT-P10 and RTX (log rank, p-value: 0.997) (Figure 2). Death from any cause were 5.7% (4/70) and 2.9% (2/70) in the CT-P10 and RTX groups, respectively. There was no statistically significant difference in OS (log rank, p-value: 0.464) between the CT-P10 and RTX groups with 2-year OS of 93.2% and 95.3%, respectively. Overall safety profile of CT-P10 was consistent with that of RTX (Table 1). A similar number of patients in each treatment group experienced at least 1 Treatment Emergent Adverse Events (TEAE) considered to be related to the study drug, infusion-related reaction, and infection. The proportion of patients with positive anti-drug antibody was also similar in both groups (4.3% [3/70] vs 5.7% [4/70] in the CT-P10 and RTX groups). Neither progressive multifocal leukoencephalopathy nor Hepatitis B virus reactivation was reported in either group. Conclusion: At the median follow-up duration of 23 months, the updated efficacy data in advanced FL patients demonstrated comparable PFS, sustained response and OS between CT-P10 and RTX. CT-P10 was also well tolerated and its safety profile was similar to that of RTX. The updated safety results did not reveal any trends or new signals noted in the patients treated with CT-P10. Disclosures Kim: Mundipharma: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Celltrion: Research Funding; Roche: Research Funding; J&J: Research Funding; Takeda: Research Funding. Buske:Roche: Honoraria, Research Funding; Bayer: Research Funding; Janssen: Honoraria, Research Funding. Ogura:MeijiSeika Pharma: Consultancy; Celltrion: Consultancy, Research Funding; Mundi Pharma: Consultancy; SymBio: Research Funding; Takeda: Honoraria; Cellgene: Honoraria. Coiffier:CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees; MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees; CELLTRION: Membership on an entity's Board of Directors or advisory committees; MORPHOSYS: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees. Lee:Celltrion, Inc: Employment. Kim:Celltrion, Inc: Employment.

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A Phase Ib/II Study of Ibrutinib in Combination with Obinutuzumab-Gazyva As First-Line Treatment for Patients with Chronic Lymphocytic Leukemia > 65 Years Old or with Coexisting Conditions

Blood ◽

10.1182/blood-2018-99-118990 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1863-1863

Author(s):

Juliana Velez Lujan ◽

Michael Y. Choi ◽

Chaja Jacobs ◽

Colin McCarthy ◽

Alaina Heinen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

Single Agent ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Grade 3

Abstract Standard treatment for patients with chronic lymphocytic leukemia (CLL) is rapidly evolving and gradually has incorporated the combined use of monoclonal antibodies (mAbs) and targeted therapy with small molecules. Single agent Ibrutinib (Ibr), a first-in-class BTK inhibitor, is effective in previously untreated patients including those that are older than 65 or considered unfit to receive chemotherapy-based combinations. The complete response rate in patients receiving single agent Ibr is relatively low (overall response rate of 86% and complete response of 4% based on 2008 iwCLL criteria), though most patients have durable remissions. The combination of Ibr with mAbs like Obinutuzumab-Gazyva (G), a third-generation anti-CD20 mAb, can ameliorate the Ibr-induced lymphocytosis and increase the overall and complete response rates. Accordingly, we initiated an open-label phase Ib/II clinical study of Ibr in combination with G for first-line therapy of previous untreated pts with CLL. The study completed enrollment of 32 previously untreated patients with CLL. Patients received G administered based on FDA dosing recommendations for 6 cycles (28 days/cycle) and Ibr 420mg po (1-3 hours before starting G infusion), and daily for up to 3 years. All patients received prophylactic medications. Patients were assessed for response by 2008 iwCLL criteria two months after completion of G, as the primary efficacy endpoint. The median age of the patients was 65 (range: 46-78) years. 84% of the patients had a CIRS >6, 45% had a Rai stage III-IV and 19% had an ECOG performance ≤2. The median baseline absolute lymphocyte count (ALC) was 79x103/mm3(range: 1.4-412.4). Patients showed the following FISH/cytogenetic abnormalities: del(13q) in 55%, trisomy 12 in 23% and del(11q) in 19%. Only 2 (6%) of these patients showed del(17p). From the patients with IGVH mutational status available (n=17), 11 (65%) were unmutated (>98% homology). Most adverse events (AEs) were grade 1-2 (74%). Six patients (19%) had grade 1-2 G-infusion-related reaction (IRR) and only one patient (3%) showed grade 3 IRR (without the need for G discontinuation). We observed neutropenia (all grades: 52%, grade 3-4: 23%), thrombocytopenia (all grades: 71%, grade 3-4: 19%) and anemia (all grades: 26%). There were no cases of febrile neutropenia. Two patients (6%) had grade 1 bleeding (one patient with asymptomatic lower gastrointestinal bleeding and the second patient with epistaxis) that resolved spontaneously without requirement of blood transfusion or study treatment discontinuation. Two patients (6%) developed pneumonia, one was community-acquired pneumonia requiring inpatient treatment with IV antibiotics; the study treatment was held until resolution of symptoms and re-initiated at full dose. The most frequent non-hematological AEs were diarrhea, transaminitis, hyperbilirubinemia, hyperglycemia, and electrolyte alterations (grade 1-2). Three patients (9%) discontinued Ibr due to atrial fibrillation grade 1 (n=1), rash and headaches grade 2 (n=1), and persistent grade 4 thrombocytopenia (n=1). Twenty-three patients were evaluable for response assessment by 2008 iwCLL criteria (median follow-up of 11 months). 84% of the patients showed a rapid decrease in ALC from baseline during the first cycle of treatment and only four patients (13%) required more than 3 cycles of treatment to achieve an ALC response. The overall response rate was 100%. The majority of pts had a partial response and six of 23 evaluable patients (26%) achieved a complete remission with detectable Minimal Residual Disease in the bone marrow by multiparametric flow cytometry. In summary, Ibr-G combination has been generally well tolerated. AEs have been consistent with the known safety profiles of Ibr and G individually. The patients that discontinued Ibr remain in follow-up without disease progression. 100% of evaluable patients achieved response after 6 months of combination therapy, and 26% of patients met CR criteria. One important finding thus far has been a very low rate of IRR, (19% grade 1-2 and 3% grade 3-4), suggesting that Ibr can strongly mitigate the incidence and severity of G associated IRR. Disclosures Choi: AbbVie, Inc: Consultancy, Speakers Bureau; Rigel: Consultancy; Gilead: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Speakers Bureau. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Kipps:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy; Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Genentech Inc: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees. Castro:F. Hoffmann-La Roche: Consultancy; Genentech, Inc: Consultancy; Pharmacyclics, LLC, an AbbVie Company:: Consultancy.

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Measurement of Serum microRNAs in US Veterans with Monoclonal Gammopathy of Undetermined Significance

Blood ◽

10.1182/blood-2018-99-114821 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5576-5576

Author(s):

Weixin Wang ◽

Youn K Shim ◽

Joel E Michalek ◽

Emily Barber ◽

Layla M Saleh ◽

...

Keyword(s):

Board Of Directors ◽

Monoclonal Gammopathy ◽

Research Funding ◽

Plasma Cells ◽

Univariate Analysis ◽

Serum Levels ◽

Advisory Committees ◽

Rank Regression ◽

Study Base

Abstract Background Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic condition arising from clonal plasma cells and has the risk of transformation to multiple myeloma (MM). Dysregulated expression of microRNAs (miRs) has been well demonstrated in MM, but miRs are not as well characterized in MGUS. We previously found an increased risk for MGUS in Vietnam veterans exposed to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here we report the effect of age on serum levels of 13 miRs in MGUS cases and controls from that study cohort. Methods The study base population comprised 958 US veterans who participated in the 2002 follow-up of the Air Force Health Study (AFHS). A total of 49 MGUS cases were identified by using their serum stored at the AFHS 2002 follow-up (Landgren O et al. JAMA Oncology, 2015). The current study included 47 MGUS cases and 85 controls. The controls were selected from the veterans who did not have MGUS, did not have a history of tumors, and whose TCDD level was below the third quartile value among the study base. Quantitative real-time PCR (qPCR) was used to determine the serum levels of 13 miRs (let-7a, let-7i, miR-16, miR-20a, miR-21, miR-34a, miR-106b, miR-146a, miR-181a, miR-192, miR-205, miR-335 and miR-361) that were previously shown to be dysregulated in MM or other cancers . The cycle threshold (Ct) values obtained from qPCR were normalized by using spiked-in cel-miR-39 as a control. Univariate rank regression was used to examine the relationships between relative expression of each miR and age, and each miR and MGUS status (MGUS vs control); each miR-MGUS relation was also examined with adjustment for age. All miR values were analyzed in log2 units. Continuously distributed age was summarized by the median and interquartile range (IQR): age variation with MGUS status was assessed with Kruskal-Wallis test. All statistical testing was two-sided with a significance level of p<0.1. Corrections for multiple comparisons were not made. We used R for rank regression analysis and SAS Version 9.4 for Windows for all other analyses. Results Overall MGUS cases were older than controls (median, controls 66 years [IQR 61, 69] versus MGUS 67 years [IQR 64, 71], p=0.03). Rank regression analysis showed that age was significantly and negatively correlated with the serum levels of 9 (let-7a, let-7i, miR-146a, miR-361, miR-106b, miR-16, miR-20a, miR-21, and miR-335) of the 13 miRs examined in controls. Among MGUS cases, age was significantly negatively correlated with only 5 (let-7a, miR-146a, miR-106b, miR-16, and miR-20a) of the 13 miRs and positively correlated with miR-181a and miR-205 (Table 1). In the univariate analysis of the miR-MGUS relationship, the serum levels of 4 miRs (let-7a, miR-106b, miR-16, and miR-21) were significantly associated with MGUS. However, none of these miRs remained significant after adjusting for age. In both adjusted and unadjusted analyses, the miR levels were lower in MGUS cases than in controls with the exceptions of miR-205 (unadjusted) and miR-335 (adjusted). Conclusions and Discussions In this study population, serum levels of the majority of miRs tested were negatively correlated with age in controls. Most of the same miRs were similarly decreased in MGUS with age, with the exception of miR-181a and miR-205 which were positively correlated with age. miR-181a is an important regulator of apoptosis, that is altered in many cancers, and was previously shown to be elevated in plasma cells of MM and MGUS. miR-205 inhibits tumor suppressors PTEN and SMAD4, and has been shown to be increased in several cancers. Of note, based on univariate analysis, several miRs were significantly differentially expressed in MGUS, but failed to remain significant after adjusting for age effect. This finding underscores the importance of assessing the need for age adjustment when analyzing serum miR data. We are currently exploring this data set to determine whether TCDD levels had any independent effect on miR levels in this population. Note: The first two authors contributed equally. Disclosures Landgren: Pfizer: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Karyopharm: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees.

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