Higher Intensity of Cell Surface Glucose-Regulated Protein 78 (csGRP78) Expression Is Seen in Patients with Early Progressive Disease/Mortality in a Cohort of Relapsed, Refractory Multiple Myeloma Patients Treated with Carfilzomib, Thalidomide and Dexamethasone

Background: GRP78, an endoplasmic reticulum stress-inducible molecular chaperone, is up-regulated at times of cellular stress to limit proteotoxicity and promote cell survival. Translocation of GRP78 to the cell surface (csGRP78) is emerging as a critical step providing tumour cells with a survival advantage. Here we quantified, monitored and correlated plasma cell (PC) csGRP78 expression in patients (pts) with relapsed/refractory multiple myeloma (RRMM) treated with carfilzomib, thalidomide and dexamethasone (KTd). Method: Patients enrolled in the single arm, multicentre, phase II Australasian Leukaemia & Lymphoma Group MM018/Asian Myeloma Network 002 study were treated with KTd as described previously (Quach et al. Blood 2018 132:1955). Formalin-fixed, paraffin-embedded BM trephine sections collected at baseline (n=29), after 6-months (mo) of KTd (n=19) and at time of disease progression (PD; n=5) were stained for CD138 and GRP78 by multiplex immunofluorescence histochemistry using the OpalTM workflow. Membrane expression of CD138 and GRP78 was extracted using inForm® software, compared across timepoints and correlated to disease characteristics and treatment outcomes. Descriptive statistics, paired/unpaired two-tailed t-test, Pearson's or Spearman's correlation were applied as appropriate. Results: Correlative BM biopsies were collected for 29 pts [male = 18, mean age = 65.0 years (range 41.9-83.2), 2 median prior lines of therapy (range 1-3)] at baseline, 21 pts after 6 months of KTd (7 had PD/died prior to cycle 6, 1 came off study due to grade 4 AE after 5 cycles) and 5 pts at time of PD. There was no difference in the number of fields, BM cellularity (%) or number of nucleated cells (NCs) assessed at baseline and 6mo (p=0.927, 0.331 and 0.491 respectively). PC burden (%; mean±SD) reduced significantly following 6mo KTd (28.3±28.1 vs. 2.12±2.37; p=0.0007). The number of plasma cells expressing csGRP78 (% of all NCs) was reduced following 6mo KTd treatment (27.04±26.83 vs. 2.05±2.32; p=0.0007) while the % of CD138-ve BM cells expressing csGRP78 (% of all NCs; mean±SD) increased (62.61±27.55 vs. 87.46±10.11; p=0.0005). Globally, there was a trend for reduced intensity of csGRP78 expression after 6mo KTd (H-score 70.79±62.16 vs. 53.53±51.45; p=0.2073). There was no correlation between baseline BM NC GRP78 H-score and baseline paraprotein level, involved/uninvolved serum free light chain ratio or depth of response to KTd. Pts with early (<6mo) disease progression/mortality (n=7) had a significantly higher baseline H-score (136±78.8 vs. 75.1±65.2; p=0.049). There was a separation of survival curves, but no significant difference regarding risk of early PD/mortality based a baseline H-score >75th percentile of the cohort (>152); p=0.1472 (Figure 1). Conclusion: Here we demonstrate that cell surface expression of GRP78 is prominent in both the plasma cells and cells of the tumour microenvironment in patients with RRMM and persists in the TME cells in patients on treatment. Early (<6mo) disease progression or mortality is associated with higher baseline intensity of global cell surface GRP78 expression. Additional studies are being performed to evaluate the promise of cell surface GRP78 expression on plasma cells as a potential biomarker of response to therapy. Disclosures Harrison: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding. Quach:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Crowdsourced High-Risk Classifiers for Multiple Myeloma Patients Commonly Identify PHF19 As a Robust Progression Biomarker

Blood ◽

10.1182/blood-2019-127362 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4370-4370

Author(s):

Michael J Mason ◽

Carolina D. Schinke ◽

Christine Eng ◽

Fadi Towfic ◽

Fred Gruber ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

High Risk ◽

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Multiple myeloma (MM) is a hematological malignancy of terminally differentiated plasma cells residing within the bone marrow with 25,000-30,000 patients diagnosed in the United States each year. The disease's clinical course depends on a complex interplay chromosomal abnormalities and mutations within plasma cells and patient socio-demographic factors. Novel treatments extended the time to disease progression and overall survival for the majority of patients. However, a subset of 15%-20% of MM patients exhibit an aggressive disease course with rapid disease progression and poor overall survival regardless of treatment. Accurately predicting which patients are at high-risk is critical to designing studies with a better understanding of myeloma progression and enabling the discovery of novel therapeutics that extend the progression free period of these patients. To date, most MM risk models use patient demographic data, clinical laboratory results and cytogenetic assays to predict clinical outcome. High-risk associated cytogenetic alterations include deletion of 17p or gain of 1q as well as t(14;16), t(14;20), and most commonly t(4,14), which leads to juxtaposition of MMSET with the immunoglobulin heavy chain locus promoter, resulting in overexpression of the MMSET oncogene. While cytogenetic assays, in particular fluorescence in situ hybridization (FISH), are widely available, their risk prediction is sub-optimal and recently developed gene expression based classifiers predict more accurately rapid progression. To investigate possible improvements to models of myeloma risk, we organized the Multiple Myeloma DREAM Challenge, focusing on predicting high-risk, defined as disease progression or death prior to 18 months from diagnosis. This effort combined 4 discovery datasets providing participants with clinical, cytogenetic, demographic and gene expression data to facilitate model development while retaining 4 additional datasets, whose clinical outcome was not publicly available, in order to benchmark submitted models. This crowd-sourced effort resulted in the unbiased assessment of 171 predictive algorithms on the validation dataset (N = 823 unique patient samples). Analysis of top performing methods identified high expression of PHF19, a histone methyltransferase, as the gene most strongly associated with disease progression, showing greater predictive power than the expression level of the putative high-risk gene MMSET. We show that a simple 4 feature model composed of age, stage and the gene expression of PHF19 and MMSET is as accurate as much larger published models composed of over 50 genes combined with ISS and age. Results from this work suggest that combination of gene expression and clinical data increases accuracy of high risk models which would improve patient selection in the clinic. Disclosures Towfic: Celgene Corporation: Employment, Equity Ownership. Dalton:MILLENNIUM PHARMACEUTICALS, INC.: Honoraria. Goldschmidt:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; John-Hopkins University: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Research Funding; Amgen: Consultancy, Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; MSD: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; John-Hopkins University: Research Funding. Avet-Loiseau:takeda: Consultancy, Other: travel fees, lecture fees, Research Funding; celgene: Consultancy, Other: travel fees, lecture fees, Research Funding. Ortiz:Celgene Corporation: Employment, Equity Ownership. Trotter:Celgene Corporation: Employment, Equity Ownership. Dervan:Celgene: Employment. Flynt:Celgene Corporation: Employment, Equity Ownership. Dai:M2Gen: Employment. Bassett:Celgene: Employment, Equity Ownership. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Shain:Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy. Munshi:Abbvie: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Celgene: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Celgene Corporation, Janssen: Research Funding; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses. Walker:Celgene: Research Funding. Thakurta:Celgene: Employment, Equity Ownership.

Download Full-text

Tumor Circulating Plasma Cells Detected By Flow Cytometric Single Platform Method Correlate with Clinical Response to Therapy and Unfavorable Patients' Characteristics

Blood ◽

10.1182/blood-2019-122657 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4357-4357

Author(s):

Vittorio Emanuele Muccio ◽

Milena Gilestro ◽

Elona Saraci ◽

Andrea Capra ◽

Alessandro Costa ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Response ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Plasma Cells ◽

Response To Therapy ◽

Advisory Committees ◽

Flow Cytometric ◽

Baseline Characteristics

Background: In multiple myeloma (MM), different clinical parameters and molecular prognostic factors can predict disease course and response to therapy. The classification of myeloma patients includes laboratory parameters associated with higher tumor activity, resistance to therapy and proliferative competence. Tumor circulating plasma cells (TCPC) in MM patients showed a strong correlation with a more aggressive disease. Aim: For the first time, we quantified the amounts of TCPC with single platform flow cytometric method and evaluated their relationship with patients' baseline characteristics and response to therapy before maintenance. Methods: Whole peripheral blood samples from 413 newly diagnosed MM patients ≤65 years enrolled in the UNITO-MM-01/FORTE trial were collected. Patients were randomized [1:1:1; stratification: International Staging System (ISS) and age] to ARM A: carfilzomib-cyclophosphamide-dexamethasone (KCyd) followed by melphalan 200 mg/m2 and autologous stem-cell transplantation (MEL200-ASCT) and consolidation with 4 KCyd; ARM B: carfilzomib-lenalidomide-dexamethasone (KRd) followed by MEL200-ASCT and 4 KRd; ARM C: 12 KRd cycles. Enrollment was completed in March 2017; data cut-off was November 30, 2018. For the single platform tube, the antibody combination CD38PC7/CD138PC5.5/ CD45KO/CD56PE/CD19PB was mixed with 100µL of EDTA peripheral blood, dispensed with reverse pipetting, and incubated for 15 min, added with 500µL of lysing solution and, after 15 min, 100µL of flow count fluorospheres were dispensed with reverse pipetting and cells acquired with Navios flow cytometer. Intracytoplasmic tube was set up to confirm the clonality of CPC. Results: Circulating plasma cells (CPC) were quantified in 413 samples, with median values of 0.03% (range: 0-51%) and 2.37/mm3 (range: 0-6272/mm3). White blood cells were 5710/mm3 (range: 1752-26102/mm3); total events acquired 1285000 (range: 40000-2000000); median CPC events were 58 (range: 0-441000); cellular events acquired were 190000 (range: 4428-1300000). In 390 out of 413 samples (94.4%), CPC were detected; 272 samples (66%) showed TCPC with a median of 1.24/mm3 (range 0.06- 6272/mm3). Patients were sorted according to different baseline characteristics and the medians of absolute TCPC were compared. The most statistically significant differences (p<0.001) were: haemoglobin (Hb) <10 (12.9/mm3) vs. ≥10 (0.81/mm3); ISS I (0.30/mm3) vs. ISS II (2.85/mm3) vs. ISS III (5.14/mm3); R-ISS I (0.25/mm3) vs. II (2.76/mm3) vs. III (7.45/mm3); albumin <3.5g/dL (2.76/mm3) vs. ≥3.5g/dL (1.05/mm3); β2-microglobulin <3.5mg/dL (0.67/mm3) vs. 3.5mg/dL-5.5mg/dL (3.88/mm3) vs. >5.5mg/dL (16.47/mm3); lactate dehydrogenase (LDH) ≤upper limit of normal (ULN, 1.14/mm3) vs. >ULN (7.36/mm3); plasma cells (PC) in biopsy <60% (0.60/mm3) vs. ≥60%(2.76/mm3); with (3.18/mm3) vs. without amp1q (1.18/mm3); Morgan risk standard (1.21/mm3) vs. high (3.00/mm3). Finally, we compared the absolute number of TCPC and the quality of response at the end of consolidation therapy. Higher values of TCPC were related to worst response: <partial response (PR, 4.23/mm3) vs. ≥PR (1.23/mm3); <very good PR (VGPR, 2.91/mm3) vs. ≥VGPR (1.20/mm3); <complete response (CR, 1.95/mm3) vs. ≥CR (1.09/mm3); <stringent CR (sCR, 1.71/mm3) vs. ≥sCR (1.00/mm3), p<0.05. Conclusions: Single-platform flow cytometry is a simple method to quantify TCPC, present in almost all peripheral blood from MM patients; a high number is related to poor clinical response to therapy and helps in identifying high-risk patients. Moreover, it allows the discrimination between normal and pathological plasma cell population in peripheral blood. However, a longer follow up is needed to evaluate how TCPC can affect survival in patients with MM. Disclosures Musto: Amgen: Honoraria; Celgene: Honoraria. Gay:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Honoraria, Research Funding; 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. Omedé:Janssen: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma.

Download Full-text

Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-117871 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 804-804 ◽

Cited By ~ 7

Author(s):

Mark Bustoros ◽

Chia-jen Liu ◽

Kaitlen Reyes ◽

Kalvis Hornburg ◽

Kathleen Guimond ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

High Risk ◽

Disease Progression ◽

Board Of Directors ◽

Rna Sequencing ◽

Research Funding ◽

Response Rate ◽

Advisory Committees ◽

Equity Ownership

Abstract Background. This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods. Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al., Blood 2014. The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and Dexamethasone at days 1, 8, 15, and 22. This induction phase is followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle is defined as 28 consecutive days, and therapy is administered for a total of 24 cycles total. Bone marrow samples from all patients were obtained before starting therapy for baseline assessment, whole exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle to isolate cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Stem cell collection is planned for all eligible patients. Results. In total, 26 of the planned 56 patients were enrolled in this study from February 2017 to April 2018. The median age of the patients enrolled was 63 years (range, 41 to 73) with 12 males (46.2%). Interphase fluorescence in situ hybridization (iFISH) was successful in 18 patients. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 11 patients (61.1%). The median number of cycles completed was 8 cycles (3-15). The most common toxicities were fatigue (69.6%), followed by rash (56.5%), and neutropenia (56.5%). The most common grade 3 adverse events were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). One patient had grade 4 neutropenia during treatment. Additionally, grade 4 hyperglycemia occurred in another patient. As of this abstract date, the overall response rate (partial response or better) in participants who had at least 3 cycles of treatment was 89% (23/26), with 5 Complete Responses (CR, 19.2%), 9 very good partial responses (VGPR, 34.6%), 9 partial responses (34.6%), and 3 Minimal Responses (MR, 11.5%). None of the patients have shown progression to overt MM to date. Correlative studies including WES of plasma cells and single-cell RNA sequencing of the bone microenvironment cells are ongoing to identify the genomic and transcriptomic predictors for the differential response to therapy as well as for disease evolution. Furthermore, we are analyzing the cfDNA and CTCs of the patients at different time points to investigate their use in monitoring minimal residual disease and disease progression. Conclusion. The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma. The high response rate, convenient schedule with minimal toxicity observed to date are promising in this patient population at high risk of progression to symptomatic disease. Further studies and longer follow up for disease progression are warranted. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy.

Download Full-text

Vantage 088: Vorinostat in Combination with Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Global, Randomized Phase 3 Trial

Blood ◽

10.1182/blood.v118.21.811.811 ◽

2011 ◽

Vol 118 (21) ◽

pp. 811-811 ◽

Cited By ~ 8

Author(s):

Meletios Athanasios Dimopoulos ◽

Sundar Jagannath ◽

Sung-Soo Yoon ◽

David S. Siegel ◽

Sagar Lonial ◽

...

Keyword(s):

Multiple Myeloma ◽

New Zealand ◽

Board Of Directors ◽

Histone Deacetylase ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 3 ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Chemotherapy Agents

Abstract Abstract 811 Introduction: Vorinostat (VOR), an oral inhibitor of histone deacetylase class I and class II proteins, regulates genes and proteins involved in tumor growth and survival. The synergistic effects of VOR and bortezomib (BTZ) have been shown in preclinical studies and were confirmed in independent phase 1 trials in patients with relapsed/refractory multiple myeloma (MM), producing objective response rates (ORRs) of up to 42% and overall clinical benefit of up to 90%. Materials and methods: Eligible patients were aged ≥ 18 years, had measurable secretory MM, had received 1 to 3 prior systemic anti-myeloma regimens, and had an Eastern Cooperative Oncology Group status ≤ 2. Previous exposure to BTZ and the presence of extracellular plasmacytoma were allowed per protocol, but patients with prior resistance to BTZ were excluded. Patients were randomized 1:1 to receive 21-day cycles of BTZ (1.3 mg/m2 intravenously; days 1, 4, 8, and 11) in combination with oral VOR 400 mg/d, or matching placebo, on days 1 to 14. Additional use of corticosteroids for the treatment of MM was not allowed during the trial. Patients were treated until disease progression, unacceptable toxicities, or withdrawal from the study. The primary endpoint for this trial was progression-free survival (PFS; occurrence of 412 PFS events). Secondary and exploratory endpoints included ORR (≥ partial response), clinical benefit response (ORR + minimal response), overall survival, time to progression, patient-reported outcomes questionnaires (QLQ-C30, QLQ-MY20), and safety/tolerability of this novel drug combination. Responses and progression were determined according to the European Bone and Marrow Transplantation Group criteria and will be confirmed by an Independent Adjudication Committee. Results: Between January 2009 and January 2011, 637 patients were enrolled from 174 centers in 33 countries across the globe making this trial one of the largest studies conducted in patients with relapsed/refractory myeloma. Median age of the study population was 62 years (range, 29–86 years). Of the enrolled patients, 59% were male and 56% were Caucasian. Patients had received a median of 2 prior regimens (range, 1–3). Prior anti-myeloma agents included BTZ (24%), thalidomide (56%), lenalidomide (13%), melphalan (56%), and stem cell transplantation (35%). As of July 2011, 635 patients had received study medication, with a median exposure of 7 cycles (mean: 7.6 cycles; range 1–30 cycles). Reported median exposure to BTZ monotherapy in previous phase 3 trials was approximately 5 cycles. Conclusions: The study passed the protocol-specified futility analyses by the independent data monitoring committee in November 2010. Database lock is anticipated in November 2011, and top-line data on primary and secondary endpoints will be available at the meeting. Disclosures: Dimopoulos: Celgene, Ortho-Biotech: Consultancy, Honoraria. Off Label Use: Vorinostat, an inhibitor of histone deacetylase, is approved in the US for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. Vorinostat is currently under investigation for the treatment of relapsed malignant pleural mesothelioma, relapsed/refractory B cell lymphoma (in combination with other chemotherapy agents), and relapsed/refractory multiple myeloma (in combination with bortezomib and other chemotherapy agents). Jagannath:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Yoon:Celgene: Consultancy; NK Bio: Consultancy. Siegel:Millennium: Honoraria, Research Funding, Speakers Bureau; Merck: Honoraria. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Hajek:Celgene: Honoraria; Janssen: Honoraria; Merck: Educational lecture. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees. Rosiñol:Celgene: Honoraria; Janssen-Cilag: Honoraria. Blacklock:New Zealand Bone Marrow Donor Registry: Consultancy, Employment; Mercy Hospital, Auckland New Zealand: Consultancy; Leukaemia and Blood Foundation, New Zealand: Consultancy, Membership on an entity's Board of Directors or advisory committees; Middlemore Hospital: Employment, Research Funding. Goldschmidt:Amgen, Novartis, Chugai: Research Funding; Janssen-Cilag, Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Merck: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reece:Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Graef:Merck: Employment. Houp:Merck Research Laboratories: Employment. Sun:Merck & Co., Inc.: Employment. Eid:Merck Research Laboratories: Employment. Anderson:Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy; Acetylon: founder.

Download Full-text

Identification of Alpha 1-Acid Glycoprotein (AAG) As a Potential Patient Selection Biomarker for Improved Clinical Activity of the Novel KSP Inhibitor ARRY-520 in Relapsed and Refractory Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v120.21.1868.1868 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1868-1868 ◽

Cited By ~ 4

Author(s):

Brian Tunquist ◽

Karin Brown ◽

Gary Hingorani ◽

Sagar Lonial ◽

Jonathan L. Kaufman ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Phase 1 ◽

Clinical Activity ◽

Advisory Committees ◽

Blood Samples ◽

Refractory Multiple Myeloma

Abstract Abstract 1868 Background ARRY-520 is a kinesin spindle protein (KSP) inhibitor that has demonstrated clinical activity in patients with relapsed and refractory multiple myeloma (MM). Although ARRY-520 is administered IV, it displays variable pharmacokinetics (PK) among patients. The degree of binding of certain drugs to serum proteins can alter their free fraction (fu) and PK, with a possible impact on clinical activity. Alpha 1-acid glycoprotein (AAG) is an acute-phase reactant protein that is often elevated in the blood of patients with cancer, including multiple myeloma. We investigated the significance of the interaction of ARRY-520 with AAG, and other relevant blood proteins, using both in vitro models and clinical data. Methods Compound-protein binding was assessed using several in vitro assays. In addition, the effect of increasing concentrations of AAG on MM cell line viability was measured. Patient data were obtained from 3 clinical studies of ARRY-520: a Phase 1 solid tumor study, a Phase 1/2 AML study, and a Phase 1/2 study in MM. The MM Phase 2 portion consists of 2 separate, 2-stage cohorts. Cohort 1 evaluated ARRY-520 administered as a single agent, and cohort 2 investigated ARRY-520 in combination with low-dose dexamethasone (LoDex). The concentrations of multiple proteins, including AAG, and the degree of ARRY-520 total protein binding, were measured in pre- and post-dose blood samples for patients in the analysis. AAG levels in MM patients were further correlated with time-on-study and clinical response rate. Results ARRY-520 exhibits low micromolar affinity for AAG in in vitro assays, but not for other common serum proteins, such as albumin. To investigate whether AAG binding impacts biological activity, we found that increasing AAG concentrations within a clinically relevant range resulted in increasing IC50 values for ARRY-520 on MM cell line viability. Of other MM agents tested, none exhibited high affinity binding to AAG in vitro, and a range of AAG concentrations did not alter the cellular activity of these compounds. Pre-dose concentrations of AAG were measured using blood samples collected from patients on all 3 ARRY-520 studies (0.4 – 4.1 g/L AAG in solid tumor study; 0.5 – 2.4 g/L in AML study; 0.2 – 2.8 g/L in MM study). Post-dose blood samples from the MM study also indicated that AAG levels do not significantly change with time. The fu of ARRY-520 in blood was meaningfully reduced among patients with the highest AAG concentrations. Furthermore, AAG and fu were correlated with changes in clinical PK: CL and Vd decreased with increasing AAG, trends consistent with a lower fu. Among the MM patients, 72 patients were evaluable for AAG determination (27 from the dose-escalation portion, 27 from Cohort 1, and 18 from Stage 1 of Cohort 2). Across all of these cohorts, the group of patients with AAG above an empirically-determined cutoff of 1.1 g/L showed a decreased median time on study (1.5 months vs 4.7 months) and no clinical responses (0/19 vs 12/53) as compared to patients below this cutoff. For example, as reported separately, ARRY-520 in combination with LoDex showed a promising 22% overall response rate (≥PR) in the 1st-stage of Cohort 2. In this cohort, 6 patients were determined to have AAG concentrations above the empirical cutoff. None of these patients had clinical benefit. Excluding these 6 patients would significantly improve the overall response rate (≥PR) from 22% (4/18) to 33% (4/12). Summary AAG has been proposed as a prognostic marker for MM disease severitya. Our preliminary data suggest that AAG levels can affect the free fraction of ARRY-520 in blood over a clinically relevant range both preclinically and in clinical studies. In retrospective analysis, patients with higher AAG levels show a lower fu and therefore may not achieve sufficient exposure to gain therapeutic benefit from ARRY-520. In preclinical analyses, this effect is specific to ARRY-520, suggesting that AAG levels may be predictive for ARRY-520 activity relative to other MM drugs. We hypothesize that prospective screening for AAG may enable exclusion of patients who may not achieve therapeutic exposure to ARRY-520, increasing the overall activity of ARRY-520 and preventing exposure of non-responders to an ineffective therapeutic dose. Further, experiments are currently underway to investigate the relevance of other acute-phase proteins in blood. Disclosures: Tunquist: Array BioPharma: Employment. Off Label Use: ARRY-520 alone and with dexamethasone for the treatment of relapsed/refractory multiple myeloma. ARRY-520 is not currently approved for any indication. Brown:Array BioPharma: Employment. Hingorani:Array BioPharma: Employment. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Zonder:Celgene: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Koch:Array BioPharma: Employment. Litwiler:Array BioPharma: Employment. Walker:Array BioPharma: Employment.

Download Full-text

Targeting EZH2 in Multiple Myeloma Could be Promising for a Subgroup of MM Patients in Combination with IMiDs

Blood ◽

10.1182/blood.v128.22.311.311 ◽

2016 ◽

Vol 128 (22) ◽

pp. 311-311 ◽

Cited By ~ 4

Author(s):

Laurie Herviou ◽

Alboukadel Kassambara ◽

Stephanie Boireau ◽

Nicolas Robert ◽

Guilhem Requirand ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Newly Diagnosed ◽

Advisory Committees ◽

Myeloma Cells ◽

Ezh2 Expression ◽

Bone Marrow Plasma

Abstract Multiple Myeloma is a B cell neoplasia characterized by the accumulation of clonal plasma cells within the bone marrow.Epigenetics is characterized by a wide range of changes that are reversible and orchestrate gene expression. Recent studies have shown that epigenetic modifications play a role in multiple myeloma (MM) by silencing various cancer-related genes. We investigated the epigenetic genes differentially expressed between normal bone marrow plasma cells (BMPC ; N=5) and MM plasma cells from patients (N=206). Using SAM (Significance Analysis of Microarrays) analysis, only 12 genes significantly differentially expressed between BMPC and MM cells (ratio > 2 and FDR (false discovery rate) < 5%) were identified, including the EZH2 histone methyltransferase. EZH2, the enzymatic subunit of Polycomb Repressive Complex 2, is a histone methyltransferases able to repress gene expression by catalyzing H3K27me3 histone mark. EZH2 overexpression has been associated with numerous hematological malignancies, including MM. We thus studied EZH2 role in MM physiopathology and drug resistance. EZH2 expression was analyzed in normal bone marrow plasma cells (BMPCs; N=5), primary myeloma cells from newly diagnosed patients (MMCs; N=206) and human myeloma cell lines (HMCLs; N=40) using Affymetrix microarrays. EZH2 gene is significantly overexpressed in MMCs of patients (median 574, range 105 - 4562) compared to normal BMPCs (median = 432; range: 314 - 563) (P < 0.01). The expression is even higher in HMCLs (median 4481, range 581 - 8455) compared to primary MMCs or BMPCs (P < 0.001). High EZH2 expression is associated with a poor prognosis in 3 independent cohorts of newly diagnosed patients (Heidelberg-Montpellier cohort - N=206, UAMS-TT2 cohort - N=345 and UAMS-TT3 cohort - N =158). Furthermore, GSEA analysis of patients with high EZH2 expression highlighted a significant enrichment of genes involved in cell cycle, downregulated in mature plasma cells vs plasmablasts, and EZH2 targets. Specific EZH2 inhibition by EPZ-6438 EZH2 inhibitor induced a significant decrease of global H3K27me3 in all the HMCLs tested (P < 0.01) and inhibited MM cell growth in 5 out of the 6 HMCLs tested. The inhibitory effect of EZH2 inhibitor on MM cell growth appeared at day 6 suggesting that it is mediated by epigenetic reprogramming. To confirm that EZH2 is also required for the survival of primary MMCs from patients, primary MM cells (n = 17 patients) co-cultured with their bone marrow microenvironment and recombinant IL-6 were treated with EPZ-6438. As identified in HMCLs, EZH2 inhibition significantly reduced the median number of viable myeloma cells by 35% (P = 0.004) from a subset of patients (n=9) while the other group (n=8) was resistant. Of interest, EPZ-6438 induced a significant global H3K27me3 decrease in both groups of patient. RNA sequencing of 6 HMCLs treated with EPZ-6438 combined with H3K27me3 ChIP analyses allowed us to create an EZ GEP-based score able to predict HMCLs and primary MM cells sensitivity to EZH2 inhibitors. We also observed a synergy between EPZ-6438 and Lenalidomide, a conventional drug used for MM treatment. More interestingly, pretreatment of myeloma cells with EPZ-6438 significantly re-sensitize drug-resistant MM cells to Lenalidomide. Investigating the effect of EPZ-6438/Lenalidomide combination in MMC, we identified that IKZF1, IRF4 and MYC protein levels were significantly more inhibited by the combination treatment (65.5%, 63.9% and 14.8% respectively) compared with Lenalidomide (51.5%, 43% and 2.2%) or EPZ-6438 (45.2%, 38.7% and 6.2%) alone. Clinical trials are ongoing with EZH2 inhibitors in lymphoma and could be promising for a subgroup of MM patients in combination with IMiDs. Furthermore, the EZ score enables identification of MM patients with an adverse prognosis and who could benefit from treatment with EZH2 inhibitors. Disclosures Goldschmidt: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Hose:EngMab: Research Funding; Takeda: Other: Travel grant; Sanofi: Research Funding.

Download Full-text

High Levels of APOBEC3B Gene Expression Contribute to Poor Prognosis in Multiple Myeloma Patients

Blood ◽

10.1182/blood-2018-99-117067 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3897-3897

Author(s):

Valeriy V Lyzogubov ◽

Pingping Qu ◽

Cody Ashby ◽

Adam Rosenthal ◽

Antje Hoering ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Poor Prognosis ◽

Target Genes ◽

Plasma Cells ◽

Nuclear Fraction ◽

Advisory Committees ◽

Significant Difference

Abstract Introduction: Poor prognosis and drug resistance in multiple myeloma (MM) is associated with increased mutational load. APOBEC3B is a major contributor to mutagenesis, especially in myeloma patients with t(14;16) MAF subgroup. It was shown recently that presence of the APOBEC signature at diagnosis is an independent prognostic factor for progression free survival (PFS) and overall survival (OS). We hypothesized that high levels of APOBEC3B gene expression at diagnosis may also have a prognostic impact in myeloma. To consider APOBEC3B as a potential target for therapy more studies are necessary to understand how APOBEC3B expression is regulated and how APOBEC3B generates mutations. Methods: Gene expression profiling (GEP, U133 Plus 2.0) of MM patients was performed. APOBEC3B gene expression levels were investigated in plasma cells of healthy donors (HD; n=34), MGUS (n=154), smoldering myeloma (SMM; n=219), MM low risk (LR; n=739), MM high risk (HR; n=129), relapsed MM (RMM; n=74), and primary plasma cell leukemia (pPCL; n=19) samples. The samples from relapse were taken on or after the progression/relapse date but within 30 days after progression/relapse from Total Therapy trials 3, 4, 5 & 6. GEP70 score was used to separate samples into LR and HR groups. We also investigated APOBEC3B expression in different MM molecular subgroups and used logrank statistics with covariate frequency distribution to determine an optimal cut off APOBEC3B expression value. Gene expression was compared in cases with low expression of APOBEC3B (log2<7.5) and high expression of APOBEC3B (log2>10), and an optimal cut-point in APOBEC3B expression was identified with respect to PFS. To explore the role of MAF and the non-canonical NF-ĸB pathway we performed functional studies using a cellular model of MAF downregulation. TRIPZ lentiviral shRNA MAF knockdown in the RPMI8226 cell lines was used to explore MAF-dependent genes. NF-ĸB proteins, p52 and RelB, were investigated in the nuclear fraction by immunoblot analysis. Results: Expression of APOBEC3B in HD control samples (log2=10.9) was surprisingly higher than in MGUS (log2=9.51), SMM (log2=9.09), and LR (log2=9.40) and was comparable to HR (log2=10.4) and RMM (log2=10.6) groups. Expression levels of APOBEC3B were gradually increased as disease progressed from SMM to pPCL. The high expression of APOBEC3B in HD places plasma cells at risk of APOBEC induced mutagenesis where the regulation of APOBEC3B function is compromised. The correlation between APOBEC3B expression and GEP70 score in MM was 0.37, and there was a significant difference in APOBEC3B expression between GEP70 high and low risk groups (p=0.0003). An optimal cut-point in APOBEC3B expression of log2=10.2 resulted in a significant difference in PFS (median 5.7 yr vs.7.4 yr; p=0.0086) and OS (median 9.1 yr vs. not reached; p<0.0001), between high and low expression. The highest APOBEC3B expression was detected in cases with a t(14;16). We analyzed t(14;16) cases with the APOBEC mutational signature and compared them to t(14;16) cases without the APOBEC signature and found elevated MAF (2-fold) and APOBEC3B (2.7-fold) gene expression in samples with the APOBEC signature. No APOBEC signature was detected in SMM cases, including those with a t(14;16). High APOBEC3B levels in myeloma patients was associated with overexpression of genes related to response to DNA damage and cell cycle control. Significant (p<0.05) increases of NF-κB target genes was seen in high APOBEC3B cases: TNFAIP3 (4.4-fold), NFKB2 (1.7-fold), NFKBIE (1.9-fold), RELB (1.4-fold), NFKBIA (2.0-fold), PLEK (2.5-fold), MALT1 (2.5-fold), WNT10A (2.4-fold). However, in t(14;16) cases there was no significant increase of NF-κB target genes except BIRC3 (2.5-fold) and MALT1 (2.0-fold). MAF downregulation in RPMI8226 cells did not lead to changes in NF-κB target gene expression but MAF-dependent genes were identified, including ETS1, SPP1, RUNX2, HGF, IGFBP2 and IGFBP3. Analysis of nuclear fraction of NF-ĸB proteins did not show significant changes in expression of p52 and RelB in RPMI8226 cells after MAF downregulation. Conclusions: Increased expression of APOBEC3B is a negative prognostic factor in multiple myeloma. MAF is a major factor regulating expression of APOBEC3B in the t(14;16) subgroup. NF-ĸB pathway activation is most likely involved in upregulation of APOBEC3B in non-t(14;16) subgroups. Disclosures Davies: TRM Oncology: Honoraria; MMRF: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ASH: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria.

Download Full-text

First Description of B Cell Maturation Antigen Expression in Light Chain Amyloidosis

Blood ◽

10.1182/blood-2019-127332 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5452-5452

Author(s):

Susan Bal ◽

Allison Sigler ◽

Alexander Chan ◽

David J. Chung ◽

Ahmet Dogan ◽

...

Keyword(s):

Multiple Myeloma ◽

B Cell ◽

Board Of Directors ◽

Light Chain ◽

Research Funding ◽

Plasma Cells ◽

Staining Intensity ◽

Advisory Committees ◽

Light Chain Amyloidosis ◽

B Cell Maturation

Background B-cell maturation antigen (BCMA) is a transmembrane protein belonging to the tumor necrosis factor (TNF) superfamily involved in the regulation of B cell proliferation and survival as well as maturation/differentiation into plasma cells. In multiple myeloma cells, overexpression of BCMA has been shown to activate mitogen activated protein kinase pathways (AKT, ERK1/2, and NF-κB) and upregulates anti-apoptotic proteins (MCL1, BCL2, BCL-xL) resulting in cellular proliferation. Immunotherapeutic strategies targeting BCMA are showing great promise in heavily pre-treated refractory multiple myeloma. Light Chain Amyloidosis (AL) is a multisystem disorder of clonal plasma cells that results in the production of an abnormal light chain which misfolds and deposits in the organs leading to disruption of tissue architecture, cellular stress, dysfunction and eventually, death. The smaller burden and lower proliferative potential of the offending clonal plasma cells in amyloidosis may potentially lend itself favorably to immunotherapeutic strategies targeting BCMA. Given the efficacy of this approach in MM, the evaluation of BCMA expression on the surface of amyloidogenic plasma cells is warranted. Methods All patients diagnosed with Light chain Amyloidosis at Memorial Sloan Kettering Cancer Center, NY between January 1, 2012, and December 31, 2018, who had unstained bone marrow samples were identified. These unstained BM biopsy samples were prospectively stained for BCMA expression using Immunohistochemistry (IHC). We utilized a clinical-grade assay (clone D6; catalog sc-390147; company Santa-Cruz; monoclonal antibody; dilution 1:400) in a CLIA compliant setting. We scored the biopsies for BCMA expression, intensity, and site of staining. We also obtained their demographic details, staging, and cytogenetic information for the patients with available samples. Results During the queried period, 28 unstained samples were available for testing from the time of disease diagnosis. The median age of the population was 63 years (range 41-73). 64% of patients were male and consistent with the literature; a majority of patients (75%) had lambda-typic clonal plasma cells. Cytogenetic abnormalities using fluorescence in situ hybridization (FISH) were reviewed, t(11;14) was seen in 36% patients, and chromosome 1q and del 13q were each seen in 32% of patients. No patient had t(4;14) or del 17p. The median clonal PC burden in BM at diagnosis was 10% (range2-80%) and 36% had > 10% plasma cells. In clonal PCs, the median BCMA expression was 80% (range 20-100%). Only one patient had a staining intensity under 50% (20%). Membranous staining was noted in 82% of patients and a Golgi pattern in 11%. The median staining intensity was 2 (range 1-3). Of the patients with baseline diagnostic samples available for testing, six patients had additional unstained bone marrow samples for staining at the time of relapse. The majority of patients (83%) who relapsed had >10% plasma cells with a higher median plasma cell burden of 35% (range 10-80). The median BCMA expression was 65% (range 50-80) with no patient having <50% expression. The staining pattern was membranous in 50%, Golgi in 17%, and Golgi-membranous in 33%. At the time of relapse, the median clonal PC burden was 13% (range 5-30). BCMA expression continued to be present at the time of relapse with a median 75% (range 50-100) with predominantly membranous staining (83%). The median staining intensity in both diagnostic and relapsed tissue within the six samples studied was 1. Conclusions Our study represents the first description of BCMA expression on the surface of amyloidogenic plasma cells to our knowledge. BCMA is uniformly expressed by pathologic PCs in AL amyloidosis both at the time of diagnosis and relapse. Given the efficacy of BCMA directed therapy in multiple myeloma, further investigation of these agents in light-chain amyloidosis are warranted and may provide an effective therapeutic strategy in this devastating disease. Figure Disclosures Dogan: Corvus Pharmaceuticals: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Roche: Consultancy, Research Funding. Giralt:Takeda: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Kite: Consultancy; Novartis: Consultancy; Actinium: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Miltenyi: Research Funding; Spectrum Pharmaceuticals: Consultancy. Hassoun:Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Landau:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Descriptive Analysis of Isatuximab Use Following Prior Daratumumab in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-140526 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-21

Author(s):

Melody R Becnel ◽

Sandra B. Horowitz ◽

Sheeba K. Thomas ◽

Swami P. Iyer ◽

Krina K. Patel ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

North America ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Laboratory Research ◽

Private Company ◽

Advisory Committees ◽

Advisory Boards

Background: Anti-CD38 monoclonal antibodies (mAb) like daratumumab (dara) have become integral in managing relapsed/refractory (RR) and newly diagnosed (ND) multiple myeloma (MM). Isatuximab (isa), a newer CD38 mAb, induces direct rather than indirect apoptosis of MM cells. However, little is known about whether the use of one prior CD38 mAb will alter the efficacy of another in subsequent lines of therapy. Methods: All patients (pts) with MM treated at MD Anderson with isa after receiving dara in prior lines of therapy were identified. We conducted a retrospective analysis with data points including patient and disease characteristics, responses to dara, response to isa, the presence of high risk features, and the presence of t(11,14). Results: 9 pts were identified, ages 56-72. 5 pts (55%) were male. 5 pts (55%) were alive at the time of data cutoff. 5 pts were Hispanic, 3 White, and 1 Black. 8 pts (89%) had high risk features as represented by the presence of del17p, t(4,14), t(14,16), t(14,20), p53 mutations, gain 1q, extramedullary disease (EMD), CNS disease, early relapse (within 1 year) after autologous transplant, or an increased (>5%) peripheral blood plasma cells (PBPC). 2 (22%) had t(11,14). 4 (44%) had IgG MM. 2 (22%) with light chain disease, 2 (22%) with IgA MM, and 1 (11%) with IgD MM. Dara was initially used in lines 2-7. Dara combinations with pomalidomide (pom), bortezomib (bor), thalidomide (thal), lenalidomide (len), or carfilzomib (car); and pom combinations that also included elotuzumab (elo) or Cytoxan (cytox) are noted in table 1. Dara was discontinued (dc'd) in 8 pts due to progressive disease (PD) and in 1 pt due to toxicity. 8 pts (89%) experienced a best overall response (ORR) of partial response (PR) to dara; 1 pt had stable disease (SD). All pts received prior len and 8 pts received prior pom at some time during the treatment of MM. All pts received isa in combination with pom/dexamethasone (dex). Best ORR to isa/pom/dex: 5 pt (55%) had PR, 2 pt with minimal response (MR), 1 SD, 1 PD. Median treatment duration of isa/pom/dex was 5 weeks (2-14 weeks) at data cutoff. 3 pts dc'd isa/pom/dex due to infections, and 2 due to later progression. 2 pts remain on therapy. 1 pt chose to dc all MM therapy for quality of life purposes despite PR with isa/pom/dex. 1 pt died from cardiac disease unrelated to MM or treatment. Conclusions: Our current study of heavily pretreated pts with RRMM demonstrates that despite prior anti-CD38 therapy with dara, most patients (77%) experienced a response of MR or better with treatment with another anti-CD38 therapy isa. To our knowledge, this is the first report of outcomes to isa in patients with prior dara therapy. Further long term follow up will be needed to determine the length of response. Additional studies are planned to further evaluate this patient population. Table 1 Disclosures Thomas: Pharmacyclics: Other: Advisory Boards; BMS: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharma: Research Funding; Xencor: Research Funding; Genentech: Research Funding. Iyer:Rhizen: Research Funding; CRISPR: Research Funding; Spectrum: Research Funding; Merck: Research Funding; Curio Biosciences: Honoraria; Target Oncology: Honoraria; Afffimed: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Trillium: Research Funding; Seattle Genetics, Inc.: Research Funding. Patel:Celgene: Consultancy, Research Funding; Cellectis: Research Funding; Nektar: Consultancy, Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Manasanch:Adaptive Biotechnologies: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Takeda: Honoraria; Quest Diagnostics: Research Funding; Merck: Research Funding; JW Pharma: Research Funding; Novartis: Research Funding; Sanofi: Research Funding. Kaufman:Janssen: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Honoraria. Lee:Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy. Orlowski:Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding.

Download Full-text

Single-Cell Pathway Enrichment and Regulatory Profiling of Multiple Myeloma across Disease Stages

Blood ◽

10.1182/blood-2019-131361 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 364-364

Author(s):

Tianjiao Wang ◽

Hua Sun ◽

Daniel Cui Zhou ◽

Ruiyang Liu ◽

Lijun Yao ◽

...

Keyword(s):

Cell Cycle ◽

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Cell Types ◽

Differentially Expressed ◽

P Value ◽

Advisory Committees ◽

Pathway Enrichment

Multiple myeloma (MM) is a hematological malignancy, defined by aberrant monoclonal proliferation of plasma cells in the bone marrow, that to date remains an incurable disease despite advances in treatment. Key genetic and epigenetic alterations that drive MM pathogenesis have been identified, but a comprehensive profile of affected cellular pathways has yet to be fully characterized. In this study, we integrate whole-genome and whole-exome sequencing data with single-cell RNA sequencing (scRNA-seq) data from 13 patients across multiple treatment stages to 1) assess differential pathway enrichment between tumor subpopulations, 2) trace the clonal evolution of dominant disease mechanisms, and 3) investigate signaling interactions between surrounding cell types. We also analyzed bulk genomic and transcriptomic data from 662 additional Multiple Myeloma Research Foundation (MMRF) tumor samples as a large reference cohort for highly prevalent pathway disturbances. To assess whether tumor subpopulations rely on different oncogenic programs for proliferation, we analyzed the differential expression of key genes (FDR-adjusted p-value <0.05) in 12 canonical oncogenic pathways. Cell cycle, Hippo, RTK/RAS, and NFkB pathways contain the highest numbers of differentially expressed genes, with certain subclusters upregulating as many as 25% of annotated cell cycle genes and over 90% of annotated Hippo genes, whereas p53, Notch, Nrf2, and DNA repair genes tend to be uniformly expressed across subpopulations. Next, we evaluated changes in pathway enrichment across different disease timepoints, with the goal of capturing the reorganization of functional profiles through successive treatment and relapse cycles. We assessed statistical enrichment of pathways containing differentially expressed genes (DEGs) unique to Smoldering Multiple Myeloma (SMM), primary, and relapse stages using the KEGG pathway database (n = 2, 17, and 7 pathways, respectively; FDR-adjusted p-value of enrichment < 0.05). SMM is the only stage where hematopoietic differentiation and the PI3K-Akt pathways are variably expressed between plasma cell subpopulations, suggesting that these pathways may play a role in initiating events. Only primary tumor samples show significant intra-tumor variability of p53 regulation, which is lost in the relapsed tumor and may reflect selection due to treatment. Relative to SMM, primary and relapse samples are enriched for changes in the MAPK, NFkB, RAP1, and cell cycle pathways, indicating potential sources of tumor resistance. We then analyzed pathway enrichment within the tumor microenvironment to enhance our understanding of tumor development in the context of surrounding tissues. We see frequent changes in many immune cell types in TLR signaling as the disease progresses, driven by differential expression of NFkB1A, JUN, and FOS, all of which are key upstream regulators of the AP-1 pathway and responders to the MAPK and PI3K signaling cascades. These microenvironment changes may be complementary to the PI3K and MAPK dysregulation observed in tumor plasma cells. Proteasome and ubiquitin genes, which affect secretion, autophagy, and apoptosis pathways that may be relevant to MM pathogenesis are also frequently differentially expressed in immune cells between disease stages. Finally, we integrate bulk whole-exome and whole-genome sequencing analysis (from both the 13-patient cohort and MMRF) to obtain a more complete understanding of how pathways become dysregulated in MM. Our findings advance the understanding of how MM tumor subpopulations differentially regulate cellular pathways and interact within the tumor microenvironment. Disclosures O'Neal: Wugen: Patents & Royalties: Patent Pending; WashU: Patents & Royalties: Patent Pending. Rettig:WashU: Patents & Royalties: Patent Application 16/401,950. Oh:Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding. DiPersio:Amphivena Therapeutics: Consultancy, Research Funding; Magenta Therapeutics: Equity Ownership; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees.

Download Full-text